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

2 0 1 8 .7

178

目次
2
OH
HO

OH
NH
OH

CO2Me
OBz

AcO

O
OH

O

NMe

HO

OH
(S)-3-Hydroxy-calystegine B5 Tropane Alkaloi d

HO

OH
OH
Gabosine F

Gabosine O

OH

O
HO

HO
HO

NH2

HO

O

HO
OH
OH
Pseudo-aryl Glucoside

O

OH

HO

OH

Valiolamine

OH

HO

HO

OH

OH

(+)-Gabosine A R = H(+)-Gabosine D R = OAc(+)-Gabosine E R = OH

OMe

HO

28

OH

HO

Carbohydrates

HO

HO
OH
Gabosine G

R

HO
HO

OH

N
H

OH

OH

OH

Validoxylamine G

HO

H3C

HO

N
H

HO

OH HO

OH
OH

Pseudo-acarviosin- Carbocyclization of Carbohydrates toHydroxylated Cycloalka(e)nes
Tony K. M. Shing
Professor, Department of Chemistry,
Faculty of Science and Technology, Keio University

O

HO

OH

寄稿論文

製品紹介

- 筒状炭素分子：(6,6)カーボンナノベルト- 高性能な液晶性半導体材料：Ph-BTBT-10- 光学活性なシクロプロパンの合成に有用な不斉ルテニウム触媒- ペルオキシダーゼ用調製済み基質溶液- c-Jun N末端キナーゼ(JNK)阻害剤：SU 3327
- シクロオキシゲナーゼ(COX)阻害剤：フルルビプロフェン2018.7 No.178

Carbocyclization of Carbohydrates to Hydroxylated Cycloalka(e)nes
Tony K. M. Shing
Department of Chemistry, Faculty of Science and Technology, Keio University
Email: shing@chem.keio.ac.jp

Abstract: Carbohydrates, inexpensive and rich in stereochemistry, are nature’s gifts to the synthetic organic
chemists. We have been conducting research on the carbocyclization of carbohydrates for many years, i.e. theconversion of simple, readily available monosaccharides into hydroxylated cycloalkanes and cycloalkenes
with pharmaceutical potential. Several key reactions are presented in this Article to illustrate such faciletransformation namely [π4s+π2s] cycloaddition - intramolecular nitrone-alkene and nitrile oxide-alkene
cycloadditions, intramolecular direct aldol reaction and intramolecular Horner–Wadsworth–Emmons olefination.
These protocols provide facile entries to 6 and 7-membered hydroxylated carbocycles in enantiomerically pureforms which then could be further elaborated into target molecules. Examples including calystegines, tropane
alkaloid, cyclohexanyl and cyclohexenyl gabosines, cycloheptanones, valiolamine, validoxylamine G, pseudoacarviosin, and a SGLT2 inhibitor are presented.
Keywords: carbohydrates, natural products, organic synthesis, pericyclic reactions, hydroxylated carbocycles

This review article describes our research efforts on finding a short, facile, and efficient way of transforming
carbohydrates into hydroxylated carbocycles over a period of about 30 years. There are excellent reviews on the
topic published elsewhere.1
The story begins when I was a postdoctoral fellow at Oxford working with Professor George Fleet in 1983.
We were trying to synthesize shikimic acid from D-mannose using an intramolecular aldol condensation or a
Wittig-type alkenation as the key step. Installing a phosphono-acetate moiety at the C-5 of the benzyl furanosideintermediate 1 to form the Wittig–Horner–Emmons precursor met with difficulty (Scheme 1).2
Simple SN2 displacement reactions in carbohydrates are known to be sluggish/difficult due to the highconcentration of oxygen functions (electron rich). Thus the derived standard electrophiles, 5-tosylate 2 and5-iodide 3 were found to be inert towards substitution. We then attempted to use the 5-triflate 4 as a reactive
leaving group (this was new at that time). Gratifyingly, the alkylation proceeded smoothly to give the Horner–
Wadsworth–Emmons (HWE) alkenation precursor in a good yield. Subsequent unmasking the aldehyde functionin 5 by hydrogenolysis afforded lactol 6 that was treated with base to give the cyclohexene motif, the protectedshikimic acid 7. Acid catalysed removal of the blocking groups in 7 furnished shikimic acid in an excellent
overall yield.22

2018.7 No.178

HO
HO
HO

O
(MeO)2POH
O

D-MannoseO

5 steps~60%
overall yieldOH

OCH2Ph

X
O

CO2H

HO

+ -

CO2tBu

OR
O

O

Na

1 X = OH
2 X = OTs
3X=I
4 X = OSO2CF3~39%
overall yieldO

DMF, 15-crown- 5O(MeO)2P

O

CO2tBu5 R = CH2Ph
6R=H
NaH,
THF
CO2tBuHO

aq. TFA

HO

O
O

OH
Shikimic acid7

Scheme 1. Synthesis of shikimic acid

Up to date, this intramolecular HWE alkenation is still one of the most powerful strategies for the
carbocyclization of sugar molecules. A notable example of using this strategy was demonstrated by Fang andco-workers3 to synthesize anti-viral agent Tamiflu® 12 and its more potent phosphonate analog 13 in a similarmanner (Scheme 2).
* Tamiflu® is a registered trademark of F. Hoffmann-La Roche, Ltd.

O
(MeO)2P

E
O

OCH2PhD-Xylose

AcNO

8 E = CO2Et
9 E = PO(OEt)2E

HO

H2PO4- H3N

E

AcHN
O

AcN
O
10 E = CO2Et
11 E = PO(OEt)212 E = CO2Et (Tamiflu )
13 E = PO(OEt)2

Scheme 2. Synthesis of Tamiflu® and its phosphonate analog

The reasons for researching on carbocyclization of carbohydrates are attributed to the fact that many
biologically active molecules are hydroxylated cycloalkanes/alkenes. Carbohydrates are obvious starting
materials that offer the most facile and economical way to approach these highly oxygenated carbocycles withdefined stereochemistry.
Some hydroxlated cyclohexanes and cyclohexene are listed in Figure 1. They display a wide plethora of
bioactivities including antibiotic, antitumor, antiviral, glycosidase inhibitory activities.

3

2018.7 No.178

O
HO

EtO

O

O

OH

HO

O

OH

HO

KD16-U1 14
EtO

OH

O

Cl

OH

OH
HO

COTC 15

O

EtO
MeO

OH

OH

HO

Pericosine A 16

OH

Pericosine B 17O
HOO

H2PO4- H3N

OH
N
H

HO

NHAc

OH

HO

®

Tamiflu 12

OH
AO-128 18
VogliboseHO

NH2 HO

HO
OH

HO

OH

HO

OH

OH

HO

OH

Valiolamine 19 α-D-Glucopyranose 20

Figure 1. Bioactive hydroxylated cyclohexanes and cyclohexenes

Calystegines,4 displayed specific glycosidase inhibition, are a group of bicyclic heterocycles which arein equilibrium with the open chain form, a hydroxylated gamma-amino cycloheptanone that are potentiallyaccessible from carbohydrates (Figure 2).

HO
HO

O
NH

HO

OH
HO OH
NH

OH

OH

O

OH

HO

NH2

HO

OH
NH2
Calystegine A6

HO
HO
HO

N

Calystegine B5
O

R

HO
OH

OH

OH

HO
HO

NHR

R = H Calystegine C1
R = CH3 N-methyl calystegine C1

Figure 2. Structures of some calystegines

Gabosines are a group of hydroxylated cyclohexanones/cyclohexenones that display antibiotic, anticancer,
and DNA binding properties (Figure 3).5 All these compounds should in theory be approachable from sugars,
but how could we effect the carbocyclization efficiently?

42018.7 No.178

O

O

O
Me

HO

OR

HO

HO

HO

OH
(–)-Gabosine A

OH(–)-Gabosine B

O
HO

HO

OR

HO
OH
Gabosine K

OH
Me

HO
HO

O
R = H, (–)-Gabosine I
R = Ac, Gabosine G

HOO
Gabosine J

O
OAc

OH

HO

O
Gabosine H

OH
HO

OR

OH
R = H, (+)-Gabosine E
R = Ac, (+)-Gabosine D

OH

HO

OH
(+)-Gabosine F

HO
HO

OH
R = H, Gabosine C 14
R = crotonyl, 15

OH
Me

HO

O

HO

Me

HO

O
Me

Me

HO

OH
O
(–)-Gabosine L

HO

HO

OH
(–)-Gabosine N

OH(–)-Gabosine O

HO
HO

HO

Me

Figure 3. Gabosine family

Towards that end, we have been investigating the following strategies for the carbocyclization of sugars:
1. Carbocyclization of Carbohydrates via an Intramolecular Nitrone-Alkene Cycloaddition (INAC)
2. Carbocyclization of Carbohydrates via an Intramolecular Nitrile Oxide-Alkene Cycloaddition (INOAC)
3. Carbocyclization of Carbohydrates via an Intramolecular Direct Aldol Addition of Sugar Diketone
4. C arbocyclization of Carbohydrates via an Intramolecular Horner–Wadsworth–Emmons (HWE)
Olefination
From 1984, I started my independent research career at the University of Manchester and began toinvestigate the construction of carbocycles using an INAC reaction as the key step.

5

2018.7 No.178

Carbocyclization of Carbohydrates via an Intramolecular
1 Nitrone-Alkene Cycloaddition (INAC)
2,3-O-Isopropylidene D-ribose 23 underwent a chelation controlled Grignard vinylation to give triol
24 (Scheme 3). Glycol cleavage oxidation of the vicinal diol in 24 affoded lactol 25 which on heating with
N-methyl hydroxylamine furnished a hydroxylated cyclopentane 27 smoothly. This is an extremely short
approach towards 5-membered carbocycles and its application to the syntheses of carbocyclic nucleosides shouldhave received more attention.6
O

OH

HO
O

O

HO

OH

O

O

MgBr
HO

THF, 72%

O

94%

OH

O

HO

aq. MeOH, 90%

23
O
MeN

NaIO4

24

O

25

aq.EtOH

OMeN
+

OH

O

O 26

O 27

O

NHMeOH

Scheme 3. Synthesis of a functionalized cyclopentane 27 from ribose

On the other hand, chelation controlled vinylation of diacetone mannose 28 gave allyl alcohol 29
stereoselectively which was protected as benzyl ether 30 (Scheme 4). Regioselective mild acid hydrolysis of theterminal acetonide was feasible as the O-8 was the least hindered and therefore protonated first. The resultant
diol 31 was oxidatively cleaved to afford aldehyde 32 which was reacted with N-methyl hydroxylamine to give
nitrone 33. INAC occurred smoothly on heating to give cyclohexane 34 in good yield. In both cases, the new
C–N bond is anti to the O-2 stereochemistry and the ring fusion is cis.6

OH

O

O

O
O

OH

THF, 93%

O

OH

O

O O

O

HO

OH O

OBn

NaIO4
aq. MeOH

O
31

OBn
aq. AcOH, 64%O

THF, 79%

O O

O
30

29

28
OBn

OBn
BnBr, NaH

MgBr

O

OBn

BnO

O

32

O

MeNHOHaq. EtOH

OMeN
+
BnO

OBn
O

33 O

O
MeN
BnO
34 O

OBn
O

65% overall from 32

Scheme 4. Synthesis of a functionalized cyclohexane 34 from mannose

We had more interests in this INAC reaction because we reasoned that it could be controlled to provide
7-membered carbocycles. When a sugar molecule was elaborated to have a terminal alkene, on reaction with
N-alkyl hydroxylamine, there would be two possible modes of INAC cyclization, the exo or the endo mode
(Scheme 5), which leads to either a fused or a bridged isoxazolidine, respectively.7 To be specific, a hept-6-

6

2018.7 No.178

enose would provide either a fused bicyclo[4.3.0] system, i.e. a cyclohexane skeleton from an exo-mode ora bridged bicyclo[4.2.1] system, i.e. a cycloheptane skeleton from an endo-mode INAC cyclization. We wereparticularly intrigued by the potential formation of 7-membered carbocycles as there are few synthetic strategies
towards cycloheptanes whereas the synthetic methods for the construction of 5- and 6-membered carbocycles areplentiful.

sugar

-O

RNHOH

O
aldehyde

nitroneexo mode of cyclization
R'

-O

R'

endo mode of cyclization

-

O
N

+

N R

R'

-

O
N+ R

R'

O
N

O
N R

O
N+ R

R

( )x
fused bicyclo [X.3.0]( )xR-alkyl groupe.g. Bn, Me

N+ R

R'
( )x
bridged bicyclo [X.2.1]

R'
( )x

-O

R

O
N R

N+ R

R'

R'

bridged bicyclo [4.2.1]

fused bicyclo [4.3.0]

Scheme 5. INAC mode of cyclization

We realised that the formation of a cyclohexane skeleton via the exo-mode of cyclization of hept-6enose is the usual regioselectivity outcome with conventional protecting groups like benzyl ether, silyl ether,acetonide, and esters etc. For examples, nitrone 35 and 36, both with a cis-diol acetonide protecting group gave
cyclohexane rings in high yields (Scheme 6).8 The stereochemistry of 4-OH apparently had no effect on theregioselectivity.

O
Me N

O
Me N

1
2

O

3

O

OH
35

O

1
2

O
Bn N
3

O
92%

OH

O
N
Bn

1
2

O

3

O

OH
36

O

1
2

3

OH

O

94%

Scheme 6. INAC of hept-6-enoses with a cis-acetonide

We reasoned that the mode of cyclization might be controlled by the blocking groups as they affect theorbital overlap between the nitrone and the alkene. Thus we investigated the effect of trans-diacetal blocking
group on the regioselectivity of hept-6-enose. Epimeric nitrones 37 and 38 were readily prepared fromD-arabinose involving glycosidation with benzyl alcohol, diacetalisation, debenzylation, Grignard allylation,

glycol cleavage oxidation and reaction with N-methyl hydroxylamine. Interestingly, nitrones 37 and 38 with atrans-diacetal blocking group (the diol moiety is trans) afforded endo-mode of cyclization products 41, 44, 45, i.e.,
cycloheptane rings, for the first time (Scheme 7). Another notable feature of this reaction is that a trans-fused7

2018.7 No.178

bicyclo[4.3.0] system, i.e. cyclohexane 40 and 43 were formed. The lower yield of cis-fused 42 and higher yieldof trans-fused 43 is probably attributed to the 1,3 diaxial interaction between 4-OH and the 6-hydroxymethyl in
42, this steric interaction is absent in the cis-cycloadduct 39. The rigidity of the diacetal ring requires 2-O and3-O in the trans-diequatorial dispositions, thus 4-OH and the 6-hydroxymethyl in 42 must be axial.8

O
Me N

O
Me N

1
2

O

O

37

OMe

O

O
MeO

1
3

O

OH

1
2

MeO

O
OMe

+

OH

OMe

4

OH

+

1
2

3

OH

MeO

OMe

1
2

MeO

3

OH

O

+
MeO

OMe

O

3

OH

O
OMe
16%

O
1
2

O

Me N
+

3

OH MeO

O
OMe

44

35%

1
2

O

41

18%
Me N

O

43

+

O
40

64%

O

Me N

O
MeO

6
3

OMe
27%

3

O
Me N

O

42

1
2

O

39
O
Me N

2

38

OH

MeO

O
Me N

MeO

3

O
Me N

O

3

O
45

17%

1
2

OH

OMe
21%

Scheme 7. INAC of hept-6-enoses with a trans-diacetal

We reasoned that cycloheptane ring might be more accommodating than 6-membered rings as far as ringstrain is concerned. We therefore went on to study the effect of an acetonide with a trans-diol blocking group on
the regioselectivity of nitrone cycloaddition of hept-6-enose (Scheme 8). Nitrones 46 and 47 with an acetonideof trans-2,3-diol provided endo-cycloadducts 48 and 49 as the major products for the first time.9

O
Me N

O
Me N

1
2

O

3

O

O
Me N

O

O

OH
47

3

OH

O

O
Me N
3

1
2

46

1
2

O

OH

Me

O

1
2

+

O

OH
31%

OH

O

13%

3

3

O

81%

48
Me

1
2

O

N

O

N
1
2

+
O
49

3

O

OH
63%

Scheme 8. INAC of hept-6-enoses with a 2,3-trans-acetonide

Hept-6-enose nitrones 50 and 51 with a 3,4-trans-acetonide were even more remarkable as only the endomode cycloheptanes were harvested in good yields (Scheme 9).1082018.7 No.178

O
Me N

Me

1
2

3 4

HO
50

O

O

1
2

HO

Me

O

N

+

3 4

HO

O

O

Bn

1
2

BnO

1
2

OBz

3 4

BnO

O

O

3 4

O

8%
Bn
N

O

N

1
2

O

85%
O
Bn N

O

N

OBz

3 4

1
2

+

BnO

O

O

O
OBz

3 4

O

O

51
29%

56%

Scheme 9. INAC of hept-6-enoses with a 3,4-trans-acetonide

We were wondering if the stereochemistry of the C-2/C-5 hydroxyl groups might affect the regioselectivityof the INAC reactions. We thus constructed a hept-6-enose nitrone 60 with only a 3,4-trans-acetonide from
L-tartaric acid using standard reactions (Scheme 10). Only a cycloheptane ring 61 was obtained, thereby

confirming that the endo-mode of cyclization was controlled by the trans-acetonide ring.11

O

O

O

HO

AcCl, MeOH

OH
HO

MeO

reflux

OH

HO

OH

OH
O

I

toluene, rt
77%

O

O

5 mol% OsO4, NMO
aq. acetone 45%

O
56

55
HO

NaIO4, silica gel

HO

O

O

CH2Cl2, rt

58

O

N

2CuMgI • MgBr2

THF, –78 °C to –30 °C
73%

O

57
BnNHOHHO

MeCN, reflux
86% from 58

O

Bn

O

CH2Cl2, rt
100%

61

60

N

O

HO

OH
62

OH

H2, Pd/C
t-BuOH/H2O (v/v=5:1)
rt, 94%O

TFA, H2O

O

H2N

O

O

O

endo-mode
INAC

3 4

O

59

Bn

Bn
N O

O

OMe

54

I

I2, PPh3, ImO

MeODean & Stark trap
88% from 52

53

HO

THF, reflu x
99%

conc. H3PO4, 3-pentanone

OMe

L-Tartaric acid (52)

LiAlH4O

O(10 steps, 27% overall yieldfrom L-tartaric acid)
HO

63

OH

Scheme 10. INAC of hept-6-enose with only a 3,4-trans-acetonide

9

2018.7 No.178

Since we have established that 7-membered cycloheptanes can be accessed via a trans-acetonide
directed endo-selective INAC reactions of hept-6-enoses, we set out to synthesize calystegine analogs. In
this way, D-xylose was transformed into cycloheptanes 63, 64, 65 with a 3,4-trans-acetonide (Scheme 11).
Debenzoylation afforded the corresponding alcohols in which 66 and 68 were oxidized to the same ketone 69.
Acidic deacetonation of 69 followed by global hydrogenolysis furnished (S)-3-hydroxy-calystegine B5 71.10
We found that tert-butanol was a good solvent for hydrogenolysis of a N-benzyl group as no side products fromN-alkylation was possible.
Bn
O
HO

OH

Bn

O

N

10 steps

BnO

OH

65 (14%)

K2CO3, MeOH/CH2Cl2
rt, 8 h, 100%

Bn

O

N

Bn

O

N

OH
BnO
O

O

Bn

Bn
O

TFA, H2OOO

N

10% Pd/C, H2
t-BuOH, rt, 92%

BnO

O

HO

69

HO

66

O

CH2Cl2, rt

BnO
O

O

69

O

N

OH

70

OH

OH
HO

OH
NH

O
HO

HO

NH2

OH

71 (S)-3-Hydroxy-calystegine B5

OH

3

HO

NH2
Calystegine B5

Scheme 11. Synthesis of a calystegine B5 analog

10

OH
HO

2

OH

HO

OH
BnO

O

O

68

O

N

IBX, DMSO/CH2Cl2(v/v=1:1), rt, 100%

BnO

O

O

Bn

IBX, DMSO/CH2Cl2(v/v=1:1), rt, 100%

BnO

68

O

N

O

O

67
Bn

OH

OH

O

O

O

N

O

N

BnO

66
Bn

K2CO3, MeOH/CH2Cl2
rt, 6 h, 100%

OH

BnO
O

O

O

64 (7%)

K2CO3, MeOH/CH2Cl2
rt, 24 h, 91%

Bn

O

O

63 (14%)D-Xylose

OBz
BnO

O

O

O

N

OBz +

+

OBz
BnO

OH

Bn

O

N

7

1

OH
NH

4

OH

5
6

O

2018.7 No.178

On the other hand, D-ribose was converted into aldehyde 72 which underwent trans-acetonide directedendo-selective INAC reaction to give cycloheptane 73 in an excellent yield (Scheme 12). Acid hydrolysis of
the acetonide ring produced the diol 74 which underwent steric controlled regio-selective oxidation of the lesshindered alcohol to give ketone 75. Hydrogenolysis of the N–O bond afforded a B-type calystegine 76.10

D-Ribose

5 steps OHC
56%

72

O

MeN

OBn

O

O

O

MeN
TFA

MeNHOH
97%

BnO
73 O

O

100%

BnO
HO

OH
74

DMSO
Ac2O
O

MeN

HO

OH

MeHN
10% Pd/C, H2, t-BuOH/H2O
HO(v/v=5:1), rt, 48h, 87%

BnO

HO

O

HO

NMe

HO

75

HO

O

HO

76 B-type calystegine analog

Scheme 12. Synthesis of a B-type calystegine analog

Then we investigated this endo-selective INAC approach towards syntheses of tropane alkaloid 90 andanalogs.
(A) Strategy towards tropane alkaloid 1: INAC of a Nitrone with a 2,3-cis-Isopropylidene as Blocking
Group and an a,b-Unsaturated Ester as Dipolarophile

EtO2C
O

CO2Et
O
N
1

HO

4

3

HO

O

HO

O

CO2Et
MeN

O

4 3

80

78

O
O

Me

2

O
77

Me

1
2

endo-mode
INAC
?

N

exo-mode
INAC
?

CO2Et

H
HO
79

4

3 2

O

1

O
N
H

Me

O

Scheme 13. Orbital controlled synthetic plan towards tropane alkaloid

Since the alkene moiety in 77 is an electrophilic alkene whereas the alkenes used in our INAC cyclization
mode studies were simple nucleophilic alkenes, we were hoping that the electrophilic alkene of the enoate groupin 77 might cause an endo-selective INAC reaction attributable to HOMO–LUMO reasons (Scheme 13). This
proposal was supported by a precedent12 that in the intermolecular nitrone-alkene cycloaddition of a,b-unsaturated
ester 82, and nitrone 81, the new C–O was installed on the b-carbon in cycloadducts 83 and in 84 (Scheme 14).
If this were applied to our INAC case, the endo-mode cyclization would have taken place. We were excited withthis precedent and therefore proceeded with the synthesis.

112018.7 No.178

CO2Me

CO2Me
H

OH

H

N Me
O
+

α

CO2Me

xyleneH

140 °C

Me

α

β

82

81

OH

α

β

N O

H

+

Me

83

H

OH

β

N O

H

84

Scheme 14. Intermolecular cycloaddition of nitrone 81 and enoate 82

To our disappointment, the INAC of nitrone 85 produced only exo-mode cycloadducts 86 and 87,
6-membered carbocycles. Hence it appears that steric control is more important than electronic control for theregioselectivity (exo versus endo) of INAC reactions of hept-6-enoses (Scheme 15).11

CO2Et
O

EtO2C
O

OH

MeNHOH • HCl, py
EtOH, reflux, 2 h

O

O

H

CO2Et
O
N

HO

H
86

O
N

HO

O

O

H

Me

O

85

O
N
H

O
87

(60%)

exo-mode
INAC

CO2Et

HO

+

Me

O

Me

(11%)

Scheme 15. INAC of enoate with a cis-acetonide(B) Strategy towards tropane alkaloid 2: INAC of a Nitrone with a 3,4-trans-Isopropylidene as Blocking
Group and an a,b-Unsaturated Ester as DipolarophileSince we had shown that 3,4-trans-acetonide would direct an endo-selective mode of cyclization, we
devised a synthetic route towards cocaine based on this key step as summarised in Scheme 16.

Me
endo-mode
INAC
O
Me N

CO2Me

BnO
89

CO2Me
O

N
1
2

3 4

NMe

O

O

Tropane alkaloid 90

1

BnO
88

2

O

exo-mode
INAC

3 4

O

CO2Me
OBz

Me N O
H
1
BnO 2

CO2Me
H

3 4

O

O

Scheme 16. Steric controlled synthetic plan towards tropane alkalovid 90

122018.7 No.178

Capitalising from our studies that 3,4-trans-acetonide would produce cycloheptane ring on INAC reactionsof hept-6-enoses, we proceeded to prepare the nitrone 97 from ribose.13 The known allyl alcohol 91 was readily
obtained from D-ribose via a steric-controlled allylation (Scheme 17). Thermodynamic acetonation of 91 formed
the 7,8-O-isopropylidene first as the primary 8-alcohol was the most reactive of all. Then an acetonide wasformed between O-4,5 instead of O-5,6 because the substituents on the acetonide ring 92 were trans to eachother. The diacetonide 92 was then transformed into diol 95 without incident. Glycol cleavage oxidation of
95 with silica supported NaIO4 furnished aldehyde 96 smoothly. This solid-phase NaIO4 reagent14 is highly
recommended as the operation is very simple and the aldehyde harvested is usually un-hydrated. INAC reactionof 97 did produce the desired cycloheptane derivative 98 as the major product.13

O

HO

OH

HO

In, allyl bromide

HO

EtOH/H2O

OH

O
O

OBn

O

O

O

CO2Me
Grubbs catalyst II O

OBn
CO2Me

CH2Cl2, 95%OO
CO2Me NaIO , silica gel
4OO

80% AcOH
rt, 73%

O

94

OBn

O

O
92

93
HO

OH

91

THF, 98%

HOO
O

64% from D-Ribose

OH OH

D-Ribose

BnBr, NaH
cat. nBu4NI

anhydrous CuSO 4
acetone

OH OH

OBn
CO2Me

H

CH2Cl2, rtO95

toluene, reflux
NHMeOH

O
96

O
Me N

Me

CO2Me
INAC

BnO

75%
O

N

CO2Me
O
+

BnO
O

O

Me

CO2Me
H

O

O

98
(endo-cycloadduct)

O

H
BnO
O

1

15
97

N

99
(exo-cycloadduct)

Scheme 17. INAC synthetic route towards tropane alkaloid

As the cycloheptane skeleton was installed correctly, cycloadduct 98 was converted into natural tropane
alkaloid 90 and its analogs 100–104 as shown in Figure 4.13

13

2018.7 No.178

CO2Me
OBz

CO2Me
OBz

NMe

BnO

HO

CO2Me
OBz

NMe

NMe

Cl

Cl
100
(12 steps, 23% overall yield)

101(13 steps, 17% overall yield)

CO2Me
OBz
MsO

CO2Me
OBz

CO2Me
OBz

NMe

NMe

104
(15 steps, 12% overall yield)

Tropane alkaloid 90(15 steps, 12% overall yield)

NMe

I

103
(14 steps, 16% overall yield)

102(14 steps, 15% overall yield)

Figure 4. Tropane alkaloid 90 and its analogs

Carbocyclization of Carbohydrates via an Intramolecular
2 Nitrile Oxide-Alkene Cycloaddition (INOAC)
The use of chloramine-T in the conversion of ene-sugar oxime into a nitrile oxide and its subsequent
INOAC reaction is known.15 This cycloaddition shown in Scheme 18 can only be exo-mode as the endo-modeof cyclization would produce an impossible C=N bond at the bridge head position (Bredt’s rule).16

N

OH Chloramine-T

N

Oxime

O

exo
only

*

O
N
Isoxazoline

Nitrile oxide

Scheme 18. Intramolecular nitrile oxide-alkene cycloaddition (INOAC)

Common chemicals for the transformation of oxime into nitrile oxide include NaOCl, NaOCl/NEt3 andN-chorosuccinimde/NEt3.16

Under the basic conditions, the free hydroxyl group in nitrile oxide 105 would

attack the nitrile carbon to give oximolactone 106 and failed to produce a carbocycle. The hydroxy groupsof the sugar have to be protected in order to achieve satisfactory yields. Thus, providing a mildly acidic
environment for the INOAC reactions is crucial in achieving a fruitful carbocyclization without the formation ofoximolactone.

O
N HO

O

O

aq NaOClor NCS, Et3N

Nitrile oxide 105

HO

O

N
O

O

Oximolactone 106

Scheme 19. Formation of oximolactone under basic conditions

14

2018.7 No.178

We found that adding flash chromatography silica gel to “buffer” the reaction medium dramatically increased
the yield of the chloramine-T mediated INOAC reaction from 62 to 94% (Scheme 20).17

HO

N

Chloramine-T

O
MeO

O
N

OH

EtOH, rt

O

O

MeO

OMe
107

OH
O
OMe
108 (62%)108 (94%)

Chloramine-T, silica gel
EtOH, rt

Scheme 20. INOAC with and without silica gel

Towards the construction of 5-membered carbocycles, similar improvement in reaction yields were observed
and examples are shown in Scheme 21. It is interesting to note that other acidic conditions attempted including
the addition of acetic acid, benzoic acid, acetate buffer or phosphate buffer did not cause the INOAC to occur.
The silica gel mediated INOAC reactions were compatible with substrates containing unprotected hydroxyl
groups, thus reducing masking/unmasking steps and rendering a synthesis shorter.17

OHO1) NH2OHOOHO2) Chloramine-T,
EtOH, rt

O
N

O

N
O

109

O

O

106 (33%)

110 (87%)2) Chloramine-T, silica gel, EtOH, rt1) NH2OH
2) NaOCl (aq), CH2Cl2, 0 °C

HO

N

OH
Chloramine-T

EtOH, rtOH
111
Chloramine-T, silica gel
EtOH, rtO

110 (53%)

1) NH2OH

HO

OH

+

106 (78%)

HO

O
N

HO
OH
112 (51%)112 (87%)

Scheme 21. INOAC with and without silica gel

We have applied this methodology to the construction of gabosine O and F.18 Mannose was transformed
readily into oxime 114 with a free hydroxyl group (Scheme 22). INOAC of 114 occurred smoothly to givea 6-membered carbocycle 115 which was hydrogenolysed, dehydrated, and then hydrogenated from the lesshindered side to form ketone 118. Acidic hydrolysis of the acetonide in 118 yielded the target moleculegabosine O.18

15

2018.7 No.178

HO

O

HO

O

OH 1) acetone, H+, 92%
OH

2)

O

2) NH2OH, MeOH
100%

MgBr
O

THF, 83%

OH
D-Mannose

O
113

O
N

Chloramine-T
silica gel, EtOH
79%, α:β = 4.6:1

OH
O

O

O

116

OH

O

OH
O

97%, α:β = 6:1

O
114

O

115

Martin’s sulfuraneOHO

H2, Raney Ni, AcOHOHO1) H5IO6, Et2O, 79% HON

OH OH

H2, Raney Ni

O

OH

O
O

O

aq.TFAOH

O

89% from 116

HO

OH

Gabosine O

117

118

Scheme 22. Synthesis of gabosine O

On the other hand, L-arabinose was transformed into oxime 119 with a free hydroxyl group. INOAC
reaction of 120 furnished the 6-membered carbocycle in an excellent yield with the new C–C bond equatoriallyinstalled. Standard conversion afforded the target molecule gabosine F (Scheme 23).

O
HO

HO

OH
OH

6 steps

Chloramine-T

HOH
L-Arabinose

O
N

HO
N
O
O

OMe

silica gel, EtOH, 94%
O
MeO

MeO

OH
O
OMe
120

119
OH
O

H2, Raney Ni, AcOH
90%
MeO
121

1) AcClOOHO2) Et3N
3) H2, Raney Ni

OMe

Scheme 23. Synthesis of gabosine F

16

O
HO

OH
OH

Gabosine F2018.7 No.178

Carbocyclization of Carbohydrates via an Intramolecular
3 Direct Aldol Addition of Sugar Diketone
First of all, we started our investigation on D-glucose since voglibose 18 and valiolamine 19 are obvious
synthetic targets. Glycosidation of D-glucose with allyl alcohol and then diacetalization produced 2,3- 124 and
3,4-diacetals 123 which were readily separable upon acetonation to the 4,6-acetonide 126.19 Palladium catalysed
deallylation of glycoside 126 gave lactol 127 which underwent Grignard methyl addition followed by PDC
oxidation afforded the 2,6-diketone 129. Intramolecular aldol addition reactions of 129 were carried out undervarious basic conditions and the best results are shown in Table 1.

HO

HO
HO

2,3-butadione
CH(OMe)3
MeOH

O
HO

OAll

HO

O

O
MeO O
O
OMe

OH

HO

OAll
+

OH

O
MeO

123

122

MeO

BF3 • OEt2
HO

MeO O

OH

D-Glucose

82%

OH

O
MeO

O
OMe

126 (43%)
O

O
O

OH

O
MeO

126

OAll

+

O
Pd(PPh3)4
OAll K2CO3, MeOH

O
OMe

O
OMe

MeMgBr
THF
95%

OH
O

OH

O
MeO

127
O
O
O
MeO

O

Intramolecular
direct aldol reaction

O
OMe

O
OMe
128

O

O

PDC, 3Å MS
CH2Cl292%O

125 (40%)

O

O
MeO

O
OAll

O
OMe

OH

O

O
O

O

O

OMe

acetone
HO

HO

O
OMe
124

OH

HO

OAll

OH

O

O

O
MeO

O
OMe

129

Scheme 24. Preparation of 2,6-diketone 129 from D-glucose

The stereo-selective formation of a particular aldol product can be controlled by either L-proline, strong or
weak amine base. It is noteworthy that all the direct aldol reactions are not reversible. The resistance towards a
retro-aldol reaction is probably attributable to steric reasons.

17

2018.7 No.178

O

O

O

OH

O

OH

OH

O
O

O

O

O
MeO

O

O

O

+
O
MeO

O
OMe
129

O

O

O
MeO

O
OMe

+

O
OMe

O
MeO

130

O
OMe
131

132

Table 1. Summary of direct aldolization conditions of 2,6-diketone 129

Entry

Results

Conditions

130

131

132

1

L-Proline (0.3 eq), DMSO

82%

8%

2%

2

KHMDS (1 eq), Toluene, -78 °C

–

75%

–

3

Et3N (1.5 eq), CH2Cl2

–

–

95%

The preparation of mannose diketone 135 was executed in a similar manner (Scheme 25). Disappointingly,
all strong and weak basic conditions failed to generate an aldol product with the exception of L-proline, which
provided aldol 136 as the sole cyclohexanone in 60% yield.19

OHO1) 2-methoxypropene
p-TsOH, DMF
OH2) Ac2O, pyridine
61%
OH

O
HO
HO

93%

O

O

O
O

OH
O

O
134

133
O

O

O

88%

K2CO3
OAc MeOH

O

D-Mannose

MeMgBr
THF

O
O

OH
O

OH
O

O

1) (COCl)2, DMSO
3Å MS, CH2Cl2
2) DIPEA
75%

OH

O
O
O
O

O
135

L-proline

DMSO
60%

O

O
O

O
136

Scheme 25. Preparation of aldol 136 from D-mannose

We have also investigated an intramolecular direct aldolization of 2,7-diketones, in search for a synthetic
avenue towards hydroxylated cycloheptanones. The 2,7-diketones were prepared from D-ribose or D-mannose
using standard reactions and the results are summarized in Scheme 26.20

18

2018.7 No.178

O

HO

O

TBSO

OH

OH

O
L-proline

DMSO, 24 h

BnO
HO
OH
D-Ribose

O

TBSO

O

OH

O

OH

OBn DMSO, 21d
87%

O

O

OH

O

O

OH

HO

OBn O

OBn

BnO
O

O

138

D-Mannose

HO

O

TBSO

L-proline

BnO
HO

O

O
137

OH

HO

BnO

92%

O

O

O

TBSO

L-proline

DMSO, 3d

OH

TBSO

91%

O

O

D-Ribose

TBSO

TBSO

OH
O

O

+

OBn

O

OH
O

O

+

OBn

O

OH

TBSO
O

O

OBn
141 (17%)140 (19%)139 (55%)

O

Scheme 26. Summary of direct aldolization of 2,7-diketones from ribose and mannose

Application of the versatile intramolecular direct aldolization strategy to synthesis was demonstrated by thefollowing examples.

3a.  Synthesis of Valiolamine and Voglibose (AO128)
D-Glucose was transformed smoothly into aldol 131 as stated above. Oximation of the ketone moiety

in 131 followed by hydrogenation/hydrogenolysis furnished amine 142. Acidic removal of the acetals in 142
provided vailolamine 19 which, reportedly, could be converted into the anti-diabetic agent voglibose (AO128) 18(Scheme 27).19OHO

7 steps, 23.1%
overall yield

O
HO

OH

HO

O
MeO

OH
D-Glucose

TFA, H2O
CH2Cl2
88%

O

HO
HO

OH

1) NH2OH • HCl2) Raney Ni, H2O
EtOH, Et3N

HO

OH

85%

O
OMe
131

O

OH

O

NH2

O
MeO

O
OMe
142

OH
OH

NH2

HO
OH
Valiolamine 19

HO
HO

NH
OH
OH
Voglibose
AO-128 18

Scheme 27. Synthesis of valiolamine 19

19

2018.7 No.178

3b.  Synthesis of Pseudo-Acarviosin
Methyl acarviosin 143 was obtained from the natural anti-diabetic agent, acarbose, by acidic methanolysis(Figure 5). As methyl acarviosin is a stronger a-amylase inhibitor, we wanted to replace the sugar moiety in 143
with a cyclohexane to render the compound more stability in acid conditions. In search for an improved antidiabetic drug, we proceeded to synthesize pseudo-acarviosin 144 for biological screening.

HO

H3C

HO

N
H

HO
HO

HO

O

O

O

O

O

OH HO
OH HO
Acarbose

OH

OH HO

H3C

HO

N
H

HO

OH

HO

H3C

HO

N
H

HO

HO

OH HO

O
OMe

OH HO
OH
Methyl acarviosin 143

OH
OH

Pseudo-acarviosin 144

Figure 5. Acarbose and related compounds

Retrosythesis of pseudo-acarviosin 144 via a palladium catalysed allylic substitution would give two
fragments, an allylic chloride 145 and a cyclohexanyl amine 146. Chloride 145 would be accessed from
D-glucose via a direct aldol strategy while the amine 146 should be approached from L-arabinose through an

INAC reaction.21

O

HO
HO
HO

Pd(dba)2, TMPP
N
H
OH HO

OH

CH3CN, Et3N, rt

O
MeO

OH

144

H2N

Cl

O

O
OMe

+

OTBS

O
MeO

145

O
OMe
146

O
HO

dba =

TMPP =

O

O
OH HO

HO
O OO
P

HO

OH

OH

HO

D-GlucoseOH

L-Arabinose

Scheme 28. Retrosynthetic analysis of pseudo-acarviosin 144

The palladium-catalysed coupling plan is the result of a massive experimentation. We attempted a great
many coupling reaction conditions between different partners, amine with mesylate, ketone, allylic epoxide,
allyic cyclic sulphite, or allylic acetate.22 As most of the electrophiles are unstable under the conditions andelimination is the major side-reaction, none of the coupling reactions gave the desired product except for using
allylic chloride as the coupling partner shown in Scheme 29.23

20

2018.7 No.178

OBn
R1

N H
R2

+

Cl
O

OBn

OBn

Pd(dba)2, TMPP
Et3N, CH3CN

OBn

13-98% yield

1

R
N
R2

OBn
O

NMe2

OBn
O

Me2N

O

Scheme 29. Successful coupling reactions when allylic chloride was used

Since the coupling conditions were established, we started to construct the two coupling partners 145 and146. D-Glucose was converted into aldol 130 as said earlier.19 Elimination of the alcohol in 130 followed by
reduction of the ketone group in 147 produced allylic alcohol 148 which was separated from its epimer via anacetylation and deacetylation protocol. The isolated 148 was then transformed into the allylic chloride 145 bystandard reactions (Scheme 30).

OHO

7 steps, 25.3%
overall yield

O
HO

OH

L-proline, DMSOHOOH
D-Glucose

O

OH

O

O

O
MeO

O
OMe

POCl3
pyridine
99%

O

O

O
MeO

O
OMe

130
O

O

NaBH4,
CeCl3 • 7H2O

O
O
MeO

O
OMe

O

Ac2O, DMAP
OH Et N, CH Cl
3
2 2

O

OH

+

MeOH, –20 °C

147

O
MeO

O
OMe

98%

O
O
MeO

OAc
O
OMe

148
O

O
O

Cl

1) MsCl, Et3N
CH2Cl2

O
MeO

O
OMe

2) 3Å MS,nBu4NCl
84%

145

O
O
MeO

150

O
OH
O
OMe

K2CO3, MeOH

O

99%

O
MeO
149

OAc
O
OMe

Scheme 30. Preparation of allylic chloride 145 from D-glucose

On the other hand, the amine coupling partner 146 was assembled from L-arabinose via an INAC reactionof a protected hept-6-enose 151 as the key step (Scheme 31).21 The major exo-cycloadduct 154 with a transring fusion was formed with the correct stereochemistry. It is noteworthy that the trans-fused exo-cycloadductcould only be harvested with the nitrone containing a trans-diacetal blocking group. The cycloadduct 154 wastransformed readily into the cyclohexyl amine 146 using standard reactions with a good overall yield.

21

2018.7 No.178

O

OH

HO

BnNHOH • HCl

OH

10 stepsOH
L-Arabinose

O

O
Bn N

NaHCO3, CH3CN
rt, 100%

O

MeO

OMe
151
Bn

O
Bn N

2-propanol+O

40 °C, 9d

O

O
MeO

O
OMe
Bn
N

O

N

MeO

O

OH MeO

OH

O

OMe

OMe

OMe

154 (43%)

155 (29%)156 (7%)O
Bn N

TBSCl, imidazole
DMF, 100%

OH
OMe
OMs

1) Raney Ni, H2, EtOH

O

O

OTBS

2) MsCl, Et3N, CH2Cl2
86%

O

MeO
157

OMe

158

BnHN

BnHN

H2N

LiEt3BH, THF
OTBS

10% Pd/C, H2
O

90%

O

MeO

O
159

OMe

O

OMe

O

MeO

O

153 (19%)
O
Bn N

O

152

+
O

OH
O

OH

O
MeO

+

OH

MeO

MeO

O
Bn N

O

HO

OTBS EtOH, 100%

O
MeO

OTBS
O
OMe 146

OMe 160

Scheme 31. Preparation of amine 146 from L-arabinose

With the coupling partners in our hand, palladium catalysed allylic substitution of chloride 145 with amine
146 proceeded with retention of configuration to give the protected allylic amine 161 (Scheme 32). Hydrolysis
gave the target molecule pseudo-acarviosin 144 which was shown to be a stronger sucrose and glucoamylase
inhibitor than acarbose.21

O

O

O
O
MeO

Cl
O
OMe

+

Pd(dba)2, TMPPOTBS Et N, CH CN
3
3

H2 N
O
MeO

84%

O
OMe

O
MeO

146

145

H
N

O

O
MeO
OMe

O

161

HO
N
H

HO
144

HO

OH

OH
HO

TFA, H2O, CH 2Cl2
90%

OH

Scheme 32. Synthesis of pseudo-acarviosin 144

22

OTBS
O
OMe

2018.7 No.178

3c.  Synthesis of Validoxylamine G
Capitalising on the palladium-catalysed allylic substitution reaction, the silyl ether 162 of the afore-preparedamine 142 and allylic chloride 145 (both are direct aldol products from D-glucose) were coupled together to form
pseudo-glycosyl amine 163 which on complete acidic deprotection afforded validoxylamine G 164 in a goodyield (Scheme 33).19

O

OH

O
O
MeO

O
OMe

NH2

O

85%

O
MeO

HO

Cl

O
MeO

O
OMe
145

Pd(dba)2
TMPP
Et3N
CH3CN
99%

O

MeO
OTMS O

OMe
O

O

H
N

O

O
MeO

O
OMe

162

TFA
H2O
CH2Cl2

OH

HO

OH

N
H

OH

OH

OH

HO

O
+

O
OMe

142

HO

O

OTMS

O

TMSOTf
Et3N,
NH2 CH Cl
2 2

88%

Validoxylamine G 164

O163

Scheme 33. Synthesis of validoxylamine G 164

3d.  Synthesis of Gabosines
A number of gabosines were easily assembled from D-glucose via the direct aldol strategy. Only a few ofthem are illustrated here.24,25 Thus the aforesaid enone 147 was regio- and stereo-selectively reduced to thea-allylic alcohol 165 in an excellent yield (Scheme 34). Functional group manipulation of 165 with standard
reactions then furnished gabosine A, D, and E without incident.25
O

O
HO
O
HO

OH

8 steps, 25%
overall yield

HOOH
D-GlucoseO
TBSCl
imidazoleO
CH2Cl2

95%

O
MeO

O
MeO

O

O
MeO

O
OMe
147
HO

OTBS 80% AcOH

88%

O
OMe

R
HO

O

HO

K-selectride
THF
99%

O
OMe

OTBS

TFA, H2O
CH2Cl2

OH

O
MeO

O
OMe
165

1) MsCl
2) LiEt3BH, 84%

OTBS

O
MeO

O

or AcCl, 94%
or TBSCl, 97%

R
OTBS
O
OMe

PDC, 3Å MS
CH2Cl291-100%

O
O
MeO

O
OMe

R
O

87-90%HO

OH
OH(+)-Gabosine A R = H(+)-Gabosine D R = OAc(+)-Gabosine E R = OH

(178_RA_S34.eps)

Scheme 34. Syntheses of gabosine A, D, and E

232018.7 No.178

Carbocyclization of Carbohydrates via an Intramolecular
4 Horner–Wadsworth–Emmons (HWE) Olefination
Intramolecular HWE olefination was introduced at the beginning of this article, interestingly, it is perhaps
still the best strategy for a short and efficient carbocyclization of carbohydrate. Towards this end, we globallyprotected D-gluconolactone with 2-methoxypropene as mixed acetals 166 (Scheme 35).26 Addition of methyl
phosphonate carbanion followed by oxidation of the alcohol in 167 caused intramolecular HWE alkenation
to proceed concomitantly to give the protected cyclohexanone 169 in just 3 steps from the free sugar! Acidic
removal of the acetals afforded gabosine I 170 and regioselective acetylation at the primary alcohol provided
gabosine G 171. The relatively labile mixed acetal blocking groups were problematic, but we have circumvented
this obstacle with ethoxymethyl (EOM) protecting group.27

O
O
HO
HO

O

O

2-methoxypropene(±)-CSA, DMF
72%

OH

MeO

D-Gluconolactone

OEt
1) LDA, Me P
OEt

O

166

MeO

O
O
MeO
HO

CH2Cl2
95%

HO
HO

O
167

O
P OEt
OEt
OMe

O
O O

K2CO3, 43%

TFA, H2OO

OMeO
TPAP, NMO
3Å MS, CH3CN

OH O

O

THF, –78 °C

O

O

O

O

O

HO

O
168

O

O
O

MeO

OMe

AcCl
CollidineO–40 °C to rt
65%
OH(–)-Gabosine I 170

O

P OEt
OEt

O
OMe

169

AcO
HO
HO

O
OH

Gabosine G 171

Scheme 35. Syntheses of gabosine I and G

Since EOM protected cyclohexanone 172 could also be synthesized readily from D-gluconolactone (Scheme36), application of this route to the syntheses of streptol and other gabosines were accomplished.27,28 Exploiting
this facile carbocyclization strategy, we embarked on the construction of sodium-dependent glucose cotransporter
2 (SGLT2) inhibitors.

HO

EOMO

O
O

HO
HO

OH

D-Gluconolactone

in 3 steps as in Scheme 35

EOMO

O
OEOM

EOMO
172

Scheme 36. Synthesis of stable EOM blocked cyclohexanone 17224

2018.7 No.178

Sergliflozin is a potent SGLT2 inhibitor, but was abandoned for further investigation because phenyl
glycosides are prone to hydrolysis and therefore not suitable for development into useful medicine. Replacing
the sugar moiety in sergliflozin with a pseudo-sugar unit would provide a stable “glycoside” 173 as the “glycosidic
bond” is now an ether linkage (Figure 6).29

OMe

O

HO
HO

OMe

O

O

HO
OH

HO

OH

OH

OH
Pseudo-aryl Glucoside 173

Sergliflozin

Figure 6. Structures of sergliflozin and pseudo-aryl glucoside 173

The synthetic avenue towards pseudo glucopyranoside 173 is shown in Scheme 37. Regio- and stereoselective reduction of 172 gave a-alcohol 174 which was activated and displaced with chloride to b-chloride
175. Palladium catalysed allylic substitution of the allylic chloride 175 with phenolic alcohol 176 proceededwith retention of configuration to form allylic ether 177 in an excellent yield. Catalytic hydrogenation followedby acid removal of the EOM groups afforded the target molecule 173 which is a potent and selective SGLT2
inhibitor. Other analogs have also been made on extending this carbocyclization strategy.30,31

EOMO

EOMO
EOMO

O

LiEt3BH
THF, 76%

EOMO

OEOM

EOMO

EOMO

MsCl, Et3N

OH

EOMO

OEOM

Cl

EOMO

174

172

OEOM
175

EOMO

RO

EOMO
EOMO

EOMO

nBu NCl, 81%
4

Cl
OEOM
175

OMe

+ HO
176

Pd(dba)2, dppe

1) Pd(OH)2/C, EtOH
H2, rt2) HCl, H2O, EtOH

OMe

O

RO

K2CO3, CH3CN
94%

RO

OR

177

HO
HO
HO

5
1

O

OMe

OH

173, 66%

Scheme 37. Synthesis of pseudo-aryl glucopyranoside 17325

2018.7 No.178

Conclusion
In this Article, transformation of carbohydrates into highly oxygenated cycloalkanes and cycloalkenes
has been described using four synthetic strategies, namely intramolecular nitrone-alkene and nitrile oxidealkene cycloadditions, direct aldol addition, and Horner–Wadsworth–Emmons (HWE) olefination. The latterstrategy probably offers the most facile and efficient avenue to the pseudo-D-glucopyranose motif to date. The
carbocyclized intermediates could then elaborated into various target molecules containing hydroxyl/aminefunctional groups of defined stereochemistry. Considering the low cost, availability in large quantities, and richstereochemistry of sugar molecules, carbohydrates are perhaps the ideal starting materials for the constructionof heavily oxygenated natural products or molecules with pharmaceutical implication. Research towards thesyntheses of carbocyclic nucleosides should have received more attention.

Acknowlegments
The author wishes to thank the University of Manchester, the Chinese University of Hong Kong andthe Hong Kong Research Grant Council for supporting these works. Sincere gratitude goes to his researchcollaborators and co-workers for their efforts and stimulating ideas, especially to Professor Tohru Yamada of
Keio University for his unflagging support, encouragement, and friendship.

References1)	(a) O. Arjona, A. M. Gómez, J. C. López, J. Plumet, Chem. Rev. 2007, 107, 1919. (b) R. J. Ferrier, S.
Middleton, Chem. Rev. 1993, 93, 2779.
2.	(a) G. W. J. Fleet, T. K. M. Shing, J. Chem. Soc., Chem. Commun. 1983, 849. (b) G. W. J. Fleet, T. K. M.
Shing, S. W. Warr, J. Chem. Soc., Perkin Trans. 1 1984, 905.
3.	J.-J. Shie, J.-M. Fang, S.-Y. Wang, K.-C. Tsai, Y.-S. E. Cheng, A.-S. Yang, S.-C. Hsiao, C.-Y. Su, C.-H.
Wong, J. Am. Chem. Soc. 2007, 129, 11892.
4.	(a) B. Drager, Nat. Prod. Rep. 2004, 21, 211. (b) N. Asano, Curr. Top. Med. Chem. 2003, 3, 471.
5.	(a) K. Tatsuta, T. Tsuchiya, N. Mikami, S. Umezawa, H. Umezawa, H. Naganawa, J. Antibiotics 1974, 27,579. (b) G. Bach, S. Breiding-Mack, S. Grabley, P. Hammann, K. Hütter, R. Thiericke, H. Uhr, J. Wink, A.
Zeeck, Liebig. Ann. Chem. 1993, 3, 241. (c) Y.-Q. Tang, C. Maul, R. Höfs, I. Sattler, S. Grabley, X.-Z. Feng,
A. Zeeck, R, Thiericke, Eur. J. Org. Chem. 2000, 1, 149.
6. T. K. M. Shing, D. A. Elsley, J. G. Gillhouley, J. Chem. Soc., Chem. Commun. 1989, 1280.
7.	J. J. Tufariello, In 1,3-Dipolar Cycloaddition Chemistry, ed. by A. Padwa, Wiley, New York, 1984, Vol. 2,
pp. 83-168.
8. T. K. M. Shing, A. W. F. Wong, T. Ikeno, T. Yamada, J. Org. Chem. 2006, 71, 3253.
9. T. K. M. Shing, A. W. F. Wong, T. Ikeno, T. Yamada, Chem. Eur. J. 2009, 15, 2693.
10. T. K. M. Shing, A. W. F. Wong, T. Ikeno, T. Yamada, Org. Lett. 2007, 9, 207.
11. T. K. M. Shing, K. H. So, unpublished results.
12.	E. G. Baggiolini, J. A. Iacobelli, B. M. Hennesy, A. D. Batcho, J. F. Sereno, M. R. Uskokovic, J. Org. Chem.
1986, 51, 3098.
13. T. K. M. Shing, K. H. So, Org. Lett. 2011, 13, 2916.
14. Y.-L. Zhong, T. K. M. Shing, J. Org. Chem. 1997, 62, 2622.
15.	(a) A. Pal, A. Bhattacharjee, A. Bhattacharjya, A. Patra, Tetrahedron 1999, 55, 4123. (b) S. Majumdar, R.
Mukhopadhyay, A. Bhattacharjya, Tetrahedron 2000, 56, 8945.

26

2018.7 No.178

16.	P. Caramella, P. Grünanger, In 1,3-Dipolar Cycloaddition Chemistry, ed. by A. Padwa, Wiley, New York,
1984, Vol. 1, pp. 291-392.
17. T. K. M. Shing, W. F. Wong, H. M. Cheng, W. S. Kwok, K. H. So, Org. Lett. 2007, 9, 753.
18. T. K. M. Shing, K. H. So, W. S. Kwok, Org. Lett. 2009, 11, 5070.
19. T. K. M. Shing, H. M. Cheng, Org. Lett. 2008, 10, 4137.
20. T. K. M. Shing, H. M. Cheng, Org. Biomol. Chem. 2015, 13, 4795.
21.	T. K. M. Shing, H. M. Cheng, W. F. Wong, C. S. K. Kwong, J. Li, C. B. S. Lau, P. S. Leung, C. H. K. Cheng,
Org. Lett. 2008, 10, 3145.
22. T. K. M. Shing, S. H.-L. Kok, unpublished results.
23.	(a) T. K. M. Shing, S. H.-L. Kok, Tetrahedron Lett. 2000, 41, 6865. (b) T. K. M. Shing, C. S. K. Kwong, A. W.
C. Cheung, S. H.-L. Kok, Z. Yu, J. Li, C. H. K. Cheng, J. Am. Chem. Soc. 2004, 126, 15990.
24. T. K. M. Shing, H. M. Cheng, Synlett 2010, 21, 142.
25. T. K. M. Shing, H. M. Cheng, Org. Biomol. Chem. 2009, 7, 5098.
26. T. K. M. Shing, H. M. Cheng, J. Org. Chem. 2007, 72, 6610.
27. T. K. M. Shing, Y. Chen, W.-L. Ng, Synlett 2011, 22, 1318.
28. T. K. M. Shing, Y. Chen, H. T. Wu, Synlett 2012, 23, 1793.
29. T. K. M. Shing, W.-L. Ng, J. Y.-W. Chan, C. B.-S. Lau, Angew. Chem. Int. Ed. 2013, 52, 8401.
30. W.-L. Ng, K.-M. Lau, C. B.-S. Lau, T. K. M. Shing, Angew. Chem. Int. Ed. 2016, 55, 13818.
31. W.-L. Ng, H.-C. Li, K.-M. Lau, A. K. N. Chan, C. B.-S. Lau, T. K. M. Shing, Sci. Rep. 2017, 7, 5581.

執筆者紹介

Tony K. M. Shing
Professor, D.Sc.

Department of Chemistry, Faculty of Science and Technology, Keio University
Professor Tony K. M. Shing obtained his first degree from the University of Hong Kong,
his M.Sc. (analytical chemistry), Ph.D. (carbohydrate chemistry) and D.Sc. (organic
synthesis) degrees from the University of London. After postdoctoral work at McGill
University and Oxford University, Prof. Shing began his independent career at the
University of Manchester England, as a New Blood Lecturer in 1984. He was visiting
Associate Professor at the University of California, Irvine, before returning to Hong
Kong in 1990. He joined the Department of Chemistry at the Chinese University ofHong Kong (CUHK) as a Lecturer, was promoted to Senior Lecturer in 1993, and to fullProfessor in 1996. In 2016 August, he retired from CUHK and joined Sophia University
as an Invited Visiting Professor. Professor Shing moved to Keio University in October last year and is now afull Professor at the Department of Chemistry. He is also the Chairman of the Hong Kong Section of the Royal
Society of Chemistry. His research interest is on the syntheses of organic molecules with chemotherapeuticpotential, namely anti-cancer, anti-viral, or anti-diabetic activity.

27

2018.7 No.178

筒状炭素分子：(6,6) カーボンナノベルト
I1078 (6,6)Carbon Nanobelt Bis(tetrahydrofuran) Adduct (1)10mg 12,000 円

カーボンナノベルトは，ベンゼン環が縮環して筒状の構造をもつ炭素分子の総称として提唱され，その歴史は 1954 年に文献に記載されたことに始まります 1)。その後，さまざまな筒状炭素分子が提案され，多くの化学者がそれらの合成に挑戦しました 2)。1991 年にカーボンナノチューブが発見されると 3)，カーボンナノベルトがカーボンナノチューブの部分構造であることが明らかになり，
ますます注目を集めるようになりました。一方，カーボンナノベルトは，ベンゼン環が筒状に曲がることで大きなひずみが生じるため，有効な合成法はこれまで報告されていませんでした。
伊丹，瀬川らのグループは，ひずみのない環状分子を筒状構造に変換する方法で，パラキシレンから 11 段階で 1 を合成することに成功しました 4)。得られた 1 の基礎物性は，各種分光学的手法により解析されました。X 線を用いた構造解析法から，カーボンナノベルトはカーボンナノチューブと同様の筒状構造をもつことが明らかになりました。また，可視光の吸収および蛍光の分析からは，構造の剛直さや筒状構造全体に電子が通る性質が観測されるとともに，(6,6) カーボンナノチューブに非常に近い性質をもつ分子であることがラマン分光法によって実証されました 4)。
カーボンナノベルトは，単一構造からなるカーボンナノチューブの合成の実現や，新しい機能性
材料開発の道を拓くことが期待され，今後のナノカーボン科学を一新する分子です。今回得られた
カーボンナノベルトは赤色蛍光を発する有機分子で，発光材料や半導体材料として各種電子デバイスに搭載できる可能性があります。さらに，カーボンナノベルトをテンプレートにした製法で単一構造のカーボンナノチューブが得られれば，軽くて曲げられるディスプレイや省電力の超集積
CPU，バッテリーや太陽電池の効率化など，非常に幅広い応用が期待されます。

図 1.

(6,6)Carbon Nanobelt (1)

関連製品

図 2.

28

(6,6)Carbon Nanotube の模式図

2018.7 No.178

Scheme 1.

文献1) Molecular orbitals in homologen Reihen mehrkerniger aromatischer Kohlenwasserstoffe: I. Die Eigenwerte
yon LCAO-MO's in homologen Reihen
E. Heilbronner, Helv. Chim. Acta. 1954, 37, 921.
2) for example:a) F. H. Kohnke, A. M. Z. Slawin, J. F. Stoddart, D. J. Williams, Angew. Chem. Int. Ed. Engl. 1987, 26, 892. b) S.
Kammermeier, P. G. Jones, R. Herges, Angew. Chem. Int. Ed. Engl. 1996, 35, 2669. c) F. Vögtle, A. Schroder, D.
Karbach, Angew. Chem. Int. Ed. Engl. 1991, 30, 575. d) L. T. Scott, Angew. Chem. Int. Ed. 2003, 42, 4133. e) B.
L. Merner, L. N. Dawe, G. J. Bodwell, Angew. Chem. Int. Ed. 2009, 48, 5487.
3) Helical microtubules of graphitic carbon
S. Iijima, Nature 1991, 354, 56.
4) Synthesis of a Carbon Nanobelt
G. Povie, Y. Segawa, T. Nishihara, Y. Miyauchi, K. Itami, Science 2017, 356, 172.

29

2018.7 No.178

高性能な液晶性半導体材料：Ph-BTBT-10
100mg 32,500 円 250mg 68,500 円

D5491 Ph-BTBT-10 (1)S(CH2)9CH3
S

Ph-BTBT-10 (1)液晶性半導体材料 Ph-BTBT-10（1）は，近年報告された有機半導体材料の中でも特に優れたキャ
リア輸送特性を示す p 型半導体材料です（図 1）。半那らはスピンコート法で作製した FET 素子において，酸化物半導体（IGZO）と同等の移動度（μ max = 14.7 cm2/Vs）と大気安定性を有することを報告しています 1)。そこで，このような特性をもつ液晶性半導体材料である 1 について，蒸着法
による OFET 素子の作製および評価検討を行いました。また，1 の蒸着膜の構造解析とアニール処
理後の結晶構造の変化について 2D-GIXD による調査・解析も実施しています 2,3)。
(a)

図 1. OFET 素子構造(b)

VD = 60 V

VD = 50 V

図 2. 蒸着型 OFET 素子の伝達特性(a) w/o annealing (ODTS)(b) annealing 120 °C, 5 min (ODTS)

表 1. Ph-BTBT-10 を用いた蒸着型 OFET 素子特性
CompoundSAM

bare
Ph-BTBT-10
(1)
ODTS

Annealing Temp.
(°C)

Mobility(cm2/Vs)

Vth
(V)

w/o

0.87 ~ 0.91

-24

120

4.24 ~ 4.86

-8

w/o

1.40 ~ 1.42

-23

120

10.3 ~ 14.0

-22

関連製品
蒸着法によりトップコンタクト型の FET 素子を作製しました（図 1）。素子の FET 特性を図 2 お
よび表 1 に示します。全ての素子において安定な p 型半導体特性が得られ，かつ，Self-assemblemonolayer（SAM）の有無に関わらず，アニーリング処理（120 °C，5 min）を行うことで FET 性能の大幅な向上が見られました。bare 基板における素子性能はホール移動度 μ max = 4.86 cm2/Vs，V th= ‒8 V の良好な値が得られ，ODTS 処理基板では閾値電圧は大きい（V th = ‒22 V）ものの I DS が大幅に増加し，ホール移動度 μ max = 14.0 cm2/Vs の良好な値が得られました。

30

2018.7 No.178

bare

ODTS

3. 2D-GIXD
in-situ
図 3. 2D-GIXD
解析（加熱in-situ 測定）

4. 2D-GIXD解析（Out-of-plane,
Out-of-plane bare
図 4. 2D-GIXD
bare 基板）1
図 5. 15.の相転移イメージ

Ph-BTBT-10 薄膜の加熱 in situ 2D-GIXD 測定データを図 3，4 に示します 2,3)。室温および 60 °
C にて単分子層に起因するピークが得られ，その層間距離（d ）は 27 Å 程度であることがわかりました。一方，120 °C まで昇温した場合，回折ピークに明確な変化が現れることから，単分子層（d = 27 Å）から 2 分子層（d = 54 Å）への転移が起こったと考えられます（図 4，5）。液晶相（SmE）への相転移温
度は 144 °C であり 1)，180 °
C の加熱条件下では SmE に由来する回折ピークが観測されています
（図 4）
。
また，
180 °
C（SmE）から室温へ急冷却すると，単分子層と 2 分子層の混合層を発現することが示唆され，本系において冷却速度は均一な結晶膜を得るために極めて重要なファクターであると推測されます。
以上の結果から，蒸着法により成膜した Ph-BTBT-10 膜においても，単分子層から 2 分子層へ転移することがわかりました。本解析結果は，実際の FET 特性の大幅な変動と一致します。1 は既に報告されている塗布法に加えて，蒸着法でも使用可能な高い実用的有機半導体材料であることが見出されました。
文献
1) Liquid crystals for organic thin-film transistors
H. Iino, T. Usui, J. Hanna, Nat. Commun. 2015, 6, 6828.
2) 2D-GIXD experiments were performed at the BL46XU and BL19B2 of SPring-8 with the approval of the Japan
Synchrotron Radiation Research Institute (JASRI) (Proposal No. 2017B1817 and 2017B1629).
We acknowledge Prof. Noriyuki Yoshimoto, Assist. Prof. Daiki Kuzuhara and Mr. Shimpei Miura (Iwate Univ.),
Assist. Prof. Mitsuharu Suzuki (NAIST) and Dr. Tomoyuki Koganezawa (JASRI) for technical support in GIXD.
3) 三浦他，第 65 回応用物理学会春季学術講演会 20a-P7-1.

31

2018.7 No.178

光学活性なシクロプロパンの合成に有用な不斉ルテニウム触媒
200mg 6,600 円 1g 23,100 円

R0196 Ru(II)-(S)-Pheox Catalyst (1)Ru(II)-(S )-Pheox 触媒（1）は，岩佐らにより開発されたキラルフェニルオキサゾリン – ルテニウ
ム (II) 錯体であり，光学活性シクロプロパンの合成に用いることができます。1 の存在下，オレフィン類にジアゾ酢酸エステル 1-6,8) あるいはジアゾメチルホスホン酸エステル 7,8) を作用させると，エ
ナンチオ選択的なシクロプロパン化反応が進行します。本反応は，医薬開発に有用な光学活性シク
ロプロパンの合成への利用が期待されます。

(NCCH3)4
Ru

PF6

N
O

1
O

O
R1

+

N2

OR2

1 (1-5 mol%)

1-6,8)

OR2

R1

up to 99% yield
up to >99:1 dr
up to 99% ee

H
O
R3

+

N2

P

O
OEt

1 (3 mol%)

OEt

CH2Cl2, rt, 5 h

P
R3

OEt
OEt

7,8)
up to 93% yield
up to >99:1 dr
up to 99% ee

H文献1) A.-M. Abu-Elfotoh, K. Phomkeona, K. Shibatomi, S. Iwasa, Angew. Chem. Int. Ed. 2010, 49, 8439.
2) S. Chanthamath, K. Phomkeona, K. Shibatomi, S. Iwasa, Chem. Commun. 2012, 48, 7750.
3) S. Chanthamath, D. T. Nguyen, K. Shibatomi, S. Iwasa, Org. Lett. 2013, 15, 772.
4) S. Chanthamath, D. S. Takaki, K. Shibatomi, S. Iwasa, Angew. Chem. Int. Ed. 2013, 52, 5818.
5) S. Chanthamath, H. W. Chua, S. Kimura, K. Shibatomi, S. Iwasa, Org. Lett. 2014, 16, 3408.
6)関連製品Y. Nakagawa, S. Chanthamath, K. Shibatomi, S. Iwasa, Org. Lett. 2015, 17, 2792.
7) S. Chanthamath, S. Ozaki, K. Shibatomi, S. Iwasa, Org. Lett. 2014, 16, 3012.
8) S. Chanthamath, S. Iwasa, Acc. Chem. Res. 2016, 46, 2080.

関連製品
D5368 (S)-Pheox

32

1g 5,500 円 5g 18,600 円

2018.7 No.178

ペルオキシダーゼ用調製済み基質溶液
100mL 10,000 円
A3176 AzBTS (Ready-to-use solution) [for ELISA] (1)C3384 4-CN (= 4-Chloro-1-naphthol) (Ready-to-use solution) [for Western blotting] (2)100mL 10,000 円
ペルオキシダーゼは過酸化水素の存在下，基質を酸化させる作用をもつ酵素で，生化学の実験に広く用いられています。1 および 2 は，ペルオキシダーゼ検出に使用する調製済み基質溶液であり，それぞれ以下に示した手順により検出を行うことができます。
AzBTS (Ready-to-use solution)（1）は基質である 2,2'- アジノビス (3-エチルベンゾチアゾリン-6-スルホン酸 アンモニウム塩)（AzBTS）と過酸化水素を含む ELISA 用調製済み溶液で，ペルオキ
シダーゼと反応すると可溶性の緑色生成物を生じます。生成物は 405 nm の吸光度で測定可能です。
使用方法：96 ウェルプレートを用いた使用方法を示します。
1. 1 を室温に戻し，軽く混ぜる。
2. 1 を各ウェルに 100 μL ずつ加える。
3. 室温で 30 分間反応させる。
4. 反応開始後，1 時間以内に 405 nm の吸光度を
測定する。

図 1.

96 ウェルプレートを用いた使用例

4-CN (Ready-to-use solution)（2）は基質である 4-CN（4-クロロ-1-ナフトール）と過酸化水素を含むウェスタンブロット用調製済み溶液で，ペルオキシダーゼ（HRP）と反応すると沈殿性の青色生成物を生じます。
使用方法：
1. HRP 標識された検出用抗体でメンブレン処理
し洗浄する。
2. メンブレンに 2 を加え発色させる。
3. 溶液を捨て，メンブレンに純水を加えて反応を

kDa
70
45

M
1 Target protein A(Middle concentration)
2 Target protein A(Low concentration)32

停止させる。
M

1

図 2.

2

ウェスタンブロットの例

本製品はいずれも試薬であり，試験・研究用のみにご使用ください。

文献1) Antibodies, A Laboratory Manual, ed. by E. Harlow and D. Lane, Cold Spring Harbor Laboratory Press, New
York, 1988, p. 404, p. 506, p. 594.

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2018.7 No.178

c-Jun N 末端キナーゼ（JNK）阻害剤：SU 3327
20mg 20,500 円 100mg 71,000 円

A2940 SU 3327 (1)
N N

N
O2N

S

S

S

NH2

1
SU 3327（1）は構造活性相関の研究に基づいて開発された JNK（c-Jun N-terminal kinase）の阻害剤です 1)。1 は活性化転写因子 -2（ATF-2）の JNK 1 によるリン酸化を IC50 = 0.7 μM で基質競合的に阻害します。また，1 は JNK と JIP1* のタンパク質間相互作用を IC50 = 239 nM で阻害します。
JNK の一つの機能として，この酵素は Table 1 に示すような刺激によるオートファジーの誘導に関与していることが知られています。マウスのモデル系において急性アルコール処理によるオート
ファジーの減少が 1 によって防止されることが示されています 2) 。
*JIP1: JNK 相互作用タンパク質（JNK-interacting protein; JIP）は JNK の足場タンパク質として同定されました
3,4)。JIP1 は JIP ファミリーの 1 つで，JNK 結合ドメイン（JNK binding domain; JBD)，SRC 相同 (SH3) ドメイ
ン，ホスホチロシン結合（phosphotyrosine-binding; PTB）ドメインを有しています。JBD はコンセンサス配列
R/KXXXXLXL を有します 5)。文献 1 で使用されているプローブ pep-JIP1 にはこの配列が含まれます。

Table 1. Autophagy by various stimuli implicating JNK

Stimulation
Neuronal excitotoxic stimuli
Caspase inhibition
Starvation
T-cell receptor activation
Cytokine stimulation
ER stress

References
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J. Immunol. 2006, 177, 5163.
J. Immunol. 2006, 177, 5163.
Immunol. Cell Biol. 2006, 84, 448.
Mol. Cell. Biol. 2006, 26, 9220.

本製品は試薬であり，試験・研究用のみにご使用ください。

文献1) Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active
triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase
S. K. De, J. L. Stebbins, L.-H. Chen, M. Riel-Mehan, T. Machleidt, R. Dahl, H. Yuan, A. Emdadi, E. Barile, V.
Chen, R. Murphy, M. Pellecchia, J. Med. Chem. 2009, 52, 1943.
関連製品
2) Cytochrome P4502E1, oxidative stress, JNK and autophagy in acute alcohol-induced fatty liver
L. Yang, D.-F. Wu, X.-D. Wang, A. I. Cederbaum, Free Radic. Biol. Med. 2012, 53, 1170.
3) Scaffold proteins of MAP-kinase modules
D. N. Dhanasekaran, K. Kashef, C. M. Lee, H. Xu, E. P. Reddy, Oncogene 2007, 26, 3185.
4) A mammalian Scaffold complex that selectively mediated MAP kinase activation
A. J. Whitmarsh, J. Cavanagh, C. Tournier, J. Yasuda, R. J. Davis, Science 1998, 281, 1671.
5) Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1
S.-H. Yang, A. J. Whitmarsh, R. J. Davis, A. D. Sharrocks, EMBO J. 1998, 17, 1740.

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2018.7 No.178

シクロオキシゲナーゼ（COX）阻害剤：フルルビプロフェン
5g 10,400 円 25g 30,700 円

F0371 Flurbiprofen (1)FO
CH C OH
CH3

1

フルルビプロフェン（1）はシクロオキシゲナーゼ（COX）阻害剤の一種で，COX-1 と COX-2 をそれぞれ 0.1 μM，0.4 μM の IC50 で阻害します 1)。1 はラセミ体混合物として存在し，S 体は R 体
よりも強く COX イソ酵素を阻害します 2,3)。また，1 は非ステロイド性抗炎症剤として広く知られています 1)。さらに 1 は，ヒト胚性幹細胞の自己複製と多機能性を維持します 4,5)。
* 文献 1 では組み替え体のヒト COX-1 と COX-2 が使用されています。

本製品は試薬であり，試験・研究用のみにご使用ください。

文献
1) Expression and selective inhibition of the constitutive and inducible forms of human cyclo-oxygenase
J. K. Gierse, S. D. Hauser, D. P. Creely, C. Koboldt, S. H. Rangwala, P. C. Isakson, K. Seibert, Biochem. J. 1995,
305, 479.
2) Stoichiometric and kinetics of the interaction of prostaglandin H synthase with anti-inflammatory agents
R. J. Kulmacz, W. E. Lands, J. Biol. Chem. 1985, 260, 12572.
3) Flurprofen and enantiomers in ophthalmic solution tested as inhibitors of prostanoid synthesis in human blood
N. J. van Haeringen, A. A. van Sorge, J. L. van Delft, V. M. W. Carballosa Coré-Bodelier, J. Ocul. Pharmacol.
Ther. 2000, 16, 345.
4) High-throughput screening assay for the identification of compounds regulating self-renewal and differentiationin human embryonic stem cells
S. C. Desbordes, D. G. Placantonakis, A. Ciro, N. D. Socci, G. Lee, H. Djaballah, L. Studer, Cell Stem Cell
2008, 2, 602.
5) Histone modification profiling reveals differential signatures associated with human embryonic stem cell selfrenewal and differentiation
N. V. Bhanu, S. Sidoli, B. A. Garcia, Proteomics 2016, 16, 448.

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