I S SN 1 349-4856 C O D E N : T C I M C V

2 0 1 6 .7

170

目次
2

寄稿論文

- Development of Novel P-chiral Phosphorus Ligands forEﬃcient Transition-Metal Catalyzed Reactions
Guangqing Xu, Assistant Researcher
Wenjun Tang, Professor
State Key Laboratory of Bio-Organic &Natural Products Chemistry, Shanghai Institute ofOrganic Chemistry, Chinese Academy of Sciences

20

24

化 学 よもやま話

身 近な元 素 の 話- 典 型 元 素の新しい同 素 体（ 2 ）

製品紹介
-

佐藤

健太郎

最 小 の “ カーボン ナ ノリング ”：[ 5 ] C P P
異 性 体 を 含 まない アントラジチオフェン 誘 導 体
安 全 なシア ノニトロメチ ル 化 剤
新しい J u l i a 型 メチレン 化 試 薬
Stearoyl-CoA Desaturase阻害剤

2016.7 No.170

Development of Novel P-chiral Phosphorus Ligands for
Efficient Transition-Metal Catalyzed Reactions
Guangqing Xu, Wenjun Tang*
State Key Laboratory of Bio-Organic & Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
E-mail: tangwenjun@sioc.ac.cn

Abstract: We have developed four categories of air-stable and operationally convenient phosphorus ligands
on the basis of a benzooxaphosphole backbone. The bulky biaryl monophosphorus ligands BI-DIME and
AntPhos are efficient for sterically hindered aryl-aryl cross-couplings; two new P,P=O ligands are developed andapplicable for sterically hindered aryl-isopropyl cross-couplings; several P-chiral monophosphorus ligands arehighly efficient for asymmetric aryl-aryl cross-couplings and various chiral cyclizations; a structurally uniqueP-chiral bisphosphorus ligand WingPhos is versatile for asymmetric hydrogenation as well as asymmetricaddition of arylboron reagents to aryl ketones. The high reactivity, chemoselectivity, as well as enantioselectivity
achieved with these phosphorus ligands have allowed practical applications in construction of various therapeutic
agents and natural products.
Keywords: P-chiral phosphorus ligand, cross-coupling, reductive cyclization, dearomative cyclization, natural
products

1 Introduction
Over past several decades, the development of efficient transition-metal catalyzed reactions has become
one of the most active area in organic chemistry and transition-metal catalysis has made significant impacts
on almost every chemical fields including natural product synthesis, medicinal chemistry, material chemistry,
fine and agrochemical industry, chemical biology, and etc.[1] Numerous efficient transition-metal catalysts havebeen developed, which have not only greatly improved synthetic efficiency, but also provided opportunities
to explore new research fields and ideal synthetic chemistry. Significant efforts have been taken recently indeveloping highly efficient, cost-effective, and environmentally benign catalytic reactions. Consequently, a few
practical processes in particular asymmetric hydrogenations and cross-couplings[2] are developed and operated
at industrial scales with excellent chemo-, regio-, and enantioselectivities at extremely high substrate/catalyst
ratios (over 1,000,000). It is without any doubt that transition-metal catalyzed transformations will continue toplay increasingly important roles in construction of new molecules, and bring incredible benefits to our life andsociety.
In transition metal catalysis, the catalyst generally consists with a transition metal and one or several
ligands. In search for a new and efficient catalyst for a specific reaction, the judicial choice of a transition metal
is naturally of utmost importance. However, the electronic and steric properties of ligands can significantly
influence the reactivity and selectivity of the reaction. Since Wilkinson and co-workers discovered RhCl(PPh3)32

2016.7 No.170

as the catalyst for alkene hydrogenation, phosphorus ligands have received great attention.[3] Up today, thousandsof various phosphorus ligands have been designed and developed and a few of them have proven to be very
useful and have become indispensable tools in asymmetric hydrogenation and other related areas.[4] It is fairto say that the development of phosphorus ligands has promoted the progress of transition metal catalysis.
Conversely, the number of well-designed phosphorus ligands will continue to grow rapidly and more efficient
catalytic processes are expected to be discovered in the future.
Ligands dictate the electronic and steric properties of the transition metal catalyst. As a result, they haveoften played significant role for the reactivity and selectivity of the catalytic reaction. An excellent catalyst
often features a well-defined and predictable conformation, which requires its ligating ligands to possess anunambiguous, fixed, and rigid structural conformation. Therefore, the rational design and development of aligand with a stable configuration and a rigid structure is often a very effective way for the development ofefficient catalytic reaction.
Our research group has embarked a program on exploring efficient and practical catalytic reactions byinventing novel and highly-efficient phosphorus ligands in recent years. We designed and developed a series ofphosphorus ligands based on a benzoheterophosphole as the backbone structure[5] with the following features:
1) The 5-membered bisdihydrobenzooxaphosphole ring system makes such ligands conformationally rigid,
which help predict the conformation of its metal complex in a real reaction; 2) The physical properties of suchligands were improved as air-stable solid by the introduction of the benzene ring, leading to great operational
convenience; 3) Ease of changing the substituents on various locations of such structure allows systematic
variation of its steric and electronic properties; 4) The capability of introducing P-chirality in its structure allows
such ligands applicable for asymmetric catalysis.

O

O

P

P

tBu
OR

RO

R'

1. bulky biaryl monophosphorus ligands

O

R"
tBu

R'

3. P-chiral monophosphines

P
tBu
O

O
P
R

L

P

tBu

O H
tBu
R

O

P H P
tBu tBuR

L
2. monophosphorus ligands with 2nd coordination

4. P-chiral bisphosphorus ligand

Scheme 1. Four categories of ligands developed in our Lab

Thus, we have developed four categories of ligands for various purposes (Scheme 1): 1) bulkyl biarylmonophosphorus ligands that have enabled sterically hindered aryl-aryl cross-couplings; 2) monophosphorus
ligands with 2nd coordination that have provided greater functional group tolerance or enabled sterically hinderedaryl-isopropyl cross-couplings; 3) P-chiral monophosphorus ligands that have enabled efficient asymmetric arylaryl cross-couplings or asymmetric cyclizations; 4) P-chiral bisphosphorus ligands that are applied successfullyin asymmetric hydrogenations and asymmetric additions of arylboronic reagents. In this article, we outline someof our recent progress in exploring the application of those novel phosphorus ligands in transition metal catalysis.

32016.7 No.170

2 Sterically Hindered Aryl-Aryl Suzuki-Miyaura Cross-Couplings
In the past several decades, transition-metal catalyzed cross-couplings have received significant attention.[6]Today, it has become one of most powerful method for constructing carbon-carbon bonds for the synthesis ofvarious chemical compounds such as drugs, pesticides and materials. In particular, significant progresses havebeen achieved on Suzuki-Miyaura cross-couplings thanks to the stable and environmentally benign properties oforganoboron reagents. The last twenty years have witnessed the even-broader substrate scope of Suzuki-Miyaura
cross-couplings with excellent functional group compatibility at low catalyst loading (<0.1 mol%). Despite thesignificant advances, there have been only few reports on sterically hindered Suzuki-Miyaura couplings between
di-ortho-substituted aryl halides and di-ortho-substituted arylboronic acids. Biaryl monophosphorus ligands suchas S-Phos, X-Phos, and others developed from Buchwald’s group have shown good reactivity on some stericallyhindered substrates.[7] However, the exact capabilities of steric tolerance and functional group compatibilities
are unknown. It has been proven that a single electron-rich and steric bulky monophosphorus ligand is beneficial
to palladium catalyzed cross-couplings.[8] Electron-rich phosphorus ligands increase the oxidation power oftransition metals and hence facilitate reactions where the oxidative addition step is rate-limiting; while thesteric hindrance of the monophosphorus ligand allows to form a single-ligand-coordinated palladium species,
which is believed to be active for the transmetallation step as well as reductive elimination. On the basis ofthese principles, we have developed a conformationally rigid monophosphorus ligand BI-DIME for sterichindered Suzuki-Miyaura coupling reactions. Structurally, BI-DIME eliminates any conformational ambiguity
caused by rotation of the C–P bond as observed in Buchwald’s S-Phos system (Scheme 2). The sterically morehindered nature of BI-DIME has provided great advantages in Suzuki-Miyaura couplings of sterically hinderedarylboronic acids.[9]two coordination modes of S-Phos with Pd

a single coordination mode of BI-DIME with Pd

O

Pd
P
MeO

OMe

Pd

sterically more hindered

and

MeO

P
OMe

sterically less hindered

MeOP
OMe Pdsterically hindered

Scheme 2. Comparison of SPhos and BI-DIME

With BI-DIME as ligand, a series of ortho-disubstituted arylboronic acids were successfully coupled withortho-disubstituted aryl bromides to form corresponding tetra-ortho-substituted biaryls in excellent yields
under strong basic conditions (NaOtBu as base). Tetra-ortho-substituted biaryls bearing secondary alkyl orthosubstituents such as isopropyl groups were synthesized for the first time through cross-coupling reactions (Scheme
3). Substituents such as methyl, methoxy and phosphine oxide were well tolerable, heteroaryls such as pyrazole,quinolone and acridine were also compatible. At 2.5 mol% Pd loading, a tetra-ortho-isopropyl substituted biaryl
was also successfully formed for the first time in moderate yield by Suzuki-Miyaura coupling. Sterically hinderedaryl chlorides could also be employed. The Pd-BI-DIME/NaOtBu system has significantly expanded the scope
and utility of sterically hindered aryl-aryl cross-couplings. Mechanistic studies revealed that the NaOtBu might
have accelerated the dissociation of the inactive Pd(II) dimer species to form the active Pd(II) monomer species
during the reaction, which might have significantly improved the rate of the transmetallation step.

4

2016.7 No.170

Construction of the functionalized tetra-ortho-substituted biaryls is very important for the synthesis of biaryl
natural products and ligands.[10] Many of important functional groups such as aldehyde, ester, ketone and nitro
are not tolerable to the strong basic conditions with NaOtBu as base. Furthermore, the protodeboronation of
the functionalized arylboronic acids is greatly accelerated under strong basic conditions. Only a mild base suchas K3PO4 can be employed for those substrates and BI-DIME was not effective. For this, a more reactive andfunctional group compatible phosphorus ligand was needed. In 2002, Buchwald reported a biaryl monophosphine
ligand A bearing with a phenanthrene moiety, which provided excellent yields for a series of tetra-orthosubstituted biaryls with K3PO4 as the base.[11] Interestingly, a π coordination of the phenanthrene moiety with thepalladium center was observed in its complex. Inspired by this work, we designed and synthesized a new ligand
AntPhos with an anthryl group in its framework (Scheme 4).[12] Gratifyingly, various functionalized substrates
were coupled efficiently by AntPhos as ligand with K3PO4 as base. Functionalities such as aldehyde, ketone,
phosphate, cyano, fluoro, and trifluoromethyl group were all well tolerated. This catalytic system provides aneffective method for the synthesis of a series of sterically hindered, functionalized biaryls (Scheme 5).

R

R R''

R''
X

+ (HO)2B

R'
X=Br or Cl

R'''

Pd(OAc)2 (1 mol%) / BI-DIME (2 mol%)
R' R''
OMe iPr

iPr

OMeN
N
O

iPr

iPr

89%

99%

iPr

97%

N

iPr
97%

91%

Ph
Ph P iPr
O

iPr
iPr

iPr

iPr

OMe

N
N

R'''

NaOtBu, toluene, 110 oC, 12 h

R''

iPr

iPr
iPr

iPr

iPr

iPr

iPr

iPr

iPr

76%

95%

48%

iPr

Scheme 3. Substrates scope of sterically hindered Suzuki-Miyaura Coupling with BI-DIME as ligand

O
PCy2

R

O

R'

P

R"
tBu

A

P

tBu

AntPhos

Scheme 4. Design of AntPhos

52016.7 No.170

R"

R"

R
X

R'"
X=Br or I+R

Pd(OAc)2 (1 mol%) / AntPhos (2 mol%)(HO)2B

K3PO4, dioxane, 110 oC, 24 h
R'

R'" R'OMe OMe

OMe

O2N

OHC
OMe

CHO

89%

99%

F

O

92%
P(O)(OEt)2

N

CN
88%

81%

CF3
82%

85%

90%

Scheme 5. Substrates scope of functionalized sterically-hindered cross-coupling by AntPhos as ligand

The X-ray crystal structure of [Pd(0)((R)-AntPhos)2] revealed an interesting π-coordination between thePd center and the anthracene ring at 1,2 positions (Scheme 6). We believe that this coordination may not only
contribute to stabilize the [Pd(0)((R)-AntPhos)] complex, but also help inhibit the dimerization of its Pd(II)complex and increase the stability of its monomeric palladium(II) complex, which well explains its good activity
in functionalized sterically hindered cross-couplings.

Scheme 6. X-ray structure of [Pd(0)((R)-AntPhos)2]

3 Sterically Hindered Aryl-Alkyl Suzuki-Miyaura Cross-Couplings
The transition-metal catalyzed cross-couplings between aryl halides and alkylmetallic reagents have become
an important method for the construction of substituted aryls.[13] In particular, aryl-alkyl Suzuki-Miyaura crosscouplings have received much attention thanks to the readily availability of aryl halides as well as the goodstability of alkylboronic acids. However, few efficient catalytic systems were reported due to several challenging

6

2016.7 No.170

innate issues: a) the sp3-hybridized alkylboronic acids are much bulkier and slower for transmetallation incontrast to the sp2-hybridized arylboronic acids; b) the presence of β-hydrogen in alkylboronic acid allows the
β-hydride elimination pathway, leading to the reduction of aryl halides and the formation of the regio-isomerduring cross-coupling. These issues become more prominent in cross-couplings between sterically hinderedaryl halides and secondary alkylboron reagents (Scheme 7). Biscoe and co-workers reported a highly selective
aryl-isopropyl Suzuki-Miyaura coupling of non-hindered substrates,[14] but isomerization and low yields wereparticularly observed in aryl-isopropyl Suzuki-Miyaura couplings of ortho-substituted aryl halides.[15] An
efficient method leading to high yields and selectivities was yet to be developed for the Suzuki-Miyaura coupling
between di-ortho-substituted aryl halides and acyclic secondary alkylboronic acids. Such method would behighly desirable for late-stage introduction of alkyl groups to aromatic molecules.

X
R'

R'''
R'

R'

R'

R''

L-Pd
I
R'
R'

R'
II

R'
Pd L
X

R'
Pd

R'''

R'
III

B(OH)2
R'''

L

OH-

R'

L
Pd

R'

H
H
R''' R'R'

reduction and isomerization side products

B(OH)3

Scheme 7. Reduction and isomerization in Suzuki-Miyaura cross-couplings

We envisioned that the introduction of a hemilabile coordination by installing a P=O group adjacent toa bulky phosphorus ligand would be beneficial to steric hindered aryl acyclic secondary alkyl coupling. Our
proposal was: a) the hemilabile coordination can block an empty coordination site of the palladium center to help
inhibit β-hydride elimination; b) the bulky conformation of the ligand could promote facile reductive elimination
step. After intensive design and synthesis, we were pleased to develope two novel bulky P,P=O ligands L1 andL2 on the basis of 2,3-dihydrobenzo[d]-[1,3]oxaphosphole framework (Scheme 8).[16] Both of them were easily
prepared within 5 steps in gram scales.

O

P
P

O

Pd
Ar
iPr
• sterically bulky P,P=O ligand• a hemilabile P=O coordination

P
R

O

L
tBu

P
R

O
tBu
P
tBu
tBu

L1: R = MeO
L2: R = NMe 2

Scheme 8. The design of steric bulky P,P=O ligand

7

2016.7 No.170

With L1 as the ligand, a series of mono or di-ortho-substituted aryl bromides were coupled with acyclic
secondary alkylboronic acids in excellent yields and selectivities under 1 mol% palladium loading (Scheme 9).
Noteworthy was the excellent functional group compatibility, where methoxy, nitrile, cyano, ketone, amine andquinoline moieties were well tolerated. This method offered advantages over traditional Negishi and Kumada
aryl alkyl cross-couplings.

R

R
Br

+

[Pd(cinnamyl)Cl]2 (0.5 mol%) / L1 (2 mol%)(HO)2B

K3PO4•H2O, toluene, 100 oC, 6 h

R'

R'

MeO

NC
NO2

Yield : 92%
iPr/nPr: 23:1

Yield : 93%
iPr/nPr: 23:1
O

Yield : 91%
iPr/nPr: 10:1

Yield : 97%
iPr/nPr: 32:1

O

Yield : 96%
iPr/nPr:48:1

Yield : 96%
iPr/nPr: 24:1

MeO

H2N

(170-S09.eps)

N

Yield : 94%
iPr/nPr: 94:1

Ph

Yield : 88%
iPr/nPr: 22:1

Yield : 97%
iPr/nPr: 97:1

Yield : 94%
iPr/nPr: 94:1

Scheme 9. Substrate scope of sterically hindered aryl secondary alkyl cross-coupling

Since the isopropyl ortho-alkoxy di-ortho-substituted arene moieties exist in numerous bioactive natural
products,[17] a highly efficient cross-coupling between ortho-alkoxy di-ortho-substituted aryl halides andisopropylboronic acids is yet to be accomplished. Although ligand L1 provided only moderate yield and poor
iPr/nPr selectivity, we were pleased to find the ligand L2 led to excellent yields and iPr/nPr selectivities for thosechallenging transformations. A series of isopropyl ortho-alkoxy di-ortho-substituted arenes were efficiently
synthesized in high yields and selectivities. Various functionalities such as aldehyde, ketone and ester were alltolerable (Scheme 10). This protocol was successfully employed in the late-stage modification of estrone at gramscale and applied in a new synthetic route toward gossypol by introduction of the isopropyl group by crosscoupling,[16] demonstrating the power of this methodology.

R

R
Br

+

[Pd(cinnamyl)Cl]2 (0.5 mol%) / L2 (2 mol%)(HO)2B

K3PO4•H2O, toluene, 100 oC, 6 h

R'

O

OMe

O

OHC

MeO
OMe

OMe

R'

OMe

OMe
OMe

Yield : 94%
iPr/nPr: 31:1

Yield : 95%
iPr/nPr: 19:1

Yield : 99%
iPr/nPr: 99:1

Yield : 92%
iPr/nPr: 12:1

OBn
Yield : 90%
iPr/nPr: 18:1

Scheme 10. Substrate scope of sterically hindered aryl secondary alkyl cross-coupling8

2016.7 No.170

4 Asymmetric Suzuki-Miyaura Cross-Coupling
Chiral biaryl structures exist in numerous biological interesting natural products as well as serve as
privileged frameworks for efficient ligands. As one of the most direct and effective method, the developmentof cross-couplings for construction those chiral biaryls have received much attention during the past several
years.[18] Although much study on asymmetric cross-couplings including Kumada, Negishi, Suzuki-Miyaura
have been reported in high yields and stereoselectivities,[19] most current methods focus on the developmentof unfunctionalized substrates with little synthetic interest. We sought to explore an efficient catalytic systemthat would be compatible to various functional groups and be applicable to the synthesis of chiral biaryl natural
products. Our previous study has proven that the steric bulky and conformationally rigid monophosphorus
ligands could promote the reactivity of sterically hindered aryl-aryl couplings. The presence of P-chirality in BIDIME and related ligands encouraged us to investigate asymmetric Suzuki-Miyaura cross-coupling with thesechiral ligands. There remains a significant challenge to achieve high enantioselectivity for cross-coupling with achiral monophosphorus ligand. Unlike bidentate phosphorus ligands, chiral monophosphorus ligands allow more
space at the palladium center, resulting in a less-defined Pd structure and more difficulty in enantiocontrol (Scheme
11a). To provide a solution to this problem, we designed a new catalytic mode by introducing a secondaryinteraction between the two aryl coupling partners in combination with the employment of a well-defined chiralmonophosphorus ligand (Scheme 11b).[20] The choice of an auxiliary should follow the two principles: 1) The
auxiliary can be easily introduced and transformed; 2) The auxiliaries should have the capabilities to offer anoncovalent interaction to the other aryl group such as π-π, polar-π, hydrogen bonding, and cation-π interactions.

a: chiral bidentate ligand:chiral monophosphorus ligand:

P*
P*

Pd

more-defined
Ar1 structure
low reactivity

Ar2

P*

Pd
Ar2

Ar1 less-definedstructurehigh reactivity

b: Our design catalytic mode: the 2nd interaction in combination withbulky chiral monophosphorus ligand
P*

Pd
Ar2

Ar1

more-defined structure
high reactivity

2nd interaction

Scheme 11. New catalytic mode for highly reactive and enantioselective Suzuki-Miyaura cross-couplings

Following this strategy, we first investigated the synthesis of ortho-carbonyl substituted biaryls by SuzukiMiyaura cross-coupling. Gratifyingly, excellent enantioselectivity was achieved when 2-benzoxazolinonyl imidegroup was employed with L3 as the ligand. Functional groups such as methoxy and dimethylamino groups
were well tolerated. Heteroaryl substrates with strong coordinating abilities such as benzothiazole were also
applicable, providing excellent yield and good ee value (Scheme 12). It is noteworthy that the biaryl products
were easily derivatized to form acids and alcohols by hydrolysis or reduction, respectively.[21] DFT calculations
revealed the existence of a π-π interaction between the oxazolidinonyl group and the naphthyl group from theboronic acid. This secondary interaction played a significant role in achieving the high enantioselectivity.

9

2016.7 No.170

Br

O

O

Pd(OAc)2 (5 mol%),
L3 (6 mol%)N+
B(OH)2

O

O

MeO

N

K3PO4, THF, rt
O

NMe2

P
tBu
OMe

O

O

L3

OMe
S

O

O
N

N
O

O

O

Yield : 95%
ee: 96%

O

O

N

N
O

O

O

Yield : 95%
ee: 96%

O

Yield : 94%
ee: 94%O

Yield : 95%
ee: 82%

Scheme 12. Substrate scope of asymmetric cross-couplings with ortho-carbonylbenzooxazolidinone substituents

Since numerous biaryl natural products contain ortho-hydroxyl/methoxy substituents, efficient constructionof ortho-oxygen functionalized biaryls by asymmetric Suzuki-Miyaura couplings is highly desirable and yet
to be developed. In contrast to ortho-carbonyl groups, the ortho-oxygen functional groups are more flexible
and much more difficult to offer a reliable noncovalent interaction for high enantioselectivity. Fortunately, we
found that OBOP (BOP = bis(2-oxo-3-oxazolidinyl)phosphinyl) group could provide excellent reactivity andenantieselectivity when L4 was employed as ligand. It was noteworthy that the ortho-aldehyde substituted
substrates were well-tolerable providing high yields and ee values, and ortho-phosphonate functional biaryls
could also be synthesized efficiently (Scheme 13), indicating the compatibility of this cross-coupling with various
functional groups.[22] Using this efficient methodology, we successfully finished the total synthesis of biaryl
natural products korupensamine A & B, and their heterodimer michellamine B for the first time in a concise andhighly stereoselective fashion. This work further demonstrated the practical utility in total synthesis of natural
products.

O
Ar

Br

Ar

+

O

K3PO4, toluene/H2O, 35 oC

B(OH)2iPr

P

OR Pd(OAc)2 (1 mol%) / L4 (1.2 mol%)
R

tBu
OMe

MeO
L4

OMe OBn
OHC

OHC
OBOP

OBOP

Yield: 95%
ee: 93%

Yield: 96%
ee: 99%

OBOP OHC

Yield: 95%
ee: 90%

Yield: 98%
ee: 91%

P(O)(OEt)2

OBOP

Yield: 95%
ee: 95%

Scheme 13. Substrate scope of asymmetric cross-couplings with OBOP substituents

Recently, we reported an asymmetric Suzuki-Miyaura coupling of ortho-bromo aryl triflates with various
arylboronic acids with L3 as the ligand, affording a series of chiral biaryl triflates in high yields and up to 91%
ee. The aryl triflates were easily transformed to various chiral biaryl products via simple derivatizations.[23]102016.7 No.170

5 Efficient Cyclizations Promoted by Chiral Monophosphorus Ligands
Chiral tetrahydrofuran/tetrahydropyran moieties exist in a broad range of bioactive natural products.[24]As one of most convenient and powerful methodology for constructing those chiral structures, the transition
metal catalyzed intramolecular cyclization of alkynals/alkyones has received great interests. [25] Recent years
have witnessed the ever expanding scope of such cyclizations along with the employment of various transitionmetal catalysts including Ni, Pd, Rh, Ru and Ir catalytic systems. Among those metals, the application of costeffective Ni in reductive cyclization is particularly attractive.[26] Although a number of Ni-catalyzed cyclizationsof alkynals/alkynones with high reactivities are developed, no efficient enantioselective reductive/alkylative
cyclization of alkynones has been reported. Encouraged by early work from Jamison’s group,[27] we envisionedthat P-chiral monophosphorus ligands developed in our laboratory could be applicable for enantioselective Nicatalyzed cyclizations. With these easily prepared alkynones as substrates, we were pleased that the reductive
cyclizations proceeded smoothly with chiral monophosphorus ligand (S)-BI-DIME or (S)-AntPhos as theligand, providing cyclic allylic alcohols in excellent yields and ee values.[28] A series of aromatic and aliphaticalkynes were all suitable for this system. Aromatic ketones with various substituents such as methyl, methoxy
and trifluoromethyl were compatible with the reaction conditions. In addition, various aliphatic ketones werealso converted efficiently to chiral 2-alkyl furanols. Besides the chiral tetrahydrofuran products, a chiraltetrahydropyran product was also synthesized in high yield and 94% ee (Scheme 14).

O

O

[Ni(cod)2] (5 mol%)or (S)-BI-DIME
AntPhos (5 mol%)

R

n R'
O
R, R' = aryl, alkyl
n = 1-2

RP

H
OSiEt3n R'

O

Et3SiH, dioxane, 20 htBu(S)-AntPhos
MeO

F3C
Ph
Et

H

O

OH

H

O

O

OH

OH

OH
Ph

99% ee97% yield

Ph98% ee90% yield

95% ee93% yield

Ph

Me

Ph

96% ee97% yield

H
OH

Ph

H

O

H

O

98% ee94% yield

Ph
O

H
OH

98% ee94% yield

O

H
OH
iPr

98% ee97% yield

O

Ph

OH
iPr
96% ee97% yield

Ph
H

H
O

OH

H

TsN

OH

Ph

Ph

93% yield
94% ee97% yield
99% eeScheme 14. Substrate scope of asymmetric reductive cyclization of alkynones

This asymmetric cyclization was applied in the efficient synthesis of the lignan dehydroxycubebin as wellas the facile construction of chiral dibenzocyclooctadiene skeletons,[28] which demonstrated its utility in natural
product syntheses.
Tricyclic skeletons bearing all-carbon quaternary centers exist in numerous biological interesting natural
products, such as complex terpenes and steroids (Scheme 15).[29] Although various methods were successfully

11

2016.7 No.170

applied in synthesis of those compounds, there remains great demand for developing more powerful andefficient strategies in the construction of such chiral skeletons. We believed that the asymmetric intramoleculardearomative cyclization can offer good synthetic efficiency owing to the availability of aryl systems as well as
the convenience in the derivatization of the cyclized products (Scheme 16).[30]

OH
H
H

H

H

OH
O

H

O
HO

O

KaureneO

H

Boldenone

HO

H

H

Triptoquinone B(-)-Totaradiol

Scheme 15. Terpenes and steroids bearing all-carbon quaternary centers

R X

R

M/L
Ar

Ar

HO

O

Scheme 16. Novel asymmetric dearomative cyclization

According to this design, we screened a series of chiral monophosphorus ligands developed in ourgroup. Interestingly, high yield and excellent enantioselectivity was obtained when a new ligand L5 bearing
a 2,5-diphenylpyrrole moiety was employed and [Pd(cinnamyl)Cl]2 as the catalyst precursor.[31] A series oftricyclic phenanthrenone derivatives bearing an all-carbon quaternary center were efficiently synthesized withthis protocol. Various functional groups such as fluoro, chloro, and methoxy substituents were well tolerated.
Quinone and furan heteroaryls were also compatible with the catalytic conditions (Scheme 17).

R Br
Ar
HO

O

[Pd(cinnamyl)Cl]2(1 mol%)L5 (2 mol%)o

K2CO3, 90 C
Dioxane

R

P
Ar

Ph

O

N

Ph

tBu

L5

Cl
F

OMe
N

O

O

O
86% yield
91% ee74% yield
90% eeO
74% yield
93% ee54% yield
92% eeOO
88% yield
91% eeOO

O
96% yield
91% ee35% yield
96% ee60% yield
99% eeScheme 17. Substrates scope of asymmetric dearomative cyclizations

12

2016.7 No.170

The cyclization was applied to the construction of the skeleton of the anabolic steroid boldenone(Scheme 18). Thus, chiral ketal 1 was reacted with bromide 2 in the presence of NaH to form 3 in an unoptimized
yield of 80% based on recovered starting material. Then, conversion of 3 into the cyclized precursor vinyl
triflate 4 by two steps. Cyclization of triflate 4 by our protocol provides boldenone skeleton 5 in 90% yield
and a diastereomeric ratio of > 99:1. This strategy was also applied in the synthesis of enone 8, a key chiralintermediate[32] for the synthesis of kaurene, abietic acid, and a bruceantin analogue. Up to 98% yield and 92%
ee value of tricyclic product was obtained by the key dearomative cyclization (Scheme 19). At the same time, we
also finished the total synthesis of (-)-totaradiol by the employment of this efficient strategy.[31]

O
O

O

O

Br NaH, DMSO

+
BnO

O
1) Tf 2OO

80% brsm2) BBr3
70%

BnO
1

2
O

TfO

O

3
O

O

[Pd(cinnamyl)Cl]2(R)-L5
K2CO3, tolueneHO

90% yield> 99:1 d.r.

4O5

Scheme 18. Efficient synthesis of boldenone skeleton 5BrMe[Pd(cinnamyl)Cl]2(0.5 mol%)
L5 (2 mol%)
OH

Me

OMe
6

K2CO3, tolueneO
98 % yield
92 % ee

OMe

OMe
Me

H2

79 %

Me
7

Me

Rh(PPh3)ClOMe
8 (kaurene intermediate)

Scheme 19. Efficient synthesis of kaurene intermediate 8

6 Asymmetric Hydrogenation
Although tremendous progress has been achieved in asymmetric hydrogenation, there remains numerous
unsolved problems that call for developing new and efficient catalytic systems. P-chiral phosphorus ligands has
demonstrated several advantages owing to its innate features,[3a] and a number of well-known, efficient ligands
and catalysts were developed in recent years.[33] However, many of these are inconvenient to operate as oily
or air-sensitive ligands. From the practical point of view, and in order to meet the increasing demand of green
chemistry, highly efficient and operationally convenient phosphorus ligands are needed to be developed. Ourgroup designed a novel skeleton with benzooxaphosphole as backbone in 2010, and then synthesized a seriesof C2-symmetric P-chiral phosphorus ligands BIBOP and MeO-BIBOP (Scheme 20). Both of them are airstable, crystalline solid that has been provide a great deal of operational convenience. With BIBOP as ligand,various α-arylenamides and α-(acylamino)acrylic acid derivatives can be hydrogenated in excellent yields
and enantioselectivities with Rh(nbd)2BF4 as the metal precursor.[5] To our delight, MeO-BIBOP has provided
200,000 TON in rhodium-catalyzed asymmetric hydrogenation of N-[1-(4-bromophenyl)vinyl]acetamide,13

2016.7 No.170

which has been considered as the most efficient processes in rhodium-catalyzed asymmetric hydrogenation of
α-arylenamides up to date.
We further modified the BIBOP by introducing anthracenyl groups and thus synthesized the new ligand
WingPhos. In contrast to the traditional bisphosphorus ligands, WingPhos contains anthracenyl groups that
protrude directly forward to the substrate coordination and provide a well-defined and deep chiral pocket, which
could enable efficient asymmetric hydrogenation for some challenging substrates. Since chiral β-arylamines
exist in numerous biologically interesting natural products and therapeutic agents,[34] we embarked a programon searching for efficient phosphorus ligands to synthesize chiral β-arylamines by asymmetric hydrogenation.
Gratifyingly, we found WingPhos was an efficient ligand for asymmetric hydrogenation of both (E)-βarylenamides and cyclic β-arylenamides. A series of chiral β-arylisopropylamines, 2-aminotetralines, and3-aminochromans were easily accessed by using this method (Scheme 21). Hydrogenation of (E)-N-[1-(3,4dimethoxyphenyl]-prop-1-en-2-yl)acetamide as substrate showed that the highest TON could be reached up to
10,000 without erosion of the ee value, thus demonstrating the high efficiency and reactivity of WingPhos forthis transformation.[35]Rh[(nbd)(BIBOP)]BF4 (1 mol%)Ar

NHCOR CH2Cl2, H2 (100 psi), 12 h, 0 oC

Ar

NHCOR

O H

>98% ee, quantAr

COOR Rh[(nbd)(BIBOP)]BF4 (1 mol%)
NHCOR

O

P H P
tBu tBu

MeOH, H2 (100 psi), 12 h, 0 oC

Ar

(2S,2S',3S,3S')-BIBOP

NHCOR>96% ee, quantO

O
HN

Rh[(nbd)2]BF4 (0.0005 mol%)
MeO-BIBIOP (0.0006 mol%)

O H

HN

MeOH, H2 (100 psi), 25 oC
Br

Br

O

P H P
OMe tBu tBu

OMe(2S,2S',3S,3S')-MeO-BIBOP

Scheme 20. Asymmetric hydrogenation by BIBOP and MeOBIBOP

O H
Rh[(nbd)(WingPhos)]BF4
NHAc(0.5 mol%)R

CH2Cl2, H2 (750 psi), 0 oC

O

P H P
tBu tBu

NHAc
R

WingPhos
Cl

NHAc

MeO

Br

F
98% ee98% ee98% ee98% ee
NHAc

NHAc

NHAc

NHAc

NHAc

NHAc

MeO

NHAc

OMe
97% ee94% eeNHAc

Br

97% ee (10,000 TON)
NHAc

O

O

94% ee97% ee96% ee
NHAc

NHAc
O

O
OMe

Br

96% ee98% eeScheme 21. Substrate scope of asymmetric hydrogenation by WingPhos

14

2016.7 No.170

By using this method, several key chiral intermediates for therapeutic agents such as the α-blocker
tamsulosin and α1-adrenoceptor antagonist silodosin, can be efficiently synthesized by asymmetric hydrogenation(Scheme 22).

NHAc

Rh[(nbd)(WingPhos)]BF4(0.01 mol%)

NHAc

CH2Cl2, H2 (750 psi)

MeO

MeO
99% yield, >99% ee
OMe

O

O
S
NH2
O

N
H

OEt
tamsulosin
NHAc
N

NHAc

Rh[(nbd)(WingPhos)]BF4(0.01 mol%)N

CH2Cl2, H2 (750 psi)

OBz

OBz
95% yield, 96% ee
O

H
N

H2N

O
O

N
OH

CF3

silodosin

Scheme 22. The application in the synthesis of key intermediates for therapeutic agents

7 Enantioselective Addition of Arylboron Reagents to Arylketones
Chiral tertiary carbinol moieties bearing diaryl and alkyl groups exist in a number of therapeutic agents andnatural products,[36] such as the antidepressant escitalopram, antihistamine clemastine, and cough suppressant
chlophedianol. The efficient synthesis of these chiral tertiary alcohols have received significant attention. The
asymmetric addition of nontoxic, stable and operationally convenient aryl boron reagents to simple aryl ketones
is highly attractive yet remains challenging. In 2013, we described a highly enantioselective Rh-catalyzed
addition of trifluromethyl ketones by arylboronic acids[37] by using L6 as ligand. A series of chiral tertiary
trifluoromethyl alcohols were synthesized in good to excellent yields and excellent ee values (Scheme 23).

O
R

CF3

B(OH)2+ R'

O H[Rh(C2H4)2Cl]2(1.5 mol%)
L6 (3.6 mol%)
K2CO3, MTBE

HO
R

CF3
R'

MeO

O

P H P
tBu tBuOMe MeO

OMe

L6

Scheme 23. Highly enantioselective addition of arylboronic acids to aryl trifluoromethyl ketones

Low yield (25%) was observed for the addition of 4-methoxyphenylboronic acid to acetophenone when L6
was employed as ligand, albeit with an excellent ee (96%). This promising result encouraged us to search for15

2016.7 No.170

more efficient catalytic system. After intensive optimization of the reaction conditions, we were pleased thatan excellent yield and enantioselectivity were obtained in the addition of phenylboroxine to acetophenone with
WingPhos as Ligand. The employment of magnesium bromide as additive is very important to enhance the yieldpresumably by activating the ketone substrate. With this new protocol, a range of chiral tertiary carbinols weresynthesized in excellent ee values and yields.[38] Functional groups such as halide, nitro, ester, and sulfone were
well tolerated. Notably, the ortho-substituted aryl ketones were also compatible and provided tertiary alcohols
with excellent enantioselectivities, albeit with diminished yields. In addition, the Rh/WingPhos system could also
be employed in enantioselective addition to benzofused five-membered cyclic ketones, providing cyclic tertiary
alcohols in excellent ee values (Scheme 24).

O H
O
Ar

+

R

(Ar'BO)3

[Rh(C2H4)2Cl]2 (1.5 mol%)
L6 (3.6 mol%)

R

HO

Ar'

Ar

CsF, MTBE, MgBr 2

O

P H P
tBu tBuWingPhos
HO

Me

F

HO

Me

OMe Br
95% yield
99% eeCl
45% yield
98% ee

HO

OMe

HO

Me
O
S
O

OMe O2N
96% yield
99% eeMeHO

HO

97% yield
99% eeOMe

MeO
80% yield
95% ee

H3C

HO
OMe

O
98% yield
99% eeMeF
93% yield
99% ee
HO

Me

OMe

MeOOC
96% yield
99% eeScheme 24. Substrate scope of asymmetric addition of arylboroxines to aryl ketones

This catalytic methodology was successfully applied in enantioselective synthesis of antidepressant drug
escitalopram (Scheme 25). 4-Fluorophenylboroxine was added to 4-chloro-1-(2,4-dichlorophenyl)butan-1-one(9) with the Rh/(R,R,R,R)-WingPhos catalyst, providing the desired tertiary alcohol 10 on gram scale with 70%
yield and >99% ee value. Introduction of dimethylamine by displacement of the chloride in 10 and subsequentpalladium-catalyzed dicyanation-lactonization afforded the lactone 11 in 73% overall yield. After reductionof lactone 11 and subsequent cyclization, providing escitalopram in 61% overall yield and with greater than
98% ee. Thus, a new highly enantioselective synthesis of escitalopram was successfully developed with thismethodology.[38]162016.7 No.170

O

Cl

Cl

(4-FC6H4BO)3
WingPhos(3.6 mol%)[Rh(C2H4)2Cl]2(1.5 mol%)
MgBr2, CsF, MTBE
>99% ee, 70% yield

Cl
9

Cl

Cl
Cl

O
N

F
escitalopram

DIBAL-H, NaBH4
MsCl, Et3NF101) HNMe2·HCl2) Zn(CN)2,
Pd(dppf)Cl2

73%

NC

OH

O

NC

O
N

61%
>98% eeF
11

Scheme 25. Synthesis of escitalopram

8 SummaryIn this article, we outlined our recent efforts in the development of novel phosphorus ligands and its
applications in efficient transition metal catalyzed reactions. In particular, we developed four categories of newphosphorus ligands on the basis of a benzooxaphosphole backbone. All of those novel ligands are air-stableand operationally convenient solids. In search of highly efficienct and practical catalyst, we have developed thebulky biaryl monophosphorus ligands BI-DIME and AntPhos that have enabled sterically hindered aryl-arylcross-couplings; two P,P=O.
Ligands have been successfully applied in sterically hindered aryl-isopropyl cross-couplings; several
P-chiral monophosphorus ligands have been synthesized and employed successfully in efficient asymmetric arylaryl cross-couplings or cyclizations; several P-chiral bisphosphorus ligands are applied in highly enantioselective
asymmetric hydrogenation as well as asymmetric addition of arylboron reagents. The high reactivity,
chemoselectivity, and enantioselectivity achieved in these catalytic systems allow practical applications inconstruction of therapeutic agents and natural products. Despite those progresses, the current applications
remains very limited with respect to the increasing demand of numerous catalytic reactions. We are convincedthat the development of novel phosphorus ligands will continue to be an important method for discovering
efficient and practical catalytic reactions and the future is bright down this path.

Acknowledgment
We are grateful to NSFC-21432007, 21272254, 21572246, the “Thousand Plan” Youth program, theInnovation Fund of State Key Laboratory of Bioorganic and Natural Products Chemistry.

17

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執筆者紹介

Guangqing Xu Assistant Researcher, Ph.D.
Guangqing Xu was born in 1987 in Shandong Province, China. He received his Bachelorof Science from Qingdao University of Science and Technology in 2009. After one
year of experience in pharmaceutical company, he then joined in Shanghai Instituteof Organic Chemistry, Chinese Academy of Sciences, and received his Ph.D. in 2015
under the guidance of Prof. Wenjun Tang. Now, he is working on development of efficient
asymmetric catalyst and reactions in Prof. Wenjun Tang’s group as assistant researcher.

Wenjun Tang Professor, Ph.D.
Wenjun Tang was born in 1974 in Zhejiang Province, China. He received his B. Eng.
degree in 1995 from East China University of Sciences and Technology, his M.S.
degree in 1998 from Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, and his Ph.D. in 2003 from the Pennsylvania State University. After twoyear postdoctoral research at the Scripps Research Institute, he worked six years as
a process chemist at Boehringer Ingelheim Pharmaceuticals Inc. In 2011, he took
his current position as a research professor at Shanghai Institute of Organic Chemistry, Chinese Academyof Sciences. His research interests are in the areas of asymmetric catalysis, total synthesis of natural
products, and development of efficient chemical processes.

19

2016.7 No.170～身近な元素の話～

典型元素の新しい同素体（2）佐藤健太郎

前々回に続き，近年登場した典型元素の新しい同素体を紹介しよう。
ケイ素
ケイ素はクラーク数 25.8 で，地殻上に酸素に次いで多く存在する。最もよく知られている同素体
は，ケイ素原子がダイヤモンド型につながったもので，暗灰色の硬くてもろい固体だ。半導体材料
としてあらゆる場所で使われ，現代社会になくてはならない存在となっている。
もうひとつ，常圧で安定なケイ素の同素体として，アモルファスシリコンがある。これはケイ素
同士が無秩序に三次元網目状構造を成したもので，見た目は茶色い粉末状だ。やはり半導体材料となるが，結晶ケイ素に比べてエネルギーギャップが大きく，成膜しやすいなどの特徴があるため，薄膜トランジスタや太陽電池などへの応用がなされている。ただしアモルファスシリコンは，ケイ素の骨格にところどころ水素が結合していると考えられ，正確な意味での同素体とは言いがたい。
その他，結晶ケイ素に高圧をかけて行くと，β スズ構造などいくつかの結晶構造へと相転移することが知られているが，これらの用途はまだ十分に拓かれていない。
新たな 3 次元ケージ
しかし最近になり，
3 次元網目状ケイ素の新顔が登場した（Nat. Mater. 2015, 14, 169.）。カーネギー研究所の T. A. Strobel らは，まず高温高圧下でナトリウムとケイ素を反応させ，ケイ素のケージの中にナトリウムが閉じ込められた形の NaSi6 という組成の化合物を得た。これを真空下で 400 K に加熱すると，徐々にナトリウムが抜け，ケイ素のケージがほぼそのままの形で残るのだ。
こうして得られた新しいケイ素の同素体は，5，6，8 員環から成るネットワークを持ち，単位格
子は 24 個のケイ素原子からできている。空気中でも 750 K 付近まで安定に存在でき，バンドギャッ
プも 1.3 eV 程度と，太陽電池などへ応用するのに適した性質を備えている。また，この方法の応用で，さらに新しい構造のケイ素同素体が得られてくる可能性もあり，今後の展開が期待される。
シリセン登場
炭素材料におけるナノカーボン類に相当する構造は，ケイ素では得られないのだろうか？フラーレン同様の構造をとる Si60 分子については，いくつかの理論計算が行なわれているものの，いまだ合成はされていない。炭素と異なり，ケイ素原子同士の π 共役系が弱いことが要因と考えられる。
グラファイトに相当するケイ素同素体も，まだ知られていない。
しかし最近，ケイ素版グラフェンというべき，シリセンという新材料が注目を浴びている。グラフェン同様，ケイ素がハニカム状に広がった構造だ。シリセンは以前より興味が持たれ，理論面か202016.7 No.170

らの研究が行なわれてきたが，銀の表面にケイ素を蒸着させることで，初めてシリセンが作り出されたのは 2010 年のことだった（Appl. Phys. Lett. 2010, 97, 223109.）。
ただしケイ素は，炭素のような sp2 混成軌道が安定でないため，完全な平面ではなく凸凹しており，また空気に不安定という欠点もある。しかし，グラフェンでは実現不可能な機能を持たせうるなど期待も大きく，2015 年には早くもシリセンを用いたトランジスタが作り出されている。超高速コンピュータの実現へ向けて，夢が広がる新素材だ。
NHC でケイ素を挟む
また 2008 年には，２つの N- ヘテロサイクリックカルベン（NHC）に 2 原子のケイ素が挟まれた形の化合物が，Robinson らによって合成された（Science 2008, 321, 1069.）。NHC が配位した四塩化ケイ素を，KC8 で還元することによって生成する。C-Si-Si の角度は約 93°と，ほぼ直角に近い折れ曲がり方をしている。
これまで Si2 という分子は，極低温でスペクトル的に存在が確認されていただけだったが，カルベンによって安定化され，結晶として取り出すことが可能になった。カルベンはあくまで配位子であり，中央の Si2 は新たなケイ素同素体とみなすことができる。元素科学の金字塔と評される研究だ。

NHC に挟まれて安定化された Si2（中央の緑色）

複雑なリンの同素体
高校の教科書を見ると，リンの同素体には黄リン・赤リンなどがあるとされている。黄リンは P4という分子から成る発火性の淡黄色固体，赤リンは赤褐色の粉末で比較的反応性に乏しく，マッチなどに用いられるとの記述がある。
しかし近年では，黄リンという純物質は存在せず，赤リンなどの不純物をわずかに含んだ白リンがその正体と考えられるようになった。その他，黒リン・紫リン・紅リンなどの「同素体」が記載されている本もあるが，これらにも正確な意味での同素体とはいえないものがあることがわかってきた。たとえば紅リン（scarlet phosphorus）と呼ばれるものは，実のところ赤リンの微細な結晶と見られている。というわけで，リンの同素体の世界はなかなか複雑だ。

21

2016.7 No.170

1 次元ポリマー状のリン同素体が発見されたのは，21 世紀に入ってからのことだ。A. Pfitzner，
H. Eckert らのグループは，赤リンとヨウ化銅 (I) から得られる付加体を，シアン化カリウム水溶液で洗浄することで銅を除き，ほぼ純粋なリンから成る赤茶色の固体を得た。これを分析したとこ
ろ，12 原子のリンからできた単位構造を繰り返した形のポリマーであることがわかった（Angew.
Chem. Int. Ed. 2004, 43, 4228.）。うちひとつの構造を図に示す。製法の工夫次第で，さらに新しい同素体ができる可能性もまだまだありそうだ。

リン原子から成る 1 次元ポリマー

NHC による安定化
周期表でひとつ上に位置する，窒素は二原子分子 N2 が最も安定だ。リンでも，これに相当する
P2 という分子が知られている。リン原子同士は三重結合で結びついており，結合距離は約 189.5
pm と，通常の P-P 単結合（220 pm 前後）よりはるかに短い。この「二リン」は，白リンを 1100
K まで加熱することで生成するが，極めて不安定で取り扱いは難しい。近年，ジエンと反応してヘテロ Diels–Alder 反応を起こすことが判明し，リン化合物の新たな合成法として応用が拓ける可能性がある。
ではこの二リンも，ケイ素のように NHC の配位によって安定化させられないのだろうか？実はRobinson らのグループが，ケイ素の場合とほぼ同様の手法によって，安定化された二リン分子を作り出している（J. Am. Chem. Soc. 2008, 130, 14970.）。NHC が化学の世界にもたらした，大きな変化の一例に挙げられよう。
リンのシート黒リンは古くから知られているリンの同素体のひとつで，白リンを 12,000 気圧下で加熱することで生成する。リン原子から成るハニカム構造のシートが積み重なったもので，炭素でできたグラ
ファイトに似た構造といえる。
現在盛んに研究が行われているグラフェンは，グラファイトから一層だけを剥がし取ることで初めて作り出された。同じように，黒リンから一層だけを剥ぎ取れば，ユニークな性質を持った物質が得られるのではないか？これが P. D. Ye らによって実現したのは，2014 年のことだ（ACS Nano
2014, 8, 4033.）。
フォスフォレンと名付けられたこの 2 次元材料は，グラフェンと異なって波打った構造をとる。
また，グラフェンが良導体であるのに対し，フォスフォレンは半導体として振る舞う。この新物質はすでに大きな注目を集めており，前述の論文の引用数はすでに 800 を超えている。安価なリンから優れた電子デバイスが誕生する可能性を秘めており，先行きが期待される材料のひとつだ。

22

2016.7 No.170

フォスフォレンの構造（Wikipedia より）ケイ素とリン，なじみ深い二つの元素にも，これだけ新たな発見が相次いでいる。化学の可能性の広さを，改めて思い知らされる気がする。

執筆者紹介

佐藤

健太郎 （Kentaro

Sato）[ ご経歴 ] 1970 年生まれ，茨城県出身。東京工業大学大学院にて有機合成を専攻。製薬会社にて創薬研究に従事する傍ら，
ホ ー ム ペ ー ジ「 有 機 化 学 美 術 館 」（http://www.org-chem.org/yuuki/yuuki.html， ブ ロ グ 版 は http://blog.livedoor.jp/
route408/）を開設，化学に関する情報を発信してきた。東京大学大学院理学系研究科特任助教（広報担当）を経て，現在はサイエンスライターとして活動中。著書に「有機化学美術館へようこそ」（技術評論社），「医薬品クライシス」（新潮社），「『ゼロリスク社会』の罠」（光文社），「炭素文明論」（新潮社），「世界史を変えた薬」（講談社）など。
[ ご専門 ] 有機化学

232016.7 No.170

最小の “ カーボンナノリング ”：[5] シクロパラフェニレン（[5]CPP）
C2931 [5]Cycloparaphenylene (= [5]CPP) (1)20mg 39,000 円 100mg 118,000 円[5]CPP (1)シクロパラフェニレン（CPP）はベンゼン環をパラ位で環状につなげた化合物で，カーボンナノ
リングとも呼ばれます。この構造はカーボンナノチューブ（CNT）の最小構成単位に相当し，基礎化学のみならず材料科学などの応用分野からも注目されています。実際，伊丹らはこの CPP をテンプレートとし，炭素骨格をつなげていくことで，均一な直径を持つ CNT をボトムアップ合成できることを見出しました 1)。特定のサイズの CPP がフラーレンを包摂することも報告されており，
ホスト分子材料としても注目されています 2)。
最近では，より大きな歪みを持った小さいサイズの CPP が合成されています。山子 3,4) およびJasti5) らのグループは，これまで合成された CPP の中で最も小さな環サイズを持つ [5]CPP（1）の合成手法をそれぞれ独自に報告しています。1 をテンプレートとすることで，最小の直径を有する
CNT をボトムアップ合成できると期待されます。1 はフラーレン（C60）の部分構造で，かつ同じ
直径（0.7 nm）を有しており，C60 に匹敵する狭い HOMO-LUMO ギャップを持ちます。また，有機溶媒への高い溶解性を示します。

C60[5,5]CNT

文献1) Initiation of carbon nanotube growth by well-defined carbon nanorings
H. Omachi, T. Nakayama, E. Takahashi, Y. Segawa, K. Itami, Nat. Chem. 2013, 5, 572.
2) Size-selective encapsulation of C60 by [10]cycloparaphenylene: Formation of the shortest fullerene-peapod
T. Iwamoto, Y. Watanabe, T. Sadahiro, T. Haino, S. Yamago, Angew. Chem. Int. Ed. 2011, 50, 8342.
3) Synthesis and characterization of [5]cycloparaphenylene
E. Kayahara, V. K. Patel, S. Yamago, J. Am. Chem. Soc. 2014, 136, 2284.
4) 山子茂，茅原栄一，国立大学法人京都大学，特願 2014-009789.
5) Efficient room-temperature synthesis of a highly strained carbon nanohoop fragment of buckminsterfullerene
P. J. Evans, E. R. Darzi, R. Jasti, Nat. Chem. 2014, 6, 404.

24

2016.7 No.170

異性体を含まないアントラジチオフェン誘導体
100mg 19,500 円
100mg 19,500 円

D4617 anti-DMADT (purified by sublimation) (1)D4618 syn-DMADT (purified by sublimation) (2)

CH3

S
S
anti-DMADT (1)

CH3

CH3

S

S

CH3

syn-DMADT (2)ペンタセンは優れた p 型有機半導体ですが，その高い HOMO レベルに起因する酸化への不安定性のため，デバイス作成時の性能のバラつきや長期的安定性に問題があります。それに対して，低い HOMO レベルを有するアントラジチオフェンは酸化に対してより安定であり，ペンタセン同様の優れた p 型半導体特性を示します。しかしながら，多くのアントラジチオフェン誘導体は，チオフェン環の向きによる syn -，anti - 異性体の混合物であるため，デバイス作成時にそれぞれの異性体が性能に与える影響が不明確でした。
ジメチルアントラジチオフェン（DMADT）は，時任・侭田らによって開発されたアントラジチ
オフェン誘導体であり，anti - 体と syn - 体を単一異性体としてそれぞれ合成しています 1)。これにより，DMADT は syn/anti それぞれの物性が報告されており，光学特性やエネルギーレベルは類似す
るも，ホール移動度はより対称性の高い anti -DMADT（μ = 0.41 cm2/Vs）が，syn -DMADT（μ = 0.084
2
cm /Vs）よりも 5 倍ほど優れた値を示します。この結果はアントラジチオフェンを使ったデバイス作製において，単一異性体を使用する重要性を示しています。
弊社では独自に異性体が混在しない合成ルートを開発し，anti -DMADT（1）と syn -DMADT（2）それぞれを高純度品として製品化しました。

文献1) M. Mamada, T. Minamiki, H. Katagiri, S. Tokito, Org. Lett. 2012, 14, 4062.

関連製品
P0030 Pentacene (purified by sublimation)
D5086 DBTTT (purified by sublimation) (This product is only available in Japan.)

100mg 4,500 円

1g 24,700 円
100mg 18,500 円

25

2016.7 No.170

安全なシアノニトロメチル化剤
1g 10,600 円

N1091 4-Nitro-5(2H)-isoxazolone Pyridinium Salt (1)ニトロアセトニトリル（NAN）は，反応性の高いシアノ基とニトロ基を有するとともに，中間のメチレン基が高い酸性度を示すため，シアノニトロメチル化剤として合成化学的に有用です。しかしながら，NAN は爆発性を有することから，安全に使用できる代替試薬が求められています。
西脇らにより開発された 4-ニトロ-5(2H )-イソオキサゾロンピリジニウム塩（1）は，2 分子の有機塩基を作用させることで開環反応が速やかに進行し，NAN の合成等価体として働くシアノアシニ
トロ酢酸塩 2 に誘導されます 1)。生成した 2 は，非極性，極性を問わず有機溶媒への溶解性が高い
ことから，安全で取り扱いの容易なシアノニトロメチル化剤として多岐にわたる多官能性化合物の合成に有用です。
例えば，発生させた 2 とビニルケトンの反応で得られたマイケル付加体 3 に，アミンを作用させる
ことで，ニトロ基とアミノ基を隣接位に有する二官能性ピリジン誘導体 4 を得ることができます 2)。
イソオキサゾリンやイソオキサゾール，ジヒドロピリジン，ナフチリジンなどの多官能性複素環の合成も報告されています 2-4)。

NO2
O
N
N
H

O

O
N

O

Pyrrolidine
2 eq.

1[N1091]

O

N

CH2

O

CH3
1 eq.

O
2

O
NC

CH3
NO2
3

R1R2NH (1 eq.)
MeCN, 120 °C, 24 h
in a sealed tube

O2N
R2

N

N

CH3

R1
4

さらに，1 から誘導されるシアノアシニトロ酢酸塩 2 を利用して得られる生成物は，シアノ基，
ニトロ基を有するため，種々多様な骨格へと導くことが可能です。

文献
1) Ring opening reaction of the pyridinium salt of 4-nitro-3-isoxazolin-5-one
N. Nishiwaki, Y. Takada, Y. Inoue, Y. Tohda, M. Ariga, J. Heterocycl. Chem. 1995, 32, 473.
2) Safe cyano(nitro)methylating reagent – Michael addition of cyano-aci-nitroacetate leading to δ-functionalized
α-nitronitriles
H. Asahara, K. Muto, N. Nishiwaki, Tetrahedron 2014, 70, 6522.
3) One-pot synthesis of polyfunctionalized isoxazol(in)es
N. Nishiwaki, T. Nogami, T. Kawamura, N. Asaka, Y. Tohda, M. Ariga, J. Org. Chem. 1999, 64, 6476.
4) Synthesis of vicinally functionalized 1,4-dihydropyridines and diazabicycles via a pseudo-intramolecular
processN. Nishiwaki, S. Hirao, J. Sawayama, H. Asahara, R. Sugimoto, K. Kobiro, K. Saigo, Tetrahedron 2014, 70, 402.
5) Review
H. Asahara, N. Nishiwaki, オレオサイエンス 2015, 15, 165.

26

2016.7 No.170

新しい Julia 型メチレン化試薬
1g 9,100 円 5g 31,700 円

M2860 1-Methyl-2-(methylsulfonyl)benzimidazole (1)安藤らは，1- メチル -2-(メチルスルホニル)ベンゾイミダゾール（1）をメチレン源に用いる
Julia–Kocienski 反応型のメチレン化反応を報告しています。1 は塩基存在下，室温でケトンやアルデヒドをメチレン化合物に変換し，α,β-不飽和ケトンやかさ高いケトンなど，幅広い基質に適用可能です。さらに，反応の副生成物であるベンゾイミダゾール誘導体は，分液操作により除去が可能なため，容易に精製が行えます。
N
N
CH3

O
R1

R2

SO2CH3
CH2

t-BuOK

1

R1

DMF, rtProduct

Product

Yield (%)

CH2
96

N

97

CH3
CH2

CH3 CH3

CH2
Boc

Yield (%)
CH2

CH3
CH3

R2

CH3

99

91

CH3

文献
1) K. Ando, T. Kobayashi, N. Uchida, Org. Lett. 2015, 17, 2554.

Stearoyl-CoA Desaturase 阻害剤
20mg 12,500 円 100mg 43,800 円

I0975 PluriSIn 1 (1)O
C NHNHN

1

iPSCs（induced pluripotent stem cells）と ESCs（embryonic stem cells）の研究の進展によって，それらの種々の細胞への分化が再生医学へ応用されることが期待されています 1-3)。しかしながら，自己再生と分化という特性が，それらの細胞を腫瘍原性にしています 4-7)。この腫瘍形成は残存す
る未分化の多能性細胞に正の相関があることが見出されています 6)。
PluriSIn 1（1）は stearoyl-CoA desaturase の阻害剤で，オレイン酸の合成を阻害し，残存する未分化のヒト多能性幹細胞（hPSCs）を選択的に除去します 8)。Ben-David らは，この阻害は小胞体
ストレス，その応答，翻訳の減少を hPSCs 内で引き起こし，結果としてアポトーシスに至るという機構を提唱しています 8)。
本製品は試薬であり，試験・研究用のみにご利用ください。
文献1) M. J. Evans, M. H. Kaufman, Nature 1981, 292, 154.
2) G. R. Martin, Proc. Natl. Acad. Sci. USA 1981, 78, 7634.
3) K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda, S. Yamanaka, Cell 2007, 131, 861.
4) D. E. C. Baker, N. J. Harrison, E. Maltby, K. Smith, H. D. Moore, P. J. Shaw, P. R. Heath, H. Holden, P. W.
Andrews, Nat. Biotechnol. 2007, 25, 207.
5) U. Ben-David, N. Benvenisty, Nat. Rev. Cancer 2011, 11, 268.
6) K. Miura, Y. Okada, T. Aoi, A. Okada, K. Takahashi, K. Okita, M. Nakagawa, M. Koyanagi, K. Tanabe, M. Ohnuki,
D. Ogawa, E. Ikeda, H. Okano, S. Yamanaka, Nat. Biotechnol. 2009, 27, 743.
7) I. Gutierrez-Aranda, V. Ramos-Mejia, C. Bueno, M. Munoz-Lopez, P. J. Real, A. Mácia, L. Sanchez, G. Ligero, J.
L. Garcia-Parez, P. Menendez, Stem Cells 2010, 28, 1568.
8) U. Ben-David, Q.-F. Gan, T. Golan-Lev, P. Arora, O. Yanuka, Y. S. Oren, A. Leikin-Frenkel, M. Graf, R. Garippa, M.
Boehringer, G. Gromo, N. Benvenisty, Cell Stem Cell 2013, 12, 167.

27

日本プロセス化学会2016サマーシンポジウム

2016年7月28日（ 木）〜29日（金） 名古屋国際会議場

第35回日本糖質学会年会

2 0 1 6 年 9月1日
（ 木 ）〜3日（ 土） 高知市文化プラザ かるぽーと

第33回有機合成化学セミナー

2 0 1 6 年 9月6日
（ 火 ）〜8日（木） ヒルトンニセコビレッジ（北海道ニセコ町）

JASIS 20162016年9月7日（ 水）〜9日（金） 幕張メッセ国際展示場

第 89回日本 生 化 学会大会

2016年9月25日（日）〜27日（ 火） 仙台国際センター／東北大学川内北キャンパス