SV (SHORT VISIT)PROGRAM
Zhong and Mase Laboratories
Tuesday, February 26 – Monday, March 4, 2013at Hangzhou Normal University in China

Just enjoy research and discussion!!
Just enjoy the beginning of a friendship!!
And just enjoy more and more!!
Supported byHangzhou Normal University (China)
Shizuoka University (Japan)

Mini Conference Program
SV (Short visit) Program between Zhong and Mase Laboratories
February 28, 2013 (Thu) 13:00 - 16:00 at Hangzhou Normal University, College of Materials,
Chemistry & Chemical Engineering, Room #518, Hangzhou, Zhejiang (China)
Opening remarks 13:00 - 13:05 (Prof. Nobuyuki MASE)
1st Session 13:05 - 14:30 (Chairman: Takahiro KATO [Mase Laboratory])
15 min / person (10 min: Presentation / 4 min: Discussion / 1 min: change)
1. Yue DENG (Zhong Laboratory / Graduate student, 2nd year) 13:05-13:20“Catalytic Asymmetric [4+2] Annulation Initiated by an Aza-Rauhut–Currier Reaction:
Facile Entry to Highly Functionalized Tetrahydropyridines”
2. Katsuyuki INAZAWA (Mase Laboratory / Undergraduate student, 4th year) 13:20-13:35“Development of Environmentally-Friendly Organic Synthesis with Micronanobubble
Strategy to Increase Gas Concentration in Liquid Phase Reactions”
3. Youqiang LIN (Zhong Laboratory / Graduate student, 2nd year) 13:35-13:50“Core Structure-Based Design of Organocatalytic [3+2]-Cycloaddition Reactions: Highly
Efficient and Stereocontrolled Syntheses of 3,3’-Pyrrolidonyl Spirooxindoles”
4. Aiko SASAKI (Mase Laboratory / Undergraduate student, 4th year) 13:50-14:05“Development of Efficient Catalyst Screening by Fluorescence Monitoring Using OFF-ON
Fluorogenic Sensors”
Break time 14:05-14:30
2nd Session 14:30-15:50 (Chairman: Yue DENG [Zhong Laboratory])
5. Hoshimi JITSUKATA (Mase Laboratory / Undergraduate student, 4th year) 14:30-14:45“Synthesis of Quantum Dot/Hydroxy-apo-10’-carotenal Conjugates for in vivo Visualizationof Carotenoid-derived Volatile Compounds”
6. Dongdong CHEN (Zhong Laboratory / Graduate student, 1st year) 14:45-15:00“Chiral Brønsted Acid Catalyzed Enantioselective alpha-Aminoxylation of Enecarbamates”
7. Shoji YAMAMOTO (Mase Laboratory / Undergraduate student, 4th year) 15:00-15:15“Organocatalytic Ring-Opening Polymerization of L-Lactide in Supercritical Carbon
Dioxide”
8. Zhiming ZHANG (Zhong Laboratory / Graduate student, 1st year) 15:15-15:30“N-Heterocyclic Carbene (NHC)-Catalyzed Highly Diastereo- and Enantioselective
Oxo-Diels_Alder Reactions for Synthesis of Fused Pyrano[2,3-b]indoles”
9. Takahiro Kato (Mase Laboratory / Graduate student, 2nd year) 15:30-15:45“Organocatalytic Michael Addition Using 2-Aminopyridine Catalyst Based on Molecular
Recognition”
Closing remarks 15:45 – 15:50 (Prof. Guofu ZHONG)

A participants list
From China
Name

E-mailProf. Dr. Guofu ZHONG

zgf@hznu.edu.cn

Ms. Yue DENG (Master student, 2nd year)

dysdy1314@yahoo.cn

nd

Mr. Youqiang LIN (Master student, 2 year)

lyq19881230@163.com

Ms. Dongdong CHEN (Master student, 1st year)

cddhyc@163.com

st

Mr. Zhiming ZHANG (Master student, 1 year)

zzmoliver@126.com

From Japan
Name

E-mailProf. Dr. Nobuyuki MASE

tnmase@ipc.shizuoka.ac.jp
ndMr. Takahiro KATO (Master student, 2 year)f0130189@ipc.shizuoka.ac.jp

Mr. Katsuyuki INAZAWA (Undergraduate student, 4th year)

f0812018@ipc.shizuoka.ac.jp

thMs. Aiko SASAKI (Undergraduate student, 4 year)

f0912057@ipc.shizuoka.ac.jp

Ms. Hoshimi JITSUKATA (Undergraduate student, 4th year)

f0912062@ipc.shizuoka.ac.jp

thMr. Shoji YAMAMOTO (Undergraduate student, 4 year)

f0912139@ipc.shizuoka.ac.jp

ItineraryDate
2/26 (Tue)

Arrive at Hangzhou Xiaoshan International Airport (HGH)
09:35(NRT) => 12:25 (HGH) ANA929

Stay at the Zhejiang University of Finance and Economics Hotel during 2/26-3/3 (6 days).
Address: No.18, Xueyuan Street, Jianggan district, Hangzhou
2/27 (Wed)

Visiting Hangzhou Normal University

2/28 (Thu)

Mini conference
Drinking party

3/1 (Fri)

Attend a class of organic chemistry

3/2 (Sat)

Sightseeing in Shanghai

3/3 (Sun)

Sightseeing in Hangzhou

3/4 (Mon)

Depart from China
13:45(HGH) => 17:40(NRT) ANA930

Catalytic Asymmetric [4+2] Annulation Initiated by an Aza-Rauhut–Currier Reaction:
Facile Entry to Highly Functionalized Tetrahydropyridines
Zugui Shi, Yue Deng, Guofu Zhong*College of Materials, Chemistry and Chemical Engineering Hangzhou Normal University
16 Xue-Lin Street, Hangzhou 310036, Zhejiang (China)
zgf@hznu.edu.cn
Chiral tetrahydropyridines are important organic synthons. They can be readily reduced to piperidines,
which frequently occur in many natural products of biological relevance. Existing methodologies for their
preparation are largely attributed to the aza-Diels–Alder reaction of N-sulfonly-1-aza-1,3-butadiene withelectron-rich dieno-philes, and the [4+2] annulation reaction of 2-methylene-but-3-enoate with imines,
which are either limited by a narrow substrate scope or restricted by rigorous reaction conditions. Thus, thedevelopment of a more general and efficient protocol is highly desirable. As part of our long-standing
interest in organocatalysis, and on the basis of our recent achievement, we report herein an alternative
approach to the synthesis of enantioenriched tetrahydropyridines by a catalytic asymmetric [4+2]annulation pathway initiated by an aza-Rauhut–Currier reaction using chiral phosphine catalysts derived
from natural amino acids. To the best of our knowledge, this is the first example of the catalytic
asymmetric cross-aza-Rauhut–Currier reaction.
With the optimal reaction conditions established, the scope of the 1-aza-1,3-dienes was then explored(Table 2). In the presence of 10 mol% 4p, ortho-, meta-, and para-substituted aryl 1-aza-1,3-dienes
underwent the [4+2] annu- lation process with MVK smoothly, thus generating tetrahy-dropyridine adductswith exclusively transdiastereoselectivity and excellent enantioselectivity in high to excellent chemicalyields. Halogenated substrates, which can participate in subsequent transformations such as coupling
reactions, were well tolerated in this reaction (entries 4, 5, 7, and 9). Chiral fluorinated heterocycles, which
often have superior biological properties relative to their nonfluorinated counterparts, could also be
efficiently synthesized (entries 2 and 10). The electronic nature of the ring system slightly influenced thereaction outcome, with electron-rich substrates delivering products under better enantiocontrol (entries 3
and 6). More sterically demanding 2-naphthyl-substituted N-4-methoxy-benzenesulfonyl-1-aza-1,3-diene
proved to be a suitable sub-strate to give a [4+2] adduct with greater than 95:5 d.r. and 95%eein 78% yield(entry 11). Further exploration revealed that this methodology had remarkable tolerance for the Lewis
basic 4-heteroaryl-1-aza-1,3-diene, thus enabling the highly diastereo- and enantioselective synthesis ofthienyl- and furyl-substituted tetrahydropyridines (entries 13 and 14). Notably, the reaction could befurther extended to aliphatic 1,3-azadienes, for instance, a simple methyl-substituted azadiene participatedin this [4+2] annulation process, thus affording product with excellent stereocontrol, in good yield (entry
15). Additionally, ethyl vinyl ketone (1b) proved to be a suitable substrate in this transformation (entry 16).

Table 1: Generality of [4+2] annulation reaction.[a]Although the detailedmechanism is not clear at this stage, a transition state is proposed to account forthe observed stereochemistry. The hydrogen bonding between the pivaloyl amide and the 1,3-azadiene
could direct the alkene side chain outwards to a sterically less-demanding area and away from the bulky
pivaloyl group, thus the enolate generated by nucleophilic addition of the phosphine moiety, preferentiallyattacks from the Si face. Subsequent intramolecular proton transfer deliveres the enolate inter-mediateC.
After expulsion of the catalyst, an intramolecular Micheal addition occurrs to generate the final [4+2]annulation product.
In summary, an unprecedented catalytic asymmetric [4+2] annulation reaction initiated by anaza-Rauhut–Currier reaction has been developed by utilizing amino phosphine catalysts derived fromnatural amino acids. This protocol provides a new entry to the synthesis of a broad spectrum of densely
functionalized tetrahydropyridines with high stereo-control in good to excellent yields. Further mechanistic
investigations and applications to the synthesis of biologically active molecular complexes are currently
underway in our laboratory, and will be reported in due course.
Reference: Shi, Z.; Yu, P.; Loh, T.-P.; Zhong, Guofu* Angew. Chem. Int. Ed., 2012, 51, 7825-7829.

Development of Environmentally-Friendly Organic Synthesis with
Micronanobubble Strategy to Increase Gas Concentration in Liquid Phase Reactions
Katsuyuki Inazawa, Nobuyuki Mase
Department of Molecular Science, Faculty of Engineering, Shizuoka University
3-5-1 Johoku, Hamamatsu, 432-8561, Japantnmase@ipc.shizuoka.ac.jp
Micronanobubbles

possess

characteristic

properties

incomparison with usual cm-mm scale bubbles. For example,
micronanobubbles exhibit excellent gas-dissolution abilities
because of larger gas/liquid interfacial areas; in addition, alonger stagnation in liquid phase compared to cm-mm bubbles
is monitored owing to their small buoyancy. These phenomena
cause micronanobubbles gradually to decrease in size, with
eventual disappearance into the liquid phase (Figure 1). Here
we proposed a new experimental methodology for gas/liquid
methods involving vigorous stirring or high pressure to increase
the interfacial surface between gas and liquid.
Prior to start this study, a special micronanobubble generator,
which is resistant to corrosion with acids, bases, and organic
solvents, was produced. Performance evaluations of dissolved
oxygenlevelsindistilledwater

showedthatthemicronanobubble generator rapidly supersaturated without

Figure 1. Properties of micronanobubble
140

Oxygen saturation factor (%)

phase reactions using micronanobubble instead of conventional

Micronanobubble
120

Bubbling

100
80

Open

60
40
0

10

20

30

40

50

60

Time (min)Figure 2. Degree of oxygen saturation

stirring. After stopping the air supply for 20 minutes, itremained oversaturated for at least 40 min (Figure 2). On the other hand, air bubbling at an air-flow rate 3
mL/min using a conventional gas dispersion tube with a porous fritted glass tip resulted in low saturationof oxygen after 60 minutes with vigorous stirring.
Encouraged by these results, we started to investigate novel micronanobubble strategies in aerobic
oxidation, which is one of the most fundamental methods to oxidize alcohols to corresponding carbonylcompounds in modern organic synthesis. As a model reaction, we chose copper-TEMPO catalytic systemdeveloped by Sheldon Group (Table 1). The best result was achieved under micronanobubble condition, in
which the desired benzaldehyde (2) was obtained in 94% conversion (entry 7). On the other hand, attempts
under open flask and/or air-bubbling (air-flow rate: 3 mL min) using a conventional gas dispersion tube
resulted in 30% and 48% conversion, respectively (entries 2 and 3). Even the air-flow rate increased from3 up to 15 mL/min, conversion was lower than that of the micronanobubble procedure (entries 3-7).

Table 1. Aerobic copper/TEMPO-catalyzed oxidation of benzyl alcohol to benzaldehyde

Entry Condition

Flow RateConv.

(mL/min)

(%)

a

Entry

Condition

Flow RateConv.

(mL/min)

(%)a

15

84

1

Openb

-

30

5

Bubblingb

2

Bubblingb

3

48

6

Micronanobubblec

3

93

3

b

Bubbling

7

c

3

94

4

Bubblingb

a

5

56

7

73

Micronanobubbleb

Determined by GC analyses. Reaction was carried out with magnetic stirring at 500 rpm. c O2-micronanobubble was used.

We next examined oxidations of geraniol (3) using micronanobubble procedure. Geranial (4) was
obtained in 84% isolated yield and 97% purity after standard work-up and reduced-pressure distillation. In
contrast, oxidation with usual air-bubbling procedure resulted in only 73% conversion (Scheme 1).

Scheme 1. Oxidation of geraniol with micronanobubble procedure.
Next, we demonstrated oxidation of secondary alcohol to ketone (Scheme 2). 1-Phenylethanol (5) wasconverted to acetophenone (6) in 82% under air-bubbling condition, whereas better conversion wasobserved under micronanobubble condition.

Scheme 2. Iron/4-HO-TEMPO catalyzed oxidation of secondary alcohol
In conclusion, efficient aerobic TEMPO oxidation of primary and secondary alcohols using
micronanobubble strategy was achieved.
Reference: Mase, N.; Mizumori, T.; Tatemoto, Y. Chem. Commun. 2011, 47 (7), 2086-2088.

Core Structure-Based Design of Organocatalytic [3+2]-Cycloaddition Reactions: Highly
Efficient and Stereocontrolled Syntheses of 3,3’-Pyrrolidonyl Spirooxindoles
Bin Tan, Youqiang Lin, Guofu Zhong*College of Materials, Chemistry & Chemical Engineering and School of Medicine,
Hangzhou Normal University, Hangzhou 310036, China
zgf@hznu.edu.cn
A spirocyclic oxindole core is the structural

3,3’-pyrrolidonyl spirooxindole skeletons in acenterpiece of a wide variety of natural andhighlysynthetic

Scheme 1).

compoundsthat

exhibitdiversestereoselective

transformation(seebiological activities. Consequently, approaches
towards the efficient asymmetric synthesis ofthese molecules have received considerable
attention. As part of a program to address thisfamily of molecules with orga-nocatalysis, we

Scheme 1. Initial test of [3+2]-cycloaddition

have recently reported strategies based onreaction catalyzed by quinine.

oxindoles

that

providebispirooxindoles,
and

rapid

accesstospirocyclopenteneoxindoles,

carbazolespirooxindoles.

While

In

our

exploratory

effort,

this

new

these

methodology provided access to a range ofapproaches have met with some success, these

multi-substituted spirocyclic oxindole derivatives

efforts do not address the 3,3’-pyrrolidonyl

and served as an expedient approach for the

spirooxin-dole motif common to many bioactive

preparation of a range of substituted spirocyclo

molecules from this family of molecules (Scheme

oxindoles containing three chiral centers in1). Thus, an enantioselective catalytic approach

excellent enantiomeric ex-cesses (91–98%ee) andfor the direct construction of 3,3’-pyrroli-donyl

almost complete diastereoselectivi-ties (>25:1 d.r.

spirooxindole skeletons is a significant unmet

in all cases) (Scheme 2). TheIV-promoted

challenge.

[3+2]-cycloaddition reaction proceeded with a

To address this challenge, we sought to design

varietyofmethyleneindolinone

derivatives

an organocatalytic domino reaction that would

bearing various substituents at the carbon–carbon

ideally involve the reaction of two simple anddouble bond such as esters and ketones. Notably,readily accessible starting materials. Given theminimalrecent success of -isothiocyanato derivatives as

enantiose-lectivities,

nucleophiles
Mannichinorganocatalytic

reactions,we

impactonefficiencies,and diastereoselectivities

aldol

and

were observed regard less of the electronic natureenvisioned

that

and bulkiness of the substituents (Scheme 5,
3g–3k). The current system does have limitations:[3+2]-cycloaddition

reactions

between-isothiocyanato

imidesandmethyleneindolinones would yield the desired

Phenyl-substituted
virtually

methyleneindolinone

unreactive,

while

was
the

cyano(CN)-substituted

methyleneindoli-none

model.

provided product with low diastereoselectivity.

Scheme 3. Proposed mode of activation ofsubstrates

Scheme 4. Control experiment in support ofmechanism.
In summary, we have developed an efficientorganocata-lytic [3+2]-cycloaddition reaction for
Scheme 2. Generality of organocatalytic

the direct construction the 3,3’-pyrrolidonyl[3+2]-cycloaddition reactions

spirooxindole motif common to many bioactive
molecules

throughtherational

designofdual

-isothio-cyanato

imidesasactivation model proposed by Takemoto andStereochemicallycomplexproducts

co-workers, and the theoretical calculation studies

obtained in excellent chemical and optical yieldby Papai and Zhong and their co-workers, allow

allowing us to set three contiguous stereocenters,

us to suggest that the two substrates involved inincluding one all-carbon spiro quaternary center,the reaction are activated si-multaneously by thein the products. This straightforward processcatalyst

Ourfindings

astogethershown

dienophiles.
were

The

makes use of simple start-ing materials andacetyl-protecting group is

crucial tohighproceeds under mild conditions and will be usefulenantioselectivity,

from

low

in medicinal chemistry and diversity-oriented

seen

Scheme

the

3.

as

in

with

the

enantioselectivity (55%ee) obtained when asynthesis.

tert-butoxycarbonyl (Boc) protect-ing group was
utilized (Scheme 4). The absolute configurations

Reference: Tan, B.; Zeng, X.; Leong, W. W. Y.;of 3b and 3g determined by X-ray analysis are in

Shi, Z.; Barbas III, C. F.; Zhong, Guofu*

accordance with that predicted by the catalytic

Chem. Eur. J. 2012, 18, 63-67.

Development of Efficient Catalyst Screening by Fluorescence Monitoring
Using OFF-ON Fluorogenic Sensors
Aiko Sasaki, Nobuyuki Maze
Department of Molecular Science, Faculty of Engineering, Shizuoka University
3-5-1 Johoku, Hamamatsu, 432-8561, Japantnmase@ipc.shizuoka.ac.jp
Performing a large number of random chemical reactions should increase the possibility of an incidental
discovery outcome. Especially, high-throughput method of fluorometry with a rapid plate reader is
employed to perform various random reactions automatically. Fluorogenic substrates are useful for
analysis of the progress of chemical transformations because product formation is directly observed as anincrease in fluorescence. To compare with the traditional laboratory protocols in which the operation was
repeatedly, this method shows many advantages for huge savings in time, cost, and labor (Figure 1). In
order to accelerates high throughput screening in small scale, OFF-ON fluorogenic sensors were designed
to apply screening of catalysts for the formation of C-C bonds. Here, we focused aldol reaction that is oneof the most predominantly used reactions in synthetic organic chemistry, then OFF-ON fluorogenic sensorsof aldehyde-type, which is possibly used for monitoring the progress of aldol reactions via the detecting
fluorescent increase, will facilitate the rapid discovery of efficient catalysts from compound libraries.

catalyst

Acceptor

additive

A

B

C

D

a

b

c

d

E

F

G

H

e

f

g

h

I

J

K

L

i

j

k

l

flourescentsensor(OFF)

Real timeevaluation

Product
32 min, rt

flourescentsensor(ON)

C-C bond formation

Figure 1. Fluorescent monitoring system
Although fluorescence properties of aromatic carbonyl compounds are complex and often difficult topredict, many aromatic aldehydes and ketones have a low-lying n-π* excited state and thus exhibit low
fluorescence quantum yields due to intersystem crossing. Therefore, we reasoned that anthracene,
naphthalene, and fluorescent benzene derivatives with aldehyde functional group should be candidates offluorogenic aldehydes. Indeed, aldehyde 1 was weakly fluorescent, whereas aldol 2 was highly fluorescent(Figure 2).

6000

aldehyde as a donor in the presence of catalyst and

5000

Fluorescence intensity

Reactions of fluorogenic aldehyde 1 with isobutyl
additive were performed in 96-well, and theincreaseoffluorescencewasmonitoredbymicroplate reader to examine the utility of 1 formonitoring the progress of the aldol reaction. From
analyses of high velocity and integral value of

4000

2

3000

2000
1000

1

0
340

390

440

490

540

590

640

690

fluorescence intensity, the best combination of

λ em (nm) (λ ex = 330 nm, 1 μ M in DMSO)

pyrrolidine as a catalyst and isophthalic acid as an

Figure 2. OFF-ON fluorogenic compounds foracid additive was identified. Subsequently, tomonitoring the progress of C-C bond formations

evaluate

ourfluorescentmonitoring

system,pyrrolidine catalyzed cross aldol reactions between isobutyl aldehyde (3) and p-nitrobenzaldehyde (4)were performed. As the value of velocity was increased, conversion and isolated yields were improved in
the model aldol reaction (Figure 3).

2003年
In 200390

Estimated yield (%)

80
70

260

60

220

50

180

40
30
20
10
0

140
100
4

5

6

7

8

9

10

11

Integral value (×103 RFU)

catalyst

Catalyst + Additive>3000 combinations

In 2012
2012年
Template

60
12Reaction velocity (RFU/min)Figure 3. Screening results employing isobultylaldehyde as a donor
In conclusion, we have synthesized fluorogenic compounds that can be used for monitoring reactions
through increased fluorescence. These fluorogenic compounds can be useful for screening of catalysts to
identify the best combination from compound libraries.

Synthesis of Quantum Dot/Hydroxy-apo-10’-carotenal Conjugates
for in vivo Visualization of Carotenoid-derived Volatile Compounds
Hoshimi Jitsukata, Nobuyuki Mase
Department of Molecular Science, Faculty of Engineering, Shizuoka University
3-5-1 Johoku, Hamamatsu, 432-8561, Japantnmase@ipc.shizuoka.ac.jp
Recently, there has been a rapid
increase in the number of publications

Carotenoid

PLASTEDon biosynthetic pathway. However,CCD4

elucidation of the formation pathway

Apo-10’-carotenal

CYTOSOL

yielding carotenoid-derived volatiles inplant has been still a big challenges,
because very little is known about therelease as well as the location of

Apo-10’-carotenal-Qdot conjugate

synthesized volatile compounds from

CCD1

plant tissues. Herein, we focus the studyonsynthesis

andapplicationofQuantum dot (Qdot) conjugate for the invivo visualization of β-ionone as acarotenoid-derived volatile many fruits,
vegetables,andplants.

We+β-ionone-Qdot conjugate

have

proposed our hypothesis that Qdot can

Visualization

C14 Dialdehyde

Transport to storage
compartments Glycosilation

be applied for staining of plant volitiles
inside living cells because of their

Figure 1. Approach for the labeling of volatiles derived fromuniquecarotenoids with Qdot

properities,

such

as

water

solubility, photo stability, and exceptional fluorescence. The β-ionone-Qdot-conjugate which is obtained as
enzyme-cleaved product from β-apocarotenal-Qdot conjugate can be detected inside the compartments(Figure 1).
The carbonyl group of α-ionone was first protected by ethylene glycol to yield α-ionone ketal 2. Thisketal was then oxidized at the allylic position with tert-BuOOH (TBHP, 70% in water), house bleach andcatalytic amount of potassium carbonate in acetonitrile at -5°C to 0°C. The reduction of 3-keto-α-ionone 3
followed by deprotection led to 3-hydroxyl-α-ionone 4. A variety of reduction agents such as sodium
borohydride/cerium chloride (86% yield, 54%de, cis), potassium tri-sec-butylborohydride (87% yield, 14%de, trans), and diisobutylaluminium hydride (DIBAL, 91% yield, 34% de, cis) were examined todetermine whether the carbonyl group could be reduced stereoselectively at C3 and C6 position; however,no significant stereoselectivity could be achived. Among these reducing agents, DIBAL was chosen due tothe commericially availability. Conversion of 3-hydroxy-α-ionone 5 to 3-hydroxyl-β-ionone 6 wasaccomplished by base catalyzed isomerization with potassium hydroxyl/methanol (10 wt%/v) in 80%
isolated yield after purification.
In the following steps, the Grignard reaction between 3-hydroxyl-β-ionone 6 and vinylmagenesium
bromide afforded the tertiary vinyl-α-ionol 7. Treatment of this alchol 7 with triphenyl phosphine inhydrobromic acid furnished the desired phosphomium salt 8 in 93% yield. Wittig olefination of C10
dialdehyde 12 with C15-ylide salt 13 was initiated by addition of 1,2-epoxy butane to successfully access
C25 aldehyde 13 (Scheme 1).
The critical step is the coupling reaction between carboxyl Qdot 15 and apocarotenal 14 via ester bridge
as shown in Scheme 2.

Scheme 1. Synthesis of apo-10’-carotenal

Scheme 2. Synthesis of Qdot conjugate
In conclusion, we have synthesized the β-ionone-Qdot-conjugate 18 over 14 steps, which potentially canvisualize carotenoid-derived volatiles formed inside the plant cell.

Chiral Brønsted Acid Catalyzed Enantioselective -Aminoxylation of Enecarbamates
Min Lu, Youqiang Lin, Guofu Zhong*College of Materials, Chemistry & Chemical Engineering and School of Medicine,
Hangzhou Normal University, Hangzhou 310036, China
zgf@hznu.edu.cn
-Hydroxy carbonyl compounds are key motifs encountered throughout natural products andpharmacueticals; thus, the preparation of chiral -hydroxy ketones has been of great interest and has
motivated a tremendous wealth of strategies for their synthesis. Catalytic asymmetric -aminoxylation
reactions are one of the most facile and conventional synthetic methods towards chiral -hydroxy ketones.
However, despite considerable efforts in the area of -aminoxylation, so far the substrate scopes have been
limited to aldehydes, cyclic ketones, and -dicarbonyl compounds. The use of linear ketones resulted insignificant decrease in both the reactivity and selectivity, while no examples with aromatic ketones havebeen documented, possibly because of the severe steric hindrance which strongly inhibited the covalentbinding of the catalyst.
To address these challenges, enecarbamate1was chosen as an activated ketone nucleophile (Figure 1);
we envisioned that in the presence of an electron-withdrawing carbamate group (TS), instead of anelectron-donating pyrrolidine moiety (used in proline catalysis, TS*), the undesired N-addition pathway
might be suppressed. The fact that both the E and Z isomers of enecarbamates can be conveniently
prepared provides additional flexibility for this approach. Meanwhile, chiral Brønsted acids would be
attractive alternatives for overcoming the limitations of proline catalysis in -aminoxylation reactions, as
selective protonation of the basic nitrogen of nitrosobenzene should be realized by a judicious choice ofstronger acid (TS). However, no efficient C-O bond formation of enecarbamates has been reported, despite
recent successes in the catalytic asymmetric aza–ene reactions of enecarbamates with aldehydes andimines. In a continuation of our long standing work in aminoxylation chemistry, we recently discoveredthat highly enantioselective -hydroxylation of -dicarbonyl compounds can be achieved throughactivation of nitroso compounds with binol-derived phosphoric acids. To further explore the extent of thisnovel activation mode, herein we describe the first chiral-phosphoric-acid-catalyzed -aminoxylation ofenecarbamates, and its one-pot application leading to direct access of optically pure -hydroxy ketones,
-amino alcohols, and oxazolidinones.

Figure 1. Projected synthesis of chiral -hydroxy ketones 5

A broad spectrum of nitrosoarenes could be employed in the reaction to afford the desired products inexcellent yields and high enantioselectivities (Table 1, entries 1–7), with the exception of 4-nitrosotoluene(Table 1, entry 4) in which N-O bond heterolysis was observed after the initial aminoxylation.
Enecarbamates derived from aromatic ketones that have substituents with various electronic and stericproperties were also found to efficiently react with 4-chloronitrosobenzene (2b), and the products wereobtained in high enantioselectivities (Table 1, entries 8–12). Furthermore, the more-challenging
enecarbamates derived from indanones and tetralones could also successfully undergo -aminoxylation to
give -oxygenated products in good yields and ee values, although specific catalyst was needed for each
substrate. The absolute configuration of 4a, 7a, and 7d were determined to be S after catalytichydrogenation to convert them to the correspondinga-hydroxy ketones and comparing the optical rotation
with literature. The stereo-chemistry of other products was tentatively assumed by analogy.
Table 1: Substrate scope of the chiral phosphoric acid catalyzed -aminoxylation of enecarbamates.[a]In conclusion, we have reported a facile, practically appealing, highly enantioselective Brønsted
acid-catalyzed -aminoxylation of enecarbamates. This procedure considerably extend the substrate scope
for the -aminoxylation reaction to linear and aromatic ketones, allowing convergent and stereoselective
access to valuable -hydroxy ketones, -amino alcohols, and cis-oxazolidinones in their enantiopure form.
This discovery also provides mechanistic insights into the N/O selectivity of -aminoxylation. Further
applications of this activationmode to other enantioselective reactions are currently underway.
Reference: Lu, M.; Lu, Y.; Zhu, D.; Zeng, X.; Li, X.; Zhong, Guofu* Angew. Chem. Int. Ed. 2010, 49,
8588-8591.

Organocatalytic Ring-Opening Polymerization of L-Lactide
in Supercritical Carbon Dioxide
Shoji Yamamoto, Nobuyuki Mase
Department of Molecular Science, Faculty of Engineering, Shizuoka University
3-5-1 Johoku, Hamamatsu, 432-8561, Japantnmase@ipc.shizuoka.ac.jp
Polylactides are useful material in various
fields because of their biodegradable andbiocompatiblefeatures.

Polylactides

aresynthesized by condensation polymerizationfrom lactic acid or ring-opening polymerizationfromlactide(Figure1).

Condensation

polymerization is not suitable for preparationof higher-molecular-weight polylactide due to

Figure 1. Method for synthesis of polylactide

equilibrium process in ester bond-forming
reaction. On the other hand, ring-opening polymerization of lactide is catalyzed by tin 2-ethylhexanoate
under high temperature condition, and is used in industry. However, as removing toxic metal frompolylactides is rather difficult, the safety of products is not ensured. Furthermore, the coloring of productscaused by high reaction temperature is often problematic in product development. Recently,
polymerizations employing an organocatalyst have been reported, but they requires toxic volatile
halogenated solvents because polylactides cannot be dissolved in conventional solvent. Here, we reportorganocatalytic polymerization of lactide in supercritical carbon dioxide (scCO2) at lower temperaturecompared to conventional method, affording metal-, organic solvent-, and residual monomer-freepolylactide.
Polymerization using DMAP as anorganocatalyst proceeded quantitatively
and smoothly in scCO2 with high purity atlower temperature (Scheme 1). Regardingthereactionmechanism,

catalyst

isproposed to be as a nucleophile or as abase for activation of monomer, and thesemechanisms include anionic intermediate

Scheme 1. Organocatalytic polymerization of lactide in scCO2(Scheme 2). It is considered that living
anionic polymerization is generally difficult in scCO2, since anionic intermediate has possibility of reactingwith Lewis acidic scCO2. Nevertheless, in the presence of DMAP and ethanol as a reactant in scCO2 at 10

MPa and 60°C, polylactide
was quantitatively obtained
after 1 hour. In addition,livingpolymerization

proceeded according to thelinear correlation between
Mwandmonomerconversion, that is, the close
correlation

betweenScheme 2. Reaction mechanism of polymerization

thetheoretical and experimental
molecular weights. This result indicates that living anionic polymerization proceeded in scCO2.
Using surfactant showed an effect on granulation of the polylactide. We found that silicone-typesurfactant was applicable in efficient granulation (Figure 2). In the presence of silicone-type surfactant,granulated polylactide was obtained in 96% conversion after 2 hours. The particle size was around 1 mm.
Interestingly, this granulated polylactide could be easily collected from autoclave, and therefore,
handleability was greatly improved.

with surfactant

without surfactant

Figure 2. Effect of surfactant in granulation
This method can be applied for ring-opening
polymerization of other monomers. Polymerizationof valerolactone smoothly proceeded in thepresence of trifluoroacetic acid (Scheme 3). Since
polyvalerolactone is also biodegradable polymer
and the reaction undergoes via the formation of

Scheme 3. Synthesis of polyvalerolactone in scCO2

cationic intermediate, it leads to the wide application of this method for various monomers.
In summary, our method enables to accomplish environmentally-friendly organocatalytic synthesis ofpolylactide without using toxic metal catalyst and halogenated solvent. This polymerization proceeded via
living anionic polymerization even in Lewis acidic scCO2. In addition, it was simultaneously able to performpolymerization as well as granulation by use of silicone-type surfactant. This method offers many advantages
such as saving energy, safety, quality, regulatory compliance VOC, and low cost.

N-Heterocyclic Carbene (NHC)-Catalyzed Highly Diastereo- and Enantioselective
Oxo-Diels_Alder Reactions for Synthesis of Fused Pyrano[2,3-b]indoles
Limin Yang, Zhiming Zhang, Guofu Zhong*College of Materials, Chemistry & Chemical Engineering and School of Medicine,
Hangzhou Normal University, Hangzhou 310036, China
zgf@hznu.edu.cn
The synthesis of an ,-unsaturated amide
couldbeclassicallycarriedout
fromcommercially available isatins. Presumably,
activation of the isatin C3-O double bond via a
simple one-step Wittig-Horner reaction results inthe formation of 2-oxoindolin-3-ylidenes in
excellent yields. Moreover, this strategy being
based on the annulation of indoles opens up a
new avenue for the synthesis of fusedpyran[2,3-b]indole skeletons, one of the mostimportant heterocycles and key structural units ofbiologically active alkaloids. Although significant
advances have been achieved in the developmentof these derivatives for the synthesis of
biologicallyimportantcompounds,
enantioselective variants are still very limited. A
study that was carried out by Ye and co-workers
presented a formal [4+2] cycloaddition of ketenes
withoxindoles
yielding
indole-fused
dihydropyranones. However, the diastereo- andenantioselectivities
obtainedwere
quite
unsatisfactory.
To address the challenge of achieving highoptical purity, N-mesityl-substituted triazolium
salt (refer to cat.) was chosen as the catalyst forthis reaction and racemic R-chloroaldehyde 1wasused as the dienophile precursor to generate insitu the enolate species from elimination of HClfrom the NHC-R-chloroaldehyde ad-duct. We
envisioned that excellent diastereoselectivities
and absolute stereochemistries can be rationalized
due to the highly preferredendo-cis-transition
state. The hypoth-esis was based on DFT
calculations that determined that cis-enolates arethermodynamically more stable than the transforms by approximately 3.9-6.5 kcal/mol. In theactive cis-enolate, the N-substituted group isprone to be “trans” to the oxo group and thismode is reinforced by the presence of the bulky
triazolium moiety. The stereochemistry of
2-oxoindolin-3-ylidenes
in
this
[4+2]
cycloaddition reaction proved to exhibit an(E)-configuration. The cis-diastereoselectivity
would arise from acis-enolate reacting as the
dienophile with (E)-2-oxoindolin-3-ylidenes via
an endo-transition state. In this transition statemode, the re-face is completely blocked by theindane moiety of the carbene catalyst, leaving
thesi-face more accessible for the [4+2]cycload-ditionwiththe2-oxoindolin-3-ylidene
substrate (Figure1).

Fig 1. Proposed transtion state
To test the concept, we carried out the reaction
using 2.0 equiv of -chloroaldehyde 2a and3-alkylenyloxindole1a with N-mesityl-substituted
triazolium salt in the presence of base. The results
were summarized in Table 1. As expected, 20
mol % of N-mesityl substituted triazolium salt
effectively promoted the reaction in the presenceof Et3N in dichloromethane at room temperatureand deliv-ered the desired product with excellentdiastereo- and enantioselectivity (Table 1, entry1). Next, the use of different basesandsolventswas
evaluated for this reaction. DIPEA was found toslightly decrease the enantioselec-tivity (entry 2).
When DBU was employed, the yield decreased
dramatically even though there was no loss indiastereo- and enantioselectivity (entry 3). We
observed that the inorganic bases were deemed to
be unsuitable for the reaction, as they led tolowered yields and enantio-selectivities (entries 4
and 5).

lower enantioselectivity of3gwas presum-ably
due to the easier formation oftrans-enolate
species by using 3-(benzyloxy)-2-chloropropanalthan other -chloro-aldehydes. In general,
-chloroaldehydes derived from linear aliphatic
aldehydes favor the [4+2] cycloaddition reaction
with 3-alkylenyloxindole 2a to deliver goodresults (Table 2, entries 4, 5, and 8). The
reactionwas also very well tolerated with
5-(benzyloxy)-2-chloropentanalinwhich
optically pure products were obtained
quantita-tively within 30 min (Table 2, entry 6).

Table 1.Optimization of Reaction Conditionsa
Table 2.Substrate Scope of NHC-Catalyzed [4þ2]Cycloadditiona

With the optimal reaction conditions
established,thescopeof
this[4+2]
cycloadditionwas investigated (Tables 2 and 3).
The reaction proceeded smoothly for a broad
spectrumofR-chloroaldehydes to afford thedesired prod-ucts in good yields and excellent
optical purity (Table 2), with the exception of
3-(benzyloxy)-2-chloropropanal (entry 7). The

In conclusion, a chiral NHC-catalyzed
Diels-Alder reaction of 2-oxoindolin-3-ylidenes
and R-chloroalde-hydes was developed for thesynthesis of fused 3,4-dihydropyrano[2,3-b]indol2(9H)-ones in good to excel-lent yields (up to99%) with high cis-diastereoselectivities (>99:1dr) and enantioselectivities (up to 99% ee). This
protocol holds great potential in the synthesis of
biologically active fused pyrano[2,3-b]indole
derivatives in high enantiomeric purity.
Reference: Yang, L.; Wang, F.; Chua, P. J.; Lv, Y.;
Zhong, L.-J.; Zhong, Guofu* Org. Lett. 2012, 14,2894–2897.

Organocatalytic Michael Addition Using 2-Aminopyridine Catalyst
Based on Molecular Recognition
Takahiro Kato, Nobuyuki Mase
Department of Molecular Science, Faculty of Engineering, Shizuoka University
3-5-1 Johoku, Hamamatsu, 432-8561, Japantnmase@ipc.shizuoka.ac.jp
Double proton transfer including two hydrogen bonds
are used for its tautomerization of 2-pyridone (Figure 1,
left). In this study, we proposed that 2-aminopyridine isable to recognize 1,3-dicarbonyl compounds through twohydrogen bonds and generate ammonium enolate under
mild conditions (Figure 1, right).

Figure 1. Activation of carbonyl compoundIn the beginning, we examined the catalytic ability ofthrough hydrogen bonds

pyridine derivatives towards Michael addition. In thepresence of 2-aminopyridine (4), Michael product 3 was obtained in 90% yield, on the other hand, the useof 4-methoxypyridine (5) and 2,6-lutidine (6) gave 3 in 28% yield and 14% yield, respectively. These
results showed that 2-aminopyridine (4) has efficient catalytic ability despite weak basicity.

Scheme 1. Michael addition using pyridine derivatives as a catalyst
To prove the molecular recognition mechanism as mentioned in Figure 1, N-methyl-2-aminopyridine (7)and N,N-dimethyl-2-aminopyridine (8) were used. Reactions employing catalyst 7 and 8 also proceeded,which afforded the same Michael product 3 in 93% and 23% yield, respectively (Scheme 2). Therefore, thecatalyst 7 could recognize acetylacetone (1) through two hydrogen bonds and catalyst 8 could notrecognize the substrate 1 because of existence of tertiary amino group.

Scheme 2. Effect of α-substituted amino group

Encouraged by these results, we subsequently examined various 2-aminopyridine derivatives (Figure 2).
N-methyl-2-aminopyridine (7) was the most efficient catalyst among other substituted 2-aminopyridines(9-12). In addition, catalyst loading could be decreased to 0.5 mol%, giving the adduct 3 in 87% yield.

Figure 2. Substituent effect of 2-aminopyridine catalyst
With the optimized conditions, we evaluated the scope and limitation of the substrate of Michael
addition. In the presence of catalytic amount of N-methyl-2-aminopyridine (7) in DMSO, various
1,3-dicarbonyl compounds smoothly react with Michael acceptors in excellent yields (Table 1). In addition,
this catalytic system was not influenced by reactive functional groups such as phenolic hydroxyl andpyridyl groups.
Table 1. Scope and limitation of the substrate of Michael addition
R1
Me
Me
Me
Me
Me
OEt
OMe

R2
R3
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
-(CH2)3-Ar
4-CNC6H4
4-MeOC6H4
4-HOC6H4
Pyridine
Ph
Ph
Ph

EWG
NO2
NO2
NO2
NO2
COPh
NO2
NO2

Yield (%)
83
96
96
79
80
91
93

To clarify the mechanism of 2-aminopyridinecatalyzed Michael addition, 1H NMR analyses
wereperformed.

Based

on

the

result,2-aminopyridine catalyst can selectively activate
keto-form acetylacetone (1b) and convert it torelatively unstable (E)-form enolate (Scheme 3).
In conclusion, 2-aminopyridine derivatives asan organocatalyst could recognize 1,3-dicarbonylcompounds through hydrogen bond and generateammonium enolate despite weak basicity. In-situ

Scheme 3. Proposed reaction mechanism

formed enolate reacts with various Michael acceptors to construct carbon-carbon bond. Furthermore, 1H
NMR analyses suggest that 2-aminopyridine catalyst have characteristic mechanism of activation in which
keto-form acetylacetone selectively converts to relatively unstable (E)-form enolate.

Encouraged by these results, we subsequently examined various 2-aminopyridine derivatives (Figure 2).
N-methyl-2-aminopyridine (7) was the most efficient catalyst among other substituted 2-aminopyridines(9-12). In addition, catalyst loading could be decreased to 0.5 mol%, giving the adduct 3 in 87% yield.

Figure 2. Substituent effect of 2-aminopyridine catalyst
With the optimized conditions, we evaluated the scope and limitation of the substrate of Michael
addition. In the presence of catalytic amount of N-methyl-2-aminopyridine (7) in DMSO, various
1,3-dicarbonyl compounds smoothly react with Michael acceptors in excellent yields (Table 1). In addition,
this catalytic system was not influenced by reactive functional groups such as phenolic hydroxyl andpyridyl groups.
Table 1. Scope and limitation of the substrate of Michael addition
R1
Me
Me
Me
Me
Me
OEt
OMe

R2
R3
Me
H
Me
H
Me
H
Me
H
Me
H
Me
H
-(CH2)3-Ar
4-CNC6H4
4-MeOC6H4
4-HOC6H4
Pyridine
Ph
Ph
Ph

EWG
NO2
NO2
NO2
NO2
COPh
NO2
NO2

Yield (%)
83
96
96
79
80
91
93

To clarify the mechanism of 2-aminopyridinecatalyzed Michael addition, 1H NMR analyses
wereperformed.

Based

on

the

result,2-aminopyridine catalyst can selectively activate
keto-form acetylacetone (1b) and convert it torelatively unstable (E)-form enolate (Scheme 3).
In conclusion, 2-aminopyridine derivatives asan organocatalyst could recognize 1,3-dicarbonylcompounds through hydrogen bond and generateammonium enolate despite weak basicity. In-situ

Scheme 3. Proposed reaction mechanism

formed enolate reacts with various Michael acceptors to construct carbon-carbon bond. Furthermore, 1H
NMR analyses suggest that 2-aminopyridine catalyst have characteristic mechanism of activation in which
keto-form acetylacetone selectively converts to relatively unstable (E)-form enolate.