Inter-and Intramolecular Cycloaddition Reactions of Ethenetricarboxylates with Styrenes and Halostyrenes

SYNTHESIS

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2020, 52, A–W

paper

A

en

S. Yamazaki et al.

Paper

Synthesis

Inter- and Intramolecular Cycloaddition Reactions of Ethenetricar-

boxylates with Styrenes and Halostyrenes

Shoko Yamazaki*^a

Zhichao Wang^b

Kentaro Iwata^a

Khotaro Katayama^a

Hirotaka Sugiura^b

Yuji Mikata^c

Tsumoru Morimoto^d

Akiya Ogawa^b

^aDepartment of Chemistry, Nara University of Education,

Takabatake-cho, Nara 630-8528, Japan

yamazaks@cc.nara-edu.ac.jp

^bDepartment of Applied Chemistry, Graduate School of Engineering,

Osaka Prefecture University, Gakuen-cho 1-1, Nakaku, Sakai, Osaka

599-8531, Japan

^cKYOUSEI Science Center, Nara Women’s University, Nara 630-8506,

Japan

^dGraduate School of Materials Science, Nara Institute of Science

and Technology (NAIST), Takayama, Ikoma, Nara 630-0192, Japan

Corresponding Author

Received: 25.08.2020

Accepted after revision: 24.09.2020

Published online: 02.11.2020

should be prepared freshly.⁷Ethenetricarboxylate deriva-

tives have been utilized in various bond-forming reactions.⁸

They are highly electrophilic C=C components by the elec-

tron-withdrawing effect of the 2-carbonyl group and they

have a sufficient stability compared to the parent methy-

lenemalonates.

The cycloaddition reactions of styrenes to give cyclo-

butanes have been reported.⁹However, Hall, Jr. and co-

workers reported that the reaction of trimethyl ethenetri-

carboxylate and weak donors, styrene and 4-methylstyrene,

promoted by Lewis acids such as ZnCl₂, and LiClO₄gave no

[2+2] cycloadducts.^9aThe reactions of ,-unsaturated car-

bonyl compounds and styrenes also undergo alkene

Michael additions,¹⁰and [4+2] cycloadditions of styrenes as

dienes.¹¹Snider and Roush reported the FeCl₃-promoted in-

tramolecular reactions of cinnamyl ethenetricarboxylate to

give chlorinated -lactones.¹²

We have previously studied intramolecular cycloaddi-

tion reactions of styrene-derived ethenetricarboxylate am-

ides (Scheme 1).¹³Reaction of ethenetricarboxylic acid 1,1-

diester and cinnamylamines with EDCI/HOBt/Et₃N led to

pyrrolidine products via intramolecular [2+2] and [4+2] cy-

cloadditions in sequential processes depending on the sub-

stituents on the benzene ring.

Intermolecular cycloadditions of styrenes with ethene-

tricarboxylates under various Lewis acids remains unex-

plored. In addition, it is of interest to extend intramolecular

reactions, such as larger fused ring formation, and examine

the effects of substituents. In this work, intermolecular re-

actions between ethenetricarboxylates and styrenes or -

halostyrenes (X = F, Cl, Br, I) were studied (Scheme 1). The

reactions of N-4-phenylbut-3-enyl- and N-5-phenylpent-4-

DOI: 10.1055/s-0040-1706547; Art ID: ss-2020-f0452-op

Abstract Inter- and intramolecular cycloaddition reactions of ethene-

tricarboxylates with styrenes and -halostyrenes have been investigat-

ed. The reactions of ethenetricarboxylates with styrenes or -bromo-

styrenes in the presence of SnCl₄or SnBr₄stereoselectively gave 2,4-cis-

substituted cyclobutanes. The intramolecular cycloaddition reactions of

a series of styrene-functionalized ethenetricarboxylate amides, includ-

ing in situ generated derivatives, showed high diversity of reaction

modes depending on the structures and substituents of the substrates.

The regioselectivity and stereoselectivity of the reactions as well as re-

action mechanisms were discussed based on the DFT calculations.

Key words cyclobutane, ethenetricarboxylate, styrene, intermolecu-

lar cycloaddition, intramolecular cycloaddition

The construction of cyclobutane and its fused rings is an

important objective due to their occurrence in many natu-

ral products and biologically active compounds¹and utili-

zation in organic synthesis.²Photochemical [2+2] cyclo-

additions have been widely utilized for the synthesis of

cyclobutanes.³The thermal reactions to give [2+2] cycload-

ducts have also been studied.⁴The reactions of electron-de-

ficient alkenes and electron-rich alkenes without or with

Lewis acid catalysis give [2+2] cycloadducts via zwitterionic

intermediates.⁵Methylidenemalonate is highly reactive and

undergoes [2+2] cycloaddition with electron-rich alkenes to

form cyclobutanes in the presence of Lewis acids.⁶Howev-

er, Lewis acid catalyzed [2+2]-cycloaddition reactions of

methylenemalonates generally require low temperature

conditions because of their instability. In addition, methy-

lenemalonates should be stored at low temperature or

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B

S. Yamazaki et al.

Paper

Synthesis

enylamides of ethenetricarboxylate as the homologues for

cinnamamides with longer carbon tethers were also exam-

ined.

Furthermore, intramolecular cycloaddition reactions of

ethenetricarboxylates with -bromostyrenes were investi-

gated. In order to obtain some insights into the mechanism

and selectivities, DFT calculations were carried out.

Table 1 Reaction of Triethyl Ethenetricarboxylate and Styrene with

Various Lewis Acids

EtO₂C

CO₂Et

EtO₂C

Ph

4

Lewis acid

1

+

EtO₂C

CH₂Cl₂

r.t.

Ph

EtO₂C

3

2

2a

1a

3a

EtO₂C

CO₂Et

EtO₂C

CO₂Et

3

1

2

CO₂Et

EtO₂C

5

Previous work (ref.13)

EtO₂C

4

3

4

X

3

CO₂Et

6

EtO₂C

O

5

6

CO₂Et

+

EDCI

HOBt

5

4

O

Cl

5a

Ph

4

X

O

Ph

1

2

4a

3

6a

HO₂C

Et₃N

N

R

1

2

HN

Entry

Lewis acid

Equiv

Time (h)

Product Yield (%)

R

CO₂Et

O

EtO₂C

H

CO₂Et

H

1

2

3

4

SnCl₄

AlCl₃

1.0

1

3a

5a

52

O

CO₂Et

R

N

1

24 (dr 1:1)

25 (dr 1:1)

X

R

N

H

17

H

X = H, 4-F, 4-Cl, 4-Br,

4-OCH₃

X

X = 2-NO₂, 2-NO₂-5-F,

4-NO₂, 4-CN,

4-CO₂Me, 4-CO₂Et,

4-CF₃

1 M EtAlCl₂in

hexane

a

5

6

7

8

TiCl₄

1.0

0.2

17

1

–

This work

intermolecular

reaction

EtO₂C

RO₂C

CO₂Et

FeCl₃

6a

88 (dr 9.6:1)^b

54 (dr 2.6:1)^b

25 (cis)

EtO₂C

Ar

Lewis acid

+

FeCl₃

19

20

EtO₂C

RO₂C

X

Ar

Sc(OTf)₃

X = H, halogen

^aA complex mixture containing possibly alkene 4a.

^b3,5-cis-Diastereomer is the major product.

intramolecular reaction

ring size and X substitution

CO₂Et

EtO₂C

Ph

O

CO₂Et

O

Lewis acid

O

N

Ph

the benzene ring. The reaction of 1a with styrenes 2c, 2d,

2f, and 2g, as well as 2a, gave cyclobutanes 3 at room tem-

perature. The reaction of 1a with styrenes 2b and 2e at –78

°C gave cyclobutanes 3b and 3e as major products. The re-

action with styrenes 2b, 2e, and 2h at room temperature

formed alkene adducts 4 and other products such as chlo-

rine adducts 5. The reaction with 2i or 2j gave complex

mixtures under similar reaction conditions.

The reaction of 1,1-diethyl 2-benzyl ethenetricarboxyl-

ate (1b) with styrene (2a) or 4-chlorostyrene (2c) gave cis-

substituted -lactones 6a and 6b, respectively, as major

products. The reaction of 2-allyl ester 1c with styrene (2a)

and 4-chloro- 2c and 4-bromostyrene (2d) at room tem-

perature gave cyclobutanes 3h–j. The reaction of 1c with 4-

methylstyrene (2e) at –78 °C gave cyclobutane 3k in 51%

yield. The benzyl ester 1b tends to give -lactones 6 proba-

bly because of stabilization of the eliminated benzyl cation.

4-Halogen substituents in styrenes 2c,d may destabilize the

zwitterion intermediates and result in lower yields. The re-

action of 2-isopropyl and 2-methyl esters 1d and 1e with

styrene (2a) for 1 h gave cyclobutanes 3l and 3m, respec-

tively, in good yields. Using a longer reaction time for the

reaction of 1e and 2a at room temperature led to formation

of alkene 4m.

X

or

N

n

Δ

Ph

X

n

X

n = 0, 1, 2

X = H, Br

Scheme 1 Inter- and intramolecular cycloadditions of styrenes with

ethenetricarboxylates

Although [2+2] cycloadditions of electron-deficient

alkenes and electron-rich alkenes have been reported,⁵re-

actions with styrenes were relatively limited.^9aThe Lewis

acid promoted intermolecular reactions of the triester of

ethenetricarboxylate and styrenes were examined in this

study.

The reaction of triethyl ethenetricarboxylate (1a) and

styrene (2a) using 1 equiv of SnCl₄gave stereoselectively

2,4-cis-substituted cyclobutane 3a in 52% yield as the major

product (Table 1). The stereochemistry was determined by

NOE.

The reactions of 1a and styrene (2a) with various Lewis

acids were examined (Table 1). The reaction of 1a and sty-

rene 2a with 1 equiv of AlCl₃or EtAlCl₂gave a chlorine ad-

duct 5a as the isolable major product. The reaction with

TiCl₄gave a complex mixture containing alkene 4a. The re-

action with 1 equiv of FeCl₃or a catalytic amount of

Sc(OTf)₃gave a 3,5-cis predominant -lactone 6a as the ma-

jor product.

Reaction of triester 1a and 1,1-diphenylethene (7) with

either 1.0 equiv of SnCl₄at r.t., 0.2 equiv SnCl₄at –78 °C, or

Sc(OTf)₃at r.t. or –78 °C gave alkene 8 (Scheme 2). On the

other hand, the reaction with 1.0 equiv SnCl₄at –78 °C gave

cyclobutane 9 in 62% yield.

Next, the reaction of various triesters 1 and styrenes 2

with SnCl₄was examined (Table 2). The appropriate reac-

tion temperatures vary depending on the substituents on

C

S. Yamazaki et al.

Paper

Synthesis

Table 2 Reaction of Ethenetricarboxylates and Styrenes

EtO₂C

CO₂Et

1.0 equiv

SnCl₄

EtO₂C

Ar

+

EtO₂C

RO₂C

CH₂Cl₂

Ar

RO₂C

r.t. or

–78 °C

1

2

3

CO₂Et

EtO₂C

RO₂C

CO₂Et

EtO₂C

RO₂C

5

CO₂Et

EtO₂C

O

Ar

O

Ar

Cl

Ar

4

6

Entry

1

R

2

Ar

Temp. (°C)

Time (h)

Product

Yield (%)

1

1a

1b

1c

1d

1e

Et

2b

4-FC₆H₄

4-ClC₆H₄

4-BrC₆H₄

4-MeC₆H₄

3-FC₆H₄

3-ClC₆H₄

4-O₂NC₆H₄

4-F₃CC₆H₄

4-MeOC₆H₄

Ph

–78^a

r.t.

1

3b

3c

3d

4e

3e

3f

67

2

Et

2c

2d

2e

2f

1

61

3

Et

r.t.

1

74

4

Et

r.t.

1

50

5

Et

–78

r.t.

1

62

6

Et

1

27

7

Et

2g

2h

2i

r.t.

1

3g

5h

30

8

Et

r.t.

1

35 (dr 5:1)

b

9

Et

r.t.

1

–

c

10

11

12

13

14

15

16

17

18

19

Et

2j

r.t/–78

r.t.

–

CH₂Ph

CH₂CH=CH₂

ⁱPr

2a

2c

2a

2c

2d

2e

2a

1

6a

6b

3h

3i

64 (cis)

54 (cis)

46

4-ClC₆H₄

Ph

r.t.

1

r.t.

1

4-ClC₆H₄

4-BrC₆H₄

4-MeC₆H₄

Ph

r.t.

3

28

r.t.

3

3j

24

–78 °C

r.t.

17

1

3k

3l

51

92

Me

Ph

r.t.

1

3m

4m^d

80

Me

Ph

r.t.

20

74

^aThe reaction at r.t. gave 3b in 27% yield and a mixture of possible alkene 4 and chloro adduct 5.

^bA complex mixture.

^cA complex mixture at various conditions.

^dTreatment of 3m with SnCl₄(1 equiv) at r.t. for 20 h in CH₂Cl₂gave 4m in 71% yield.

EtO₂C

CO₂Et

+

EtO₂C

CO₂Et

EtO₂C

CO₂Et

Ph

EtO₂C

CO₂Et

Ph

Lewis acid

CH₂Cl₂

EtO₂C

CO₂Et

+

1.0 equiv

SnCl₄

Ph

+

EtO₂C

CH₂Cl₂

1 h

EtO₂C

Ph

7

1a

10

Ph

9

8

1a

(2 : 1)

r.t. (80%)

13

12

1.0 equiv SnCl₄, r.t., 1 h (95%)

1.0 equiv SnCl₄, –78 °C, 3 h (62%)

CO₂Et

0.2 equiv SnCl₄, –78 °C, 20 h (84%)

0.2 equiv Sc(OTf)₃, r.t., 20 h (92%)

0.2 equiv Sc(OTf)₃, –78 °C, 20 h (91%)

EtO₂C

3

4

+ a complex mixture

O

5

Ph

–78 °C (36%)

O

Scheme 2 Reaction of triethyl ethenetricarboxylate and 1,1-diphenyl-

14a

ethene

CO₂Et

1.0 equiv

EtO₂C

SnCl₄

1a

+

CH₂Cl₂

1 h

Ph

O

Ph

Furthermore, the reactions triester 1a and -methylsty-

rene (10) and trans--methylstyrene (11) were examined

(Scheme 3). The assignable main products were an insepa-

rable mixture of alkene adduct 12 and ene adduct 13 at

room temperature and -lactone 14a at –78 °C for 10 and -

lactone 14b for 11.

11

O

r.t. (74%)

–76 °C (72%)

14b

Scheme 3 Reaction of triethyl ethenetricarboxylate and -methyl-

styrene and trans--methylstyrene

D

S. Yamazaki et al.

Paper

Synthesis

Y_n

M

Vinyl halides are widely utilized in organic synthesis,

especially as substrates for transition-metal-catalyzed C–C

cross-coupling reactions.¹⁴However, the use of vinyl ha-

lides for C–C bond formation retaining a C–X bond has not

been explored fully.¹⁵Meanwhile, utilization of halogens in

ionic reactions as effective substituents have been report-

ed.¹⁶In order to examine the effects of -halogen substitu-

ents, intermolecular reactions of ethenetricarboxylates and

-halostyrenes in the presence of Lewis acid were next car-

ried out (Table 3). The reaction of 1a,d,e and -bromo-

styrenes 15a,b in the presence of SnCl₄or SnBr₄gave

stereoselectively 2,4-cis-4-arylcyclobutane-1,1,2-tricarbox-

ylates 16a,b,d,e as the major product. Reactions in the pres-

ence of a Lewis acid gave alkene adducts 17 and ketone 18

depending on the reaction conditions and substrates. Halo-

gen exchange was observed by the use of Lewis acids con-

taining different halogens (entries 4, 5, 7, 9–11). The reac-

tion may proceed via the formation of ,-dihalogen substi-

tuted intermediates. Formation of 18 may arise from the

hydrolysis of the alkene adducts 17.¹⁷

Y_n

M

EtO₂C

O

Ph

X

EtO

OEt

+

EtO

OEt

Ph

X

EtO₂C

cyclobutane

R¹

O

I

EtO₂C

CO₂Et

EtO₂C

CO₂Et

EtO₂C

CO₂Et

Ph

CO₂Et

EtO₂C

Y

X

Ph

O

Ph

O

γ-lactone

halogen adduct

ene adduct

X = Me

alkene adduct

Scheme 4 Formation of various types of products

Next, intramolecular cycloaddition reactions of various

styrene-functionalized ethenetricarboxylate amides were

investigated. Intramolecular cycloaddition reactions are ef-

ficient methods for construction of variously fused cyclic

systems such as 5-4, 6-4, and 7-4 fused rings via [2+2] cyclo-

addition,^4d–h,18and 5-6, 6-6, and 7-6 fused rings via [4+2]

cycloadditions.¹⁹

In general, 5-4 fused bicyclic compounds have cis-fused

stereochemistry by strain. For 6-4 fused bicyclic com-

pounds, both cis and trans fusions have been reported,

The paths of intermolecular reactions to give various

types of products via common zwitterionic intermediates I

are shown in Scheme 4. The detailed mechanism to give cy-

clobutanes including stereochemistry will be mainly dis-

cussed vide infra.

Table 3 Reaction of Triesters and -Halostyrenes

EtO₂C

CO₂Et

+

EtO₂C

CO₂Et

3

1.0 equiv

SnX₄

EtO₂C

Ar

1

2

4

EtO₂C

RO₂C

X

CH₂Cl₂

X

Ar

3

2

RO₂C

EtO₂C

r.t., 1 h or

–78 °C

15

16

1a: R = Et

1d: R = ⁱPr

1e: R = Me

4

X

Ph

17

(X = F, Cl, Br, I)

EtO₂C

CO₂Et

EtO₂C

O

Ph

18

Entry

1

R

15

15a

Ar

Ph

X

Lewis acid

Temp. (°C) Time (h)

Product

X

Yield (%)

1

1a

1d

1e

1a

Et

ⁱPr

Me

Et

Br

Cl

I

SnBr₄

r.t.

–78

r.t.

–78

r.t.

17

3

16a

Br

55

2

15a

15b

15c

15d

15e

Ph

SnBr₄

16d

Br

Br^a

Cl^b

Br

Cl

59

3

Ph

SnBr₄

3

16e

34

4

Ph

SnCl₄

1

16a

60^a

5

Ph

SnCl₄

1

17_Cl

17_Br/18

16b_Cl

17_Cl

16a/18

17_Cl

17_Cl/18

ca. 64

44/19

20

6

Ph

Sc(OTf)₃/TMSBr^c

SnCl₄

17

1

7

4-MeC₆H₄

8

Ph

SnCl₄

17

Cl

49^d

9

SnBr₄

Br

Cl

25/30^e

26^e

10

11

I

SnCl₄

F

SnCl₄

Cl

22/22

^aBr/Cl 3.7:1; yield is the combined yield.

^bContaining a trace amount of 17_Br (X = Br).

^cSc(OTf)₃(0.2 equiv)/TMSBr (0.9 equiv) in 1,2-dichloroethane.

^dObtained as a mixture with 1a.

^eObtained as a mixture with possible 17_I (X = I).

E

S. Yamazaki et al.

Paper

Synthesis

although the trans-fused system is relatively strained.²⁰It is

of interest to find general methods to synthesize the het-

erocyclic compounds stereoselectively.

We have reported intramolecular cycloaddition reac-

tions of styrene-derived ethenetricarboxylate amides to

give pyrrolidine-fused (5-4 and 5-6) rings via intramolecu-

lar [2+2] and [4+2] cycloadditions.¹³In this work, intramo-

lecular reactions of ethenetricarboxylate to create 6-4 and

7-4 fused rings were initially studied.

Reaction of 1,1,2-ethenetricarboxylic acid 1,1-diethyl

ester (19) and (Z)- and (E)-4-arylbut-3-en-1-amines 20Za,b

and 20Ea,b with EDCI/HOBt/Et₃N at room temperature gave

the corresponding amides 21Za,b and 21Ea,b as isolable

products (see Scheme S1 in Supporting Information).

The Lewis acid promoted reactions of (Z)- and (E)-N-4-

arylbut-3-enylamides of ethenetricarboxylate 21Z and 21E

were examined. The reaction of the (Z)-N-4-arylbut-3-enyl-

amides of ethenetricarboxylate 21Z with 1–1.5 equiv of a

Lewis acid such as SnCl₄gave cis-fused cyclobutanes 22a,b

as the major products in 50–55% yields (Table 4, entries 4–

6). On the other hand, the reaction of (E)-N-4-arylbut-3-

enylamides of ethenetricarboxylate 21E using catalytic

Lewis acid (InBr₃or AlCl₃) gave stereoselectively trans-

fused cyclobutanes 23a,b in lower yields (26–35%) (entries

8, 10–12).

Next, we examined the use of various Lewis acid condi-

tions with the corresponding precursor that would lead to

7-4 fused rings. The reaction of the (E)-N-5-phenylpent-4-

enylamide of ethenetricarboxylate 24E with 1 equiv of AlCl₃

gave a trans-fused 3-azabicyclo[5.2.0]nonane derivative 25

in 42% yield as the major product via [2+2] cycloaddition

(Scheme 5). However, the reaction of Z-isomer 24Z gave a

complex mixture under similar conditions.

Ph

O

2

O

CO₂Et

3

H

CO₂Et

1 equiv AlCl₃

N

9

N

CO₂Et

1

CH₂Cl₂, r.t.

(42%)

4

8

Ph

6

H⁷

5

Ph

25

24E

Ph

O

CO₂Et

N

CO₂Et

Ph

24Z

Scheme 5 Formation of a 7-4 fused ring

Furthermore, to extend the scope of intramolecular cyc-

loadditions of the cinnamyl derivatives, the reactions of

methyl and bromine substitution effects on the alkene moi-

ety (-substitution) of cinnamyl derivatives were investi-

gated. The effects of the benzene ring on chemo- and regio-

selectivity of cycloadditions were also examined.

Table 4 Reactions of (Z)- and (E)-N-4-Arylbut-3-enylamides of Ethenetricarboxylate

CO₂Et

O

2

EtO₂C

O

2

H

1

H

1

CO₂Et

3

Lewis

acid Ph

3

N

O

N

Ph

X

N

8

6

4

7

4

Ph

CH₂Cl₂

r.t.

18–20 h

7

5

X

5

H

21Za: X = H

21Zb: X = Cl

21Ea: X = H

21Eb: X = Cl

X

21Za→ 22a: X = H

21Zb→ 22b: X = Cl

21Ea→ 23a: X = H

21Eb→ 23b: X = Cl

Entry

21

21Za^a,b

X

Lewis acid

Equiv

Product

Yield (%)

1

H

Cl

H

Cl

AlCl₃

TiCl₄

1

22a

22b

23a

23b

21

29

39

50

53

55

25

27

21

35

28

26

2

21Za

21Zb

21Ea^c

21Ea^d

21Ea^e

21Eb

1

3

SnCl₄

AlCl₃

EtAlCl₂

InBr₃

AlCl₃

InBr₃

1

4

1.5

1

5

6

1.5

0.2

7

8

9

10

11

12

^aWithout Lewis acid, toluene, 110 °C gave no reaction.

^bUse of 0.2 equiv of Sc(OTf)₃gave 22a in 12% yield.

^cUse of 0.2 equiv of Sc(OTf)₃gave a complex mixture.

^dUse of 1 equiv of AlCl₃or EtAlCl₂gave a complex mixture.

^eThe reaction for 1 h gave 23a in 26% yield.

F

S. Yamazaki et al.

Paper

Synthesis

First, reactions of 1,1,2-ethenetricarboxylic acid 1,1-di-

ethyl ester (19) and (E)-N-benzyl-3-phenylbut-2-en-1-

amine (26a) in the presence of EDCI/HOBt/Et₃N were exam-

ined (Table 5). The reaction in THF gave cyclobutane-fused

pyrrolidines 27a in 22% yield as the major isolable product;

the reaction in DMF gave 27a in a better yield (49%). The

relative configuration of 27a was determined as shown in

Table 5 by a NOESY experiment. The intermediate amide,

[4+2] cycloadducts, and possible ene adducts were not ob-

served under the reaction conditions. The reaction of 19

and 26a at higher temperatures (80–110 C) in benzene and

toluene gave a complex mixture. The reaction of 19 and (E)-

N-benzyl-3-p-tolylbut-2-en-1-amine (26b) at room tem-

perature gave a mixture possibly containing cyclobutane-

fused pyrrolidine 27b, but the products could not be puri-

fied. The reaction of 19 and 26b at 110 °C in toluene and

DMF gave a complex mixture.

and DMF gave tetrahydrobenz[f]isoindoline 28c-ax (axial

methyl substituent) as the major product via [4+2] cyclo-

addition (Table 5, entries 4–6). The reaction of 19 and 26c

at 110 °C in toluene gave a complex mixture. The stereo-

chemistry of 28c-ax was determined by NOE.

The trans-fused tetrahydrobenz[f]isoindoline 28c-ax

may be formed via amide formation, intramolecular [4+2]

cycloaddition and H-transfer, similar to the reaction of (E)-

cinnamylamines. Selective formation of the stereochemis-

try at the 4-methyl group may arise from the protonation

from the less hindered side (cis to adjacent H), similar to the

reaction of 3,3-diarylprop-2-en-1-amines.^13b

On the other hand, reaction of 19 and (E)-N-benzyl-3-

(4-nitrophenyl)but-2-en-1-amine (26d) with EDCI/HOBt/Et₃N

at room temperature and 110 °C in DMF and toluene gave

tetrahydrobenz[f]isoindoline 28d-eq with the 4-methyl

group cis to adjacent H as the major isolable product. Epi-

merization at C4 of the stereoisomer with 4-methyl trans to

adjacent H initially formed (axial methyl substituent)

would possibly provide the more stable 28d-eq (equatorial

methyl substituent). Related epimerization at C4 of tetrahy-

drobenz[f]isoindoline, using KOH in butanol or DMSO was

reported by Oppolzer and co-workers.²¹

Next, reactions of 1,1,2-ethenetricarboxylic acid 1,1-di-

ethyl ester (19) and cinnamylamines bearing electron-

withdrawing groups in the presence of the amide conden-

sation reagents were examined. Reaction of 19 and (E)-3-

[4-(trifluoromethyl)phenyl]but-2-en-1-amine (26c) with

EDCI/HOBt/Et₃N at room temperature and 110 °C in THF

Table 5 Reaction of 1,1,2-Ethenetricarboxylic Acid 1,1-Diethyl Ester with (E)-3-Arylbut-2-en-1-amines

CO₂Et

O

2

H

1

EtO₂C

HO₂C

CO₂Et

EDCI

HOBt

Et₃N

7

R

+

N

3

5

Ph

6

4

R

H

NH

r.t., 20 h

19

27a: R = H

26a–e: R = H,

4-Me, 4-CF₃,

4-NO₂, 3-NO₂

(27b: R = 4-Me)

Ph

CO₂Et

O

H

1

N

CO₂Et

2

3

EtO₂C

H

EtO₂C

CO₂Et

8

CO₂Et

8

O

H

Ph

O

4

H

9

5

7

NO₂

9

1

CF₃

7

1

9a

O

N

9a

N

3a

N

NO₂

3a

4

N

2

6

2

4

6

Ph

3

5

3

Ph

H

5

H

28c–ax

28d–eq

29

Entry

26

26a

R

Solvent

Temp. (°C)

Product

Yield (%)

1

H

THF

r.t.

110

r.t.

110

r.t.

110

27a

22

2

26a

26b

26c

26d

26e

DMF

49

a

3

4-Me

THF or DMF

THF

–

4

4-CF₃

4-NO₂

3-NO₂

28c-ax

28d-eq

29

60

5

DMF

73

6

DMF

58

7

DMF

24

8

toluene

THF

ca. 60^b

85

9

10

11

DMF

29

80

toluene

29

40

^aA mixture possibly containing 27b, but the products could not be purified.

^bIncluding a small amount of a possible stereoisomer.

G

S. Yamazaki et al.

Paper

Synthesis

Reaction of 19 and (E)-N-benzyl-3-(3-nitrophenyl)but-

2-en-1-amine (26e) with EDCI/HOBt/Et₃N at room tem-

perature and 110 °C gave HOBt-incorporated 3,4-trans-pyr-

rolidine 29 as a single diastereomer in 40–85% yield, in

analogy to the reaction of 3-nitrocinnamylamines and also

3-(3-pyridyl)prop-2-enamide. The stereochemistry of 29

was deduced as shown in Table 5, similar to the proposed

mechanism for formation of those HOBt adducts.^13a

The reaction of 19 and (E)-N-benzyl-3-bromo-3-phenyl-

prop-2-en-1-amine (30E) was examined next (Table 6). Re-

action of 19 and 30E with EDCI/HOBt/Et₃N at room tem-

perature in THF gave the corresponding amide 31E in 75%

yield as an isolable product. The reaction of 19 and 30E on

heating at 80 °C gave cis-fused tricyclic compound 32 in

48% yield.

Treatment of 31E with Et₃N or 1 M HCl in EtOAc in ben-

zene or toluene heating at 80–110 °C gave cis-fused tricyclic

compound 32 in 47–67% yield. The stereochemistry of 32

Table 6 Reactions of 1,1,2-Ethenetricarboxylic Acid 1,1-Diethyl Ester and (E)- and (Z)-3-Aryl-N-benzyl-3-bromoprop-2-en-1-amines

CO₂Et

EtO₂C

Br

reaction

conditions

CO₂Et

+

EtO₂C

HO₂C

O

N

Br

HN

R

Ph

19

30E: R = H

Ph

30Za–d: R = H,Cl,

Me, OMe

31E: R = H

(31Z)

(eq 6)

R

EtO₂C

H

CO₂Et

EtO₂C

H

O

2

CO₂Et

8

CO₂Et

8

H

O

1

O

1

9

R

7

Ph

N

9a

5

9a

3

N

6

N

2

3a

Ph

3a

4

2

4

Ph

6

X

H

3

5

H

Br

33

O

32

N

CO₂Et

EtO₂C

N

Br

Ph

O

2

N

3

35a: R = H

35b: R = Cl

4

N

Br

5

1

Ph

35c: R = Me

34

Entry Starting materials

R

Reagents

Solvent

THF^a

Temp (°C)

Time (h)

Product (yield)

1

19 + 30E

31E

H

Cl

Me

EDCI, HOBt, Et₃N

Et₃N (1 equiv)

r.t.

80

16

18

1^f

31E (75%)

32 (48%)

32 (67%)

32 (47%)

2

benzene

toluene

benzene

DMF

3

80

4

31E

Et₃N (1 equiv)

110

80

b

5

31E

1 M HCl/EtOAc (1 equiv)

–

c

6

31E

80

–

d

7

31E

80

–

8

31E

SnCl₄

CH₂Cl₂

THF

r.t.

33a (X = Cl)/33b (X = Br) 4.4:1 (43%)^e

33b (X = Br 51%), 34 (30%)

35a (74%)

9

31E

SnBr₄

10

11

12

13

14

15

19 + 30Za

19 + 30Zb

19 + 30Zc

EDCI, HOBt, Et₃N

1^g

35a (36%)

DMF

1^h

35a (54%)

CH₂Cl₂

THF

22ⁱ

22

1

35b (38%)

35b (44%)

CH₂Cl₂

35c (18%)

^aDMF, 31E (46%).

^bA mixture mainly containing 32.

^cA mixture containing a small amount of 32.

^dA complex mixture.

^eObtained as an inseparable mixture.

^f22 h, 35a (51%).

^g22 h, 35a (16%).

^h22 h, 35a (54%).

ⁱ1 h, 35b (10%).

H

S. Yamazaki et al.

Paper

Synthesis

was determined by observed NOEs. The possible isolation of

the amide 31E by lower reactivity is probably due to both

steric and electronic effects of the Br group.

kcal/mol), and the sum of product P2 and SnCl₄(–6.00

kcal/mol), respectively, probably because of a 1,3-equatori-

al-like conformation. The paths leading to -lactones

D1 and D2 were also obtained. Activation energy TS5

(B1′ → D1) (+4.74 kcal/mol) and the resulting cis--lactone

D1 (–4.60 kcal/mol) is smaller than that of TS6 (B1 → D2)

(+5.96 kcal/mol) and trans--lactone D2 (–3.58 kcal/mol),

respectively. Reaction with chloride anion inside the reac-

tion media and/or water could give the 3,5-cis-substituted

lactone corresponding to products 6 in Tables 1 and 2. The

formation of the -lactones D1 and D2 may also be revers-

ible process.

Lewis acid catalyzed reaction of the isolated amide 31E

was also examined (Table 6, entries 8 and 9). The reaction

of (E)-N-3-bromo-3-phenylprop-2-enylamide of ethenetri-

carboxylate 31E with SnCl₄gave cyclobutane-fused pyrroli-

dine 33a via halogen exchange. Reaction of the amide 31E

with SnBr₄gave cyclobutane-fused pyrrolidines as the ma-

jor product 33b along with a dibrominated compound 34.²²

The structure of 33b was determined by X-ray crystal struc-

ture analysis (Figure S1 in Supporting Information, CCDC

2020919). The configuration of alkene in 31E was not re-

tained in this case.

Interestingly, reaction of carboxylic acid 19 and (Z)--

bromocinnamylamines 30Za–c with EDCI/HOBT/Et₃N at

room temperature, gave HOBT-incorporated 3,4-trans-pyr-

rolidine fused tricyclic compounds 35a–c as isolable prod-

ucts stereoselectively (Table 6, entries 10–15). The struc-

ture of 35b was determined by X-ray crystal structure anal-

ysis (Table 6, Figure S2 in Supporting Information, CCDC

2020926). The reaction of 19 and 30Zd under the similar

conditions gave a complex mixture.

Cl₄

Sn

MeO

O

SnCl₄

TS5

MeO

O

MeO

OMe

Ph

[+4.74]

OMe

MeO

H

O

Ph

D1

B1'

[–4.60]

[+2.68]

MeO

O

Cl₄

Sn

MeO

SnCl₄

O

SnCl₄

TS1

TS2

MeO₂C

O

[+12.36]

[+5.79]

MeO

OMe

MeO

OMe

Ph

Thus, thermal and Lewis acid promoted reactions of N-

3-bromo-3-phenylprop-2-enylamides gave various types of

cycloadducts, depending on the E- or Z-stereochemistry of

the alkene substrates.

H

Ph

H

C1

Ph

[–1.75]

H

A1

B1

[ΔG° = 0]

CO₂Me

[+1.90]

MeO₂C

We also examined reaction mechanisms for the forma-

tion of various products in an attempt to find the factors

that control the selectivity by using DFT calculations with

model compounds.

Ph

P1

+

SnCl₄

[–7.89]

Cl₄

Sn

MeO

O

TS4

SnCl₄

MeO

TS3

[+11.25]

O

SnCl₄

[+6.66]

O

MeO₂C

MeO

OMe

H

The calculation was performed by B3LYP/6-31G*^23,24(C,

H, N, O, Cl, Al) and LANL2DZ (Sn) level calculations includ-

ing the PCM²⁵solvent effect (solvent = CH₂Cl₂for Schemes

6, 7, 9–11, S2, and S3, or THF for Schemes 12 and 13). TS

geometry was characterized by vibrational analysis, which

checked whether the obtained geometry has single imagi-

nary frequencies (^‡). From TSs, reaction paths were traced

by the intrinsic reaction coordinate (IRC) method²⁶to ob-

tain the energy-minimum geometries. Relative Gibbs free

energies (T = 298.15 K, P = 1 atm) were refined by single-

point calculations of RB3LYP/6-311+G(d,p) (C, H, N, O, Cl,

Al) and SDD (Sn) SCRF = (PCM, solvent = CH₂Cl₂for Schemes

6, 7, 9–11, S2, and S3 or THF for Schemes 12 and 13).

The observed 2,4-cis stereoselectivity in the [2+2] cyclo-

addition of an ethenetricarboxylate and styrene was exam-

ined by DFT calculations (Scheme 6). SnCl₄-catalyzed intra-

molecular [2+2] cycloaddition reaction models for trimeth-

yl ethenetricarboxylate and styrene were calculated.

Stepwise [2+2] cycloaddition via zwitterion intermediates

B1 and B2 were obtained. The cyclobutane ring formation

transition state, TS2 (+5.79 kcal/mol), the cis-cyclobutane

SnCl₄-complex C1 (–1.75 kcal/mol) and the sum of the re-

sulting product P1 and SnCl₄(–7.89 kcal/mol) are more sta-

ble than TS4 (+6.66 kcal/mol), trans-cyclobutane C2 (–0.97

MeO

OMe

Ph

H

Ph

C2

O

[–0.94]

B2

Ph

A2

[+1.87]

[–0.12]

CO₂Me

[+5.96]

MeO₂C

TS6

+

SnCl₄

Ph

P2

Cl₄Sn

OMe

O

[–6.00]

O

MeO

Ph

O

MeO

D2

[–3.58]

Scheme 6 [2+2]-Cycloaddition reaction paths of trimethyl ethenetri-

carboxylate + SnCl₄and styrene; Gibbs free energies in kcal/mol (T =

298.15 K, P = 1 atm) are relative to A1.

Similar to the model calculations for the reaction of sty-

rene, [2+2] cycloaddition path for -bromostyrene was in-

vestigated (Scheme 7). SnBr₄-promoted reaction gave step-

wise [2+2] cycloaddition via zwitterion intermediates BBr1

and BBr2. Although the activation energy TSBr2 (+11.04

kcal/mol) is slightly higher than TSBr4 (+10.43 kcal/mol),

the resulting cis-cyclobutane CBr1 (+2.60 kcal/mol) is

I

S. Yamazaki et al.

Paper

Synthesis

slightly more stable than trans-cyclobutane CBr2 (+2.70

kcal/mol). After decoordination of Sn-dicarbonyl, the

cyclobutane DBr1 (–7.94 kcal/mol) is more stable than

DBr2 (–1.23 kcal/mol). The equilibrium under the reaction

conditions may give the cis (ester/Ph) product stereoselec-

tively.

figuration lead to cis- and trans-fused cyclobutane prod-

ucts. The cis-cyclobutanes Z3 (MX_n= SnCl₄+8.03 kcal/mol,

AlCl₃+6.23 kcal/mol) are more stable than the trans-cy-

clobutanes Z6 (MX_n= SnCl₄+10.84 kcal/mol, AlCl₃+10.60

kcal/mol), probably because of the strain of trans-fused bi-

cycles (Scheme 9).

MeO

O

MeO

O

MeO

Br₄

Sn

O MX_n

MX_n

O

MX_n

SnBr₄

H

O

SnBr₄

ZTS2

O

ZTS1

MeO₂C

O

TSBr2

TSBr1

[+11.73]

O

N

O

N

OMe

[+11.04]

SnCl₄

[+17.42]

AlCl₃

SnCl₄

[+21.16]

AlCl₃

OMe

MeO

OMe

Br

MeO

OMe

Ph

H

Z3

Ph

CBr1

H

Ph

Br

Z1

Ph

Z2

Ph

[+18.62]

[+21.84 ]

[+2.60]

SnCl₄[+12.04]

AlCl₃[+14.21]

SnCl₄[+8.03]

AlCl₃[+6.23]

SnCl₄[ΔG° = 0]

AlCl₃[ΔG° = 0]

Br

O

ABr1

BBr1

[ΔG° = 0]

MeO

[+2.98]

O

MeO

O

MeO

O

MeO₂C

O

ZTS3

MeO

O

ZTS4

MX_n

O

MX_n

O

MX_n

H

OMe

Br

O

SnCl₄

[+15.31]

AlCl₃

SnCl₄

[+14.78]

AlCl₃

N

DBr1

SnBr₄

Ph

OMe

Ph

[–7.94]

Ph

[+16.27]

[+14.53]

H

Ph

Z5

Br₄

Sn

Z4

Z6

MeO

O

SnCl₄[–1.67]

AlCl₃[–0.06]

SnCl₄[+7.22]

AlCl₃[+9.17]

SnCl₄[+10.84]

AlCl₃[+10.60]

O

SnBr₄

MeO₂C

O

TSBr3

TSBr4

MeO

OMe

Br

[+14.59]

OMe

[+10.43]

Scheme 9 [2+2]-Cycloaddition reaction paths of amides, Z1; Gibbs

free energies in kcal/mol (T = 298.15 K, P = 1 atm) relative to Z1 are

shown.

MeO

Ph

Br

H

Br

CBr2

Ph

[+2.70]

Ph

BBr2

ABr2

[1.40]

[+4.64]

MeO

Calculations of SnCl₄- and AlCl₃-catalyzed intramolecu-

lar [2+2]-cycloaddition reaction models for E-amide gave

stepwise [2+2] cycloadditions with retention of the E-con-

figuration leading to trans-fused cyclobutane products E3

(Scheme 10). The first piperidine ring formation transition

states ETS1 (SnCl₄+14.67 kcal/mol, AlCl₃+14.59 kcal/mol)

and the resulting cis-fused zwitterion intermediates E2

(SnCl₄+8.32 kcal/mol, AlCl₃+8.43 kcal/mol) are more stable

than ETS3 (SnCl₄+17.19 kcal/mol, AlCl₃+15.53 kcal/mol)

and E5 (SnCl₄+10.86 kcal/mol, AlCl₃+10.91 kcal/mol), re-

spectively, probably due to steric reasons. The intermediate

E2 gives trans-fused cyclobutane E3. Transition states of the

ring closure from the intermediates E5 to cis-fused cyclo-

butanes E6 could not be obtained.

O

MeO₂C

O

OMe

Ph

SnBr₄

Br

DBr2

[–1.23]

Scheme 7 [2+2]-Cycloaddition reaction paths of trimethyl ethenetri-

carboxylate + SnBr₄and -bromostyrene; Gibbs free energies in

kcal/mol (T = 298.15 K, P = 1 atm) are relative to ABr1.

Furthermore, halogen exchange mechanism was consid-

ered. The reaction path shown in Scheme S2 in the Sup-

porting Information leads to the formation of Cl-containing

products FBrCl and HBrCl via the formation of dihalogen-

substituted model intermediate DBrCl (Scheme 8).

MeO

Cl₃

Sn

Cl₃

Sn

MeO

O

MX_n

O

H

MX_n

MeO

O

ETS2

O

ETS1

O

SnCl₄

O

N

MeO₂C

N

O

OMe

MeO

OMe

Ph

MeO

OMe

Cl

SnCl₄

[+14.93]

AlCl₃

SnCl₄

[+14.87]

AlCl₃

OMe

Ph

OMe

Ph

OMe

Cl

H

Ph

E1

E2

E3

BrCl₃Sn

[+12.75]

[+14.59]

Br

Ph

O

Cl

O

H

SnCl₄[+8.32]

AlCl₃[+8.43]

SnCl₄[+11.99]

AlCl₃[+9.16]

SnCl₄[ΔG° = 0]

AlCl₃[ΔG° = 0]

Cl

Cl₄Sn

Cl₃BrSn

FBrCl

HBrCl

DBrCl

MeO

O

MeO

O

MeO

O

MX_n

O

MX_n

Scheme 8 Reaction models for halogen exchange

MX_n

H

ETS3

O

N

OMe

Ph

SnCl₄

[+17.19]

AlCl₃

OMe

Ph

H

The origin of observed selectivities of formation of the

cis- and trans-cyclobutane-fused piperidines from Z- and E-

amides was examined by DFT calculations. Lewis acids,

SnCl₄- and AlCl₃-catalyzed intramolecular [2+2]-cycloaddi-

tion reaction models for Z and E-amides were calculated.

Stepwise [2+2] cycloadditions with retention of the Z-con-

E4

E5

E6

[+15.53]

SnCl₄[+12.60]

AlCl₃[+11.24]

SnCl₄[+10.86]

AlCl₃[+10.91]

SnCl₄[+3.53]

AlCl₃[+1.46]

Scheme 10 [2+2]-Cycloaddition reaction paths of amides, E1; Gibbs

free energies in kcal/mol (T = 298.15 K, P = 1 atm) relative to E1 are

shown.

J

S. Yamazaki et al.

Paper

Synthesis

Br₄

Sn

In addition, the 7-4 ring formation was examined. As

shown in Scheme S3 in the Supporting Information, AlCl₃-

promoted reactions show preference for the E-isomer to

form the trans-fused cyclobutane over cis-fused isomer,

and the Z-isomer to form the cis-fused cyclobutane forma-

tion over trans-fused isomer. The activation energies and

relative energies of zwitterionic intermediates are higher

than those of Al-promoted 6-4 ring formation (in Scheme 9

and 10), probably because of the steric effects by the com-

mon difficulty of 7-membered ring formation compared to

6-membered ring formation. Therefore, unwanted reac-

tions such as intermolecular reactions may occur and only

trans-fused 7-4 product 25 (in Scheme 5) was obtained

from the E-alkene precursor.

SnBr₄

O

N

O

MeO

H

SnBr₄

O

MeO

O

OMe

O

TSEL2

TSEL1

O

H

OMe

[+11.07]

[+17.71]

OMe

N

Br

H

Br

AEL

BEL

[+7.52]

CEL

[+11.35]

[ΔG° = 0]

SnBr₄

O

Br₄

Sn

O

MeO

SnBr₄

O

N

MeO

O

TSZL2

O

TSZL1

H

OMe

O

H

[+13.21]

MeO

O

OMe [+8.13]

OMe

N

Br

H

Br

Next, SnBr₄-catalyzed intramolecular [2+2] cycloaddi-

tion reaction models of the E-isomer in Table 6 and the cor-

responding Z-isomer models were calculated (Scheme 11).

Here, E/Z notation is opposite to that of bromine-unsubsti-

tuted styrene derivatives with respect to the styryl geome-

try. Stepwise [2+2] cycloaddition with retention of the E-

configuration leads to cyclobutane-fused product CEL. The

cyclobutane ring formation transition state, TSEL2 (+17.71

kcal/mol) and the resulting cyclobutane CEL (+11.35

kcal/mol) are less stable than those from the corresponding

Z-isomer, TSZL2 (+13.21 kcal/mol) and CZL (+3.50

kcal/mol), respectively, probably because of the steric effect

of the phenyl group. The conversion of zwitterionic inter-

mediate BEL into more stable BZL and subsequent ring clo-

sure may occur, leading to the inversion of the original

alkene stereochemistry. The cation intermediates BEL and

BZL may be stabilized by the lone pair of the -bromine. For

example, C–Br bond lengths of BEL and BZL are 1.860 Å and

1.867 Å, respectively, while C–Br bond lengths of AEL, CEL,

AZL, and CZL are 1.932–2.007 Å. The stabilization may fa-

cilitate the interconversion of the intermediates.

H

Br

AZL

BZL

CZL

[+3.50]

[–0.75]

[+6.14]

Scheme 11 [2+2]-Cycloaddition reaction paths of amide, AEL; Gibbs

free energies in kcal/mol (T = 298.15 K, P = 1 atm) relative to AEL are

shown.

MeO₂C

CO₂Me

H

MeO₂C

CO₂Me

O

H

TSEM1

O

N

TSEM2

N

[ΔG^‡= +29.74]

[ΔE^‡= +25.95]

[ΔG^‡= +31.08]

[ΔE^‡= +26.75]

H

Br

CEM

Br

AEM

[ΔG° = 0]

[ΔE° = 0]

BEM

[ΔG° = +29.80]

[ΔE° = +26.32]

[ΔG° = +8.42]

[ΔE° = +4.18]

MeO₂C

O

CO₂Me

H

9a

e

a

N

3a

⁴e

Br

H⁺shift

H

DEM

[ΔG° = –17.01]

[ΔE° = –21.87]

MeO₂C

CO₂Me

MeO₂C

O

CO₂Me

O

CO₂Me

MeO₂C

H

TSZM1

H

Finally, the reaction mechanism for formation of [4+2]

cycloadduct without Lewis acid (Scheme 12) and the subse-

quent HOBt substitution was considered (Scheme 13). The

reason why HOBt-incorporated products 35 are formed

from Z-amines 30Z (in Table 6) and the corresponding HOBt

products are not formed from E-amine 30E is discussed.

For formation of cis-fused [4+2] cycloadduct CEM, step-

wise path via zwitterionic intermediate BEM was obtained

by DFT calculations similar to the previously reported di-

phenylpropenium substrates.^13bFor formation of trans-

fused [4+2] cycloadduct CZM, the asynchronous and con-

certed path was obtained. The activation energies TSZM1

(ΔG^‡= +24.82 kcal/mol, ΔE^‡= +21.15 kcal/mol) leading to

CZM are lower than TSEM1 (ΔG^‡= +29.74 kcal/mol, ΔE^‡=

+25.95 kcal/mol) and TSEM2 (ΔG^‡= +31.08 kcal/mol, ΔE^‡=

+26.75 kcal/mol) leading to CEM, respectively, similar to the

previously reported diphenylpropenium substrates.^13b

Thus, compound 31E (in Table 6) corresponding to model

AEM is isolable at room temperature and the [4+2] cyclo-

e

9a

3a

O

N

[ΔG^‡= +24.82]

[ΔE^‡= +21.15]

H⁺shift

⁴a

Br

e

N

H

Br

AZM

CZM

DZM

[ΔG° = 0]

[ΔE° = 0]

[ΔG° = +13.84]

[ΔE° = +10.32]

[ΔG° = –22.47]

[ΔE° = –26.06]

Scheme 12 [4+2]-Cycloaddition reaction paths of AEM and AZM;

Gibbs free energies in kcal/mol (T = 298.15 K, P = 1 atm) relative to AEM

and AZM, respectively, are shown; ΔE (sum of electronic and zero-point

energies) in kcal/mol are also shown.

addition proceeds at higher temperature (80–110 °C), while

31Z (shown in Table 6) corresponding to AZM is not ob-

served at room temperature.

The possible stepwise protonation-deprotonation (H⁺

1,3-shift) may occur next. Stereoselective protonation from

less hindered side (cis to adjacent H) leads formation of

DEM for E-isomer and DZM for Z-isomer, respectively. The

preferred conformation of the cyclohexane ring in the

formed tricyclic compound DEM may have equatorial-,

K

S. Yamazaki et al.

Paper

Synthesis

voltage of 70 eV by EI, FAB, CI, or ESI. Mass analyzer type used for EI,

FAB, and CI is double-focusing and that for ESI is TOF in the HRMS

measurements. All reactions were carried out under a nitrogen atmo-

sphere. Column chromatography was performed on silica gel (75–150

m). Abbreviations: HOBt (1-hydroxybenzotriazole), EDCI (1-[3-(di-

methylamino)propyl]-3-ethylcarbodiimide hydrochloride).

H

O

MeO

O

MeO

O

OMe

OBt

OMe

Br

H

TSa

e

N

[+12.06]

a

e

Br

a

OBt

H

Ethenetricarboxylates 1²⁷and 19²⁷and -halostyrenes 15b,²⁸15c,²⁹

15d,³⁰and 15e³¹were prepared according to the literature.

DES

DEP

[–7.76]

[ΔG° = 0]

H

2,4-Triethyl cis-4-Phenylcyclobutane-1,1,2-tricarboxylate (3a);

Typical Procedure (Table 1, Entry 1)

H

O

MeO

O

OMe

OBt

O

OMe

Br

H

To a solution of 1a (122 mg, 0.5 mmol) in CH₂Cl₂(1.5 mL) was added

SnCl₄(60 L, 130 mg, 0.5 mmol) at 0 °C, and then 2a (52 mg, 57 L,

0.5 mmol). The mixture was allowed to warm to r.t. and stirred for 1

h. Water (1.5 mL) was added to the mixture at 0 °C and it was extract-

ed with CH₂Cl₂. The organic phase was washed with sat. aq NaHCO₃

solution, dried (Na₂SO₄), and evaporated in vacuo. The residue was

purified by column chromatography (silica gel, hexane/Et₂O) to give

3a as a colorless oil; yield: 91 mg (52%); R_f= 0.4 (hexane/Et₂O 2:1).

TSb

H

e

N

e

[+11.32 ]

N

e

a

e

H

e

H

Br

OBt

DZS

[ΔG° = 0]

DZP

[–8.31]

Scheme 13 HOBt substitution reaction paths; Gibbs free energies in

kcal/mol (T = 298.15 K, P = 1 atm) relative to DES and DZS, respectively,

are shown.

IR (neat): 2982, 1733, 1448, 1369, 1267, 1196, 1093, 1029 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.776 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 1.35 (t, J = 7.1 Hz, 3 H), 2.45 (ddd, J = 11.2, 9.1, 9.0 Hz, 1 H),

3.03 (ddd, J = 11.2, 11.2, 10.4 Hz, 1 H), 3.43 (dd, J = 10.4, 9.1 Hz, 1 H),

3.64–3.81 (m, 2 H), 4.14–4.21 (m, 3 H), 4.29–4.37 (m, 2 H), 7.19–7.23

(m, 1 H), 7.26–7.30 (m, 2 H), 7.33–7.36 (m, 2 H). Selected NOEs are

between  2.45 (C3-HH) and  3.43 (C2-H), 4.14–4.21 (C4-H, over-

lapped), between  3.43 (C2-H) and  4.14–4.21 (C4-H), and between

 3.03 (C3-HH) and  7.33–7.36 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.51 (CH₃), 14.15 (CH₃), 14.20

(CH₃), 24.11 (CH₂), 40.48 (CH), 41.71 (CH), 60.81 (CH₂), 61.21 (CH₂),

61.76 (CH₂), 63.35 (C), 127.09 (CH), 127.66 (CH), 128.12 (CH), 138.13

(C), 167.67 (C), 170.76 (C), 171.60 (C). Selected HMBC correlations are

between  2.45 (C3-HH), 3.43 (C2-H), 4.14–4.21 (C4-H) and  63.35

(C1), between  3.43 (C2-H), 4.14–4.21 (C4-H) and  24.11 (C3), and

between  7.33–7.36 (Ph-H) and  41.71 (C4).

axial-, and equatorial-like substituents at C9a, C3a, and C4,

while that in DZM may have equatorial-, equatorial-, and

axial-like substituents at C9a, C3a, and C4.

Stereoselective formation of the HOBt-incorporated

product may arise from S_N2 substitution reaction of the

bromide. The S_N2 reaction of DZM (in Scheme 12) may give

stable e,e,e conformation product by inversion of C4 stereo-

chemistry. On the other hand, possible S_N2 reaction of DEM

(in Scheme 12) would give a less stable product with e,a,a-

conformation. The calculations of S_N2 reactions using the

reaction models shown in Scheme 13 give the result that

the activation energy TSb (+11.32 kcal/mol) from DZS (DZM

+ HOBt) to DZP (a model for products 35 in Table 6) is lower

than TSa (+12.06 kcal/mol) from DES (DEM + HOBt) to DEP.

Further study for formation of HOBt-incorporated product

is underway.

MS (EI): m/z (%) = 348 (M⁺, 22), 303 (47), 275 (92), 229 (96), 104

(100).

HRMS (EI): m/z calcd for C₁₉H₂₄O₆: 348.1573; found: 348.1574.

In summary, inter- and intramolecular cycloaddition re-

actions of ethenetricarboxylates with styrene and -halo-

styrene moieties under the Lewis acid promoted or sequen-

tial thermal conditions were investigated. The scope and

limitations are described. The stereoselective cyclobutane

formations for intermolecular reactions were found. The in-

tramolecular cycloaddition reactions of a series of styrene-

functionalized ethenetricarboxylate amides, including in

situ generated derivatives, show high diversity of reaction

modes depending on the structures and substituents of the

substrates. The stereoselectivity and chemoselectivity are

explained by use of DFT calculations. Further utility of

these reactions and transformation of the products to use-

ful compounds are under investigation.

Triethyl cis-4-(4-Fluorophenyl)cyclobutane-1,1,2-tricarboxylate

(3b) (Table 2, Entry 1)

Scale: 0.5 mmol; colorless oil; yield: 122 mg (67%); R_f= 0.4 (hexane/

Et₂O 1:1).

IR (neat): 2982, 1733, 1606, 1515, 1506, 1372, 1304, 1161, 1102 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.834 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 1.34 (t, J = 7.1 Hz, 3 H), 2.45 (ddd, J = 11.1, 9.6, 9.2 Hz, 1 H),

2.98 (ddd, J = 11.1, 10.9, 10.0 Hz, 1 H), 3.42 (dd, J = 10.0, 9.6, 1 H),

3.68–3.84 (m, 2 H), 4.12 (dd, J = 11.1, 9.2 Hz, 1 H), 4.14–4.22 (m, 2 H),

4.27–4.39 (m, 2 H), 6.97 (dd, J_HH= 8.7 Hz, J_FH= 8.7 Hz, 1 H), 7.32 (dd,

J_HH= 8.7 Hz, J_FH= 5.5 Hz, 1 H). Selected NOEs are between  2.45 (C3-

HH) and  3.42 (C2-H), 4.12 (C4-H), between  3.42 (C2-H) and  4.12

(C4-H), and between  2.98 (C3-HH) and  7.32 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.62 (CH₃), 14.15 (CH₃), 14.20

(CH₃), 24.35 (CH₂), 40.40 (CH), 41.10 (CH), 60.85 (CH₂), 61.31 (CH₂),

61.81 (CH₂), 63.29 (C), 114.92 (CH, J_FC= 21 Hz), 129.34 (CH, J_FC= 7.7

Hz), 133.84 (C, J_FC= 3.1 Hz), 162.05 (C, J_FC= 245 Hz), 167.56 (C), 170.68

(C), 171.44 (C). Selected HMBC correlations are between  2.45 (C3-

¹H NMR are reported relative to TMS, ¹³C NMR relative to CDCl₃( =

77.1), and ¹⁹F NMR relative to CFCl₃. ¹³C Multiplicities were deter-

mined by DEPT and HSQC. Mass spectra were recorded at an ionizing

L

S. Yamazaki et al.

Paper

Synthesis

HH), 3.42 (C2-H), 4.12 (C4-H) and  63.29 (C1), between  3.42 (C2-H),

4.12 (C4-H) and  24.35 (C3), and between  7.32 (Ar-H) and  41.10

(C4).

¹⁹F NMR (376.3 MHz, CDCl₃):  = –115.90 (tt, J_FH= 9.2, 5.7 Hz).

Triethyl cis-4-(4-Methylphenyl)cyclobutane-1,1,2-tricarboxylate

(3e) (Table 2, Entry 5)

Scale: 0.5 mmol; colorless oil; yield: 113 mg (62%); R_f= 0.5 (hexane/

Et₂O 1:1).

IR (neat): 2981, 1731, 1516, 1446, 1372, 1266, 1083, 1038 cm^–1

.

MS (EI): m/z (%) = 366 (M⁺, 1.4), 321 (2.5), 293 (20), 247 (32), 122

¹H NMR (400 MHz, CDCl₃):  = 0.809 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 1.34 (t, J = 7.1 Hz, 3 H), 2.30 (s, 3 H), 2.43 (ddd, J = 11.1, 9.4,

8.8 Hz, 1 H), 3.00 (ddd, J = 11.1, 11.1, 10.4 Hz, 1 H), 3.42 (dd, J = 10.4,

9.4 Hz, 1 H), 3.67–3.82 (m, 2 H), 4.12 (dd, J = 11.1, 8.8 Hz, 1 H), 4.13–

4.22 (m, 2 H), 4.27–4.38 (m, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 7.22 (d, J =

8.0 Hz, 2 H). Selected NOEs are between  2.43 (C3-HH) and  3.42

(C2-H), 4.12 (C4-H), between  3.42 (C2-H) and  4.12 (C4-H), and be-

tween  3.00 (C3-HH) and  7.22 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.51 (CH₃), 14.12 (CH₃), 14.18

(CH₃), 21.08 (CH₃), 24.16 (CH₂), 40.43 (CH), 41.51 (CH), 60.73 (CH₂),

61.15 (CH₂), 61.66 (CH₂), 63.35 (C), 127.54 (CH), 128.73 (CH), 134.97

(C), 136.62 (C), 167.66 (C), 170.77 (C), 171.62 (C). Selected HMBC cor-

relations are between  2.43 (C3-HH), 3.42 (C2-H), 4.12 (C4-H) and 

63.35 (C1), between  3.42 (C2-H), 4.12 (C4-H) and  24.16 (C3), and

between  7.22 (Ar-H) and  41.51 (C4).

(100).

HRMS (EI): m/z calcd for C₁₉H₂₃FO₆: 366.1479; found: 366.1474.

Triethyl cis-4-(4-Chlorophenyl)cyclobutane-1,1,2-tricarboxylate

(3c) (Table 2, Entry 2)

Scale: 0.5 mmol; colorless oil; yield: 116 mg (61%); R_f= 0.3 (hexane/

Et₂O 2:1).

IR (neat): 2982, 1735, 1493, 1374, 1268, 1197 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.848 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 1.34 (t, J = 7.1 Hz, 3 H), 2.45 (ddd, J = 11.1, 9.2, 8.9 Hz, 1 H),

2.97 (ddd, J = 11.3, 11.1, 10.5 Hz, 1 H), 3.43 (dd, J = 10.5, 9.2 Hz, 1 H),

3.70–3.85 (m, 2 H), 4.10 (dd, J = 11.3, 8.9 Hz, 1 H), 4.14–4.21 (m, 2 H),

4.27–4.39 (m, 2 H), 7.24–7.30 (m, 4 H). Selected NOEs are between 

2.45 (C3-HH) and  3.43 (C2-H), 4.10 (C4-H), between  3.43 (C2-H)

and  4.10 (C4-H), and between  2.97 (C3-HH) and  7.24–7.30 (Ar-

H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.61 (CH₃), 14.14 (CH₃), 14.19

(CH₃), 24.23 (CH₂), 40.43 (CH), 41.14 (CH), 60.87 (CH₂), 61.37 (CH₂),

61.85 (CH₂), 63.19 (C), 128.23 (CH), 129.08 (CH), 132.95 (C), 136.69

(C), 167.50 (C), 170.61 (C), 171.37 (C). Selected HMBC correlations are

between  2.45 (C3-HH), 3.43 (C2-H), 4.10 (C4-H) and  63.19 (C1),

between  3.43 (C2-H), 4.10 (C4-H) and  24.23 (C3), and between 

7.24–7.30 (Ar-H) and  41.14 (C4).

MS (EI): m/z (%) = 362 (M⁺, 4.2), 317 (3.9), 289 (20), 243 (27), 118

(100).

HRMS (EI): m/z calcd for C₂₀H₂₆O₆: 362.1729; found: 362.1724.

Triethyl cis-4-(3-Fluorophenyl)cyclobutane-1,1,2-tricarboxylate

(3f) (Table 2, Entry 6)

Scale: 0.5 mmol; colorless oil; yield: 49 mg (27%); R_f= 0.5 (hexane/

Et₂O 1:1).

IR (neat): 2983, 1731, 1616, 1589, 1445, 1374, 1272, 1197, 1090 cm^–1

.

MS (EI): m/z (%) = 384 (M⁺, 3.2), 382 (M⁺, 7.1), 337 (7.1). 309 (31), 263

¹H NMR (400 MHz, CDCl₃):  = 0.841 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 1.35 (t, J = 7.1 Hz, 3 H), 2.47 (ddd, J = 11.1, 9.2, 8.9 Hz, 1 H),

2.98 (ddd, J = 11.1, 11.1, 10.3 Hz, 1 H), 3.45 (dd, J = 10.3, 9.2 Hz, 1 H),

3.72–3.86 (m, 2 H), 4.13 (dd, J = 11.1, 8.9 Hz, 1 H), 4.14–4.22 (m, 2 H),

4.30–4.38 (m, 2 H), 6.91 (ddd, J_HH= 8.3, 2.5 Hz, J_FH= 8.3 Hz, 1 H), 7.07

(d, J_FH= 10.2 Hz, 1 H), 7.12 (dd, J = 7.6, 0.8 Hz, 1 H), 7.25 (ddd, J_HH= 7.9,

7.9 Hz, J_FH= 6.1 Hz, 1 H). Selected NOEs are between  2.47 (C3-HH)

and  3.45 (C2-H), 4.13 (C4-H), between  3.45 (C2-H) and  4.13 (C4-

H), and between  2.98 (C3-HH) and  7.07, 7.12 (Ar-H).

(37), 138 (100).

HRMS (EI): m/z calcd for C₁₉H₂₃ClO₆: 382.1183, 384.1154; found:

382.1184, 384.1178.

Triethyl cis-4-(4-Bromophenyl)cyclobutane-1,1,2-tricarboxylate

(3d) (Table 2, Entry 3)

Scale: 0.5 mmol; colorless oil; yield: 158 mg (74%); R_f= 0.4 (hexane/

Et₂O 1:1).

IR (neat): 2980, 1732, 1570, 1368, 1269, 1079, 1011 cm^–1

.

¹³C NMR (100.6 MHz, CDCl₃):  = 13.56 (CH₃), 14.13 (CH₃), 14.18

(CH₃), 24.30 (CH₂), 40.42 (CH), 41.29 (CH), 60.88 (CH₂), 61.36 (CH₂),

61.88 (CH₂), 63.13 (C), 113.95 (CH, J_FC= 21 Hz), 114.70 (CH, J_FC= 21

¹H NMR (400 MHz, CDCl₃):  = 0.850 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 1.34 (t, J = 7.1 Hz, 3 H), 2.45 (ddd, J = 11.1, 9.4, 8.8 Hz, 1 H),

2.97 (ddd, J = 11.3, 11.1, 10.2 Hz, 1 H), 3.43 (dd, J = 10.2, 9.4 Hz, 1 H),

3.70–3.85 (m, 2 H), 4.08 (dd, J = 11.3, 8.8 Hz, 1 H), 4.13–4.21 (m, 2 H),

4.27–4.39 (m, 2 H), 7.23 (d, J = 8.3 Hz, 2 H), 7.41 (d, J = 8.3 Hz, 2 H).

Selected NOEs are between  2.45 (C3-HH) and  3.43 (C2-H), 4.08

(C4-H), between  3.43 (C2-H) and  4.08 (C4-H), and between  2.97

(C3-HH) and  7.23 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.58 (CH₃), 14.10 (CH₃), 14.16

(CH₃), 24.15 (CH₂), 40.40 (CH), 41.16 (CH), 60.83 (CH₂), 61.34 (CH₂),

61.81 (CH₂), 63.09 (C), 121.04 (C), 129.41 (CH), 131.14 (CH), 137.20

(C), 167.46 (C), 170.55 (C), 171.31 (C). Selected HMBC correlations are

between  2.45 (C3-HH), 3.43 (C2-H), 4.08 (C4-H) and  63.09 (C1),

between  3.43 (C2-H), 4.08 (C4-H) and  24.15 (C3), and between 

7.23 (Ar-H) and  41.16 (C4).

Hz), 123.24 (CH, J_FC= 2.3 Hz), 129.58 (CH, J_FC= 8.4 Hz), 140.91 (C, J_FC

=

7.7 Hz), 162.74 (C, J_FC= 245 Hz), 167.50 (C), 170.56 (C), 171.35 (C). Se-

lected HMBC correlations are between  2.47 (C3-HH), 3.45 (C2-H),

4.13 (C4-H) and  63.13 (C1), between  3.45 (C2-H), 4.13 (C4-H) and

 24.30 (C3), and between  7.07, 7.12 (Ar-H) and  41.29 (C4).

¹⁹F NMR (376.3 MHz, CDCl₃):  = –113.62 (ddd, J_FH= 9.8, 9.8, 5.7 Hz).

MS (EI): m/z (%) = 366 (M⁺, 1.8), 321 (4.2), 293 (16), 247 (30), 122

(100).

HRMS (EI): m/z calcd for C₁₉H₂₃FO₆: 366.1479; found: 366.1477.

Triethyl cis-4-(3-Chlorophenyl)cyclobutane-1,1,2-tricarboxylate

(3g) (Table 2, Entry 7)

MS (EI): m/z (%) = 428 (M⁺, 2.8), 426 (M⁺, 2.8), 383 (2.8), 381 (2.8), 355

Scale: 0.5 mmol; colorless oil; yield: 57 mg (30%); R_f= 0.5 (hexane/

Et₂O 1:1).

(20), 353 (20), 309 (27), 307 (27), 184 (96), 182 (100).

IR (neat): 2983, 1735, 1598, 1570, 1476, 1374, 1271, 1195, 1084 cm^–1

.

HRMS (EI): m/z calcd for C₁₉H₂₃BrO₆: 426.0678, 428.0658; found:

426.0680, 428.0666.

M

S. Yamazaki et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃):  = 0.851 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 1.36 (t, J = 7.1 Hz, 3 H), 2.46 (ddd, J = 11.2, 9.2, 8.8 Hz, 1 H),

2.98 (ddd, J = 11.2, 11.1, 10.4 Hz, 1 H), 3.44 (dd, J = 10.4, 9.2 Hz, 1 H),

3.72–3.87 (m, 2 H), 4.09–4.22 (m, 2 H), 4.11 (dd, J = 11.1, 8.8 Hz, 1 H),

4.30–4.38 (m, 2 H), 7.18–7.26 (m, 3 H), 7.35 (br s, 1 H). Selected NOEs

are between  2.46 (C3-HH) and  3.44 (C2-H), 4.11 (C4-H), between 

3.44 (C2-H) and  4.11 (C4-H), and between  2.98 (C3-HH) and 

7.18–7.26, 7.35 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.57 (CH₃), 14.12 (CH₃), 14.18

(CH₃), 24.19 (CH₂), 40.41 (CH), 41.21 (CH), 60.88 (CH₂), 61.40 (CH₂),

61.88 (CH₂), 63.12 (C), 125.84 (CH), 127.22 (CH), 127.86 (CH), 129.39

(C), 134.05 (C), 140.32 (C), 167.44 (C), 170.51 (C), 171.32 (C). Selected

HMBC correlations are between  2.46 (C3-HH), 3.44 (C2-H), 4.11 (C4-

H) and  63.12 (C1), between  3.44 (C2-H), 4.11 (C4-H) and  24.19

(C3), and between  7.18–7.26, 7.35 (Ar-H) and  41.21 (C4).

lected NOEs are between  2.47 (C3-HH) and  3.47 (C2-H), 4.12 (C4-

H), between  3.47 (C2-H) and  4.12 (C4-H), and between  2.99 (C3-

HH) and  7.24–7.30 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.61 (CH₃), 14.15 (CH₃), 24.22

(CH₂), 40.38 (CH), 41.15 (CH), 61.47 (CH₂), 61.91 (CH₂), 63.18 (C),

65.47 (CH₂), 117.97 (CH₂), 128.24 (CH), 129.08 (CH), 132.00 (CH),

132.98 (C), 136.59 (C), 167.48 (C), 170.56 (C), 171.08 (C). Selected

HMBC correlations are between  2.47 (C3-HH), 3.47 (C2-H), 4.12 (C4-

H) and  63.18 (C1), between  3.47 (C2-H), 4.12 (C4-H) and  24.22

(C3), and between  7.24–7.30 (Ar-H) and  41.15 (C4).

MS (EI): m/z (%) = 396 (M⁺, 0.7), 394 (M⁺, 1.4), 309 (15), 263 (35), 138

(100).

HRMS (EI): m/z calcd for C₂₀H₂₃ClO₆: 394.1183, 396.1154; found:

394.1186, 396.1176.

MS (EI): m/z (%) = 384 (M⁺, 1.4), 382 (M⁺, 4.2), 337 (6.3), 309 (30), 263

(52), 138 (100).

2-Allyl 1,1-Diethyl cis-4-(4-Bromophenyl)cyclobutane-1,1,2-tri-

carboxylate (3j) (Table 2, Entry 15)

HRMS (EI): m/z calcd for C₁₉H₂₃ClO₆: 382.1183, 384.1154; found:

382.1186, 384.1174.

Scale: 0.5 mmol; colorless oil; yield: 52 mg (24%); R_f= 0.5 (hexane/

Et₂O 3:1).

IR (neat): 2983, 1732, 1649, 1489, 1368, 1300, 1079, 1012 cm^–1

.

2-Allyl 1,1-Diethyl cis-4-Phenylcyclobutane-1,1,2-tricarboxylate

¹H NMR (400 MHz, CDCl₃):  = 0.846 (t, J = 7.1 Hz, 3 H), 1.34 (t, J = 7.1

Hz, 3 H), 2.47 (ddd, J = 11.1, 9.1, 9.0 Hz, 1 H), 2.99 (ddd, J = 11.1, 11.1,

10.9 Hz, 1 H), 3.48 (dd, J = 10.9, 9.1 Hz, 1 H), 3.69–3.84 (m, 2 H), 4.10

(dd, J = 11.1, 9.0 Hz, 1 H), 4.27–4.40 (m, 4 H), 4.62 (d, J = 5.5 Hz, 2 H),

5.21 (dd, J = 10.4, 1.2 Hz, 1 H), 5.35 (dd, J = 17.2, 1.6 Hz, 1 H), 5.90 (ddt,

J = 17.2, 10.4, 5.5 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2

H). Selected NOEs are between  2.47 (C3-HH) and  3.48 (C2-H), 4.10

(C4-H), between  3.48 (C2-H) and  4.10 (C4-H), and between  2.99

(C3-HH) and  7.22 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.59 (CH₃), 14.13 (CH₃), 24.16

(CH₂), 40.37 (CH), 41.19 (CH), 61.46 (CH₂), 61.90 (CH₂), 63.10 (C),

65.44 (CH₂), 117.95 (CH₂), 121.10 (C), 129.43 (CH), 131.18 (CH),

131.97 (CH), 137.11 (C), 167.44 (C), 170.52 (C), 171.04 (C). Selected

HMBC correlations are between  2.47 (C3-HH), 3.48 (C2-H), 4.10 (C4-

H) and  63.10 (C1), between  3.48 (C2-H), 4.10 (C4-H) and  24.16

(C3), and between  7.22 (Ar-H) and  41.19 (C4).

(3h) (Table 2, Entry 13)

Scale: 0.5 mmol; colorless oil; yield: 83 mg (46%); R_f= 0.3 (hexane/

Et₂O 2:1).

IR (neat): 2983, 1736, 1648, 1497, 1449, 1369, 1266, 1197, 1092, 1074

cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.774 (t, J = 7.1 Hz, 3 H), 1.34 (t, J = 7.1

Hz, 3 H), 2.47 (ddd, J = 11.1, 9.3, 8.8 Hz, 1 H), 3.05 (ddd, J = 11.3, 11.1,

10.3 Hz, 1 H), 3.47 (dd, J = 10.3, 9.3 Hz, 1 H), 3.63–3.80 (m, 2 H), 4.18

(dd, J = 11.3, 8.8 Hz, 1 H), 4.27–4.40 (m, 2 H), 4.62 (ddd, J = 5.5, 1.6, 1.4

Hz, 1 H), 5.21 (ddt, J = 10.6, 1.5, 1.4 Hz, 1 H), 5.35 (dtd, J = 17.2, 1.6, 1.5

Hz, 1 H), 5.91 (ddt, J = 17.2, 10.6, 5.5 Hz, 1 H), 7.19–7.22 (m, 1 H),

7.26–7.30 (m, 2 H), 7.33–7.36 (m, 2 H). Selected NOEs are between 

2.47 (C3-HH) and  3.47 (C2-H), 4.18 (C4-H), between  3.47 (C2-H)

and  4.18 (C4-H), and between  3.05 (C3-HH) and  7.33–7.36 (Ph-

H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.49 (CH₃), 14.15 (CH₃), 24.10

(CH₂), 40.43 (CH), 41.72 (CH), 61.27 (CH₂), 61.78 (CH₂), 63.35 (C),

65.37 (CH₂), 117.87 (CH₂), 127.10 (CH), 127.65 (CH), 128.10 (CH),

132.09 (CH), 138.03 (C), 167.59 (C), 170.66 (C), 171.25 (C). Selected

HMBC correlations are between  2.47 (C3-HH), 3.47 (C2-H), 4.18 (C4-

H) and  63.35 (C1), between  3.47 (C2-H), 4.18 (C4-H) and  24.10

(C3), and between  7.33–7.36 (Ar-H) and  41.72 (C4).

MS (EI): m/z (%) = 440 (M⁺, 12), 438 (M⁺, 14), 355 (38), 353 (37), 309

(50), 307 (53), 184 (94), 182 (100).

HRMS (EI): m/z calcd for C₂₀H₂₃BrO₆: 438.0678, 440.0658; found:

438.0679, 440.0664.

2-Allyl 1,1-Diethyl cis-4-(4-Methylphenyl)cyclobutane-1,1,2-tri-

carboxylate (3k) (Table 2, Entry 16)

MS (EI): m/z (%) = 360 (M⁺, 2.1), 275 (23), 299 (51), 154 (52), 104

(100).

Scale: 0.5 mmol; colorless oil; yield: 96 mg (51%); R_f

= 0.5

(hexane/Et₂O 3:1).

HRMS (EI): m/z calcd for C₂₀H₂₄O₆: 360.1573; found: 360.1567.

IR (neat): 2979, 1734, 1648, 1517, 1458, 1375, 1297, 1081, 1021 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.806 (t, J = 7.1 Hz, 3 H), 1.33 (t, J = 7.1

Hz, 3 H), 2.30 (s, 3 H), 2.45 (ddd, J = 11.1, 9.3, 8.8 Hz, 1 H), 3.02 (ddd,

J = 11.3, 11.0, 10.3 Hz, 1 H), 3.45 (dd, J = 10.3, 9.3 Hz, 1 H), 3.66–3.81

(m, 2 H), 4.14 (dd, J = 11.3, 8.8 Hz, 1 H), 4.27–4.39 (m, 2 H), 4.62 (ddd,

J = 5.4, 1.6, 1.4 Hz, 2 H), 5.21 (ddt, J = 10.6, 1.5, 1.4 Hz, 1 H), 5.35 (dtd,

J = 17.2, 1.6, 1.5 Hz, 1 H), 5.91 (ddt, J = 17.2, 10.6, 5.4 Hz, 1 H), 7.08 (d,

J = 7.9 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H). Selected NOEs are between 

2.45 (C3-HH) and  3.45 (C2-H), 4.14 (C4-H), between  3.45 (C2-H)

and  4.14 (C4-H), and between  3.02 (C3-HH) and  7.22 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.53 (CH₃), 14.16 (CH₃), 21.12

(CH₃), 24.19 (CH₂), 40.42 (CH), 41.56 (CH), 61.26 (CH₂), 61.75 (CH₂),

63.38 (C), 65.37 (CH₂), 117.86 (CH₂), 127.57 (CH), 128.78 (CH), 132.10

(CH), 134.89 (C), 136.70 (C), 167.66 (C), 170.73 (C), 171.35 (C). Select-

2-Allyl 1,1-Diethyl cis-4-(4-Chlorophenyl)cyclobutane-1,1,2-tri-

carboxylate (3i) (Table 2, Entry 14)

Scale: 0.5 mmol; colorless oil; yield: 56 mg (28%); R_f= 0.5 (hexane/

Et₂O 2:1).

IR (neat): 2982, 1738, 1648, 1493, 1369, 1268, 1197, 1081, 1015 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 0.843 (t, J = 7.1 Hz, 3 H), 1.34 (t, J = 7.1

Hz, 3 H), 2.47 (ddd, J = 11.1, 9.4, 8.8 Hz, 1 H), 2.99 (ddd, J = 11.1, 11.1,

10.2 Hz, 1 H), 3.47 (dd, J = 10.2, 9.4 Hz, 1 H), 3.69–3.84 (m, 2 H), 4.12

(dd, J = 11.1, 8.8 Hz, 1 H), 4.27–4.40 (m, 2 H), 4.62 (ddd, J = 5.5, 1.6, 1.4

Hz, 2 H), 5.22 (ddt, J = 10.6, 1.5, 1.4 Hz, 1 H), 5.35 (dtd, J = 17.2, 1.6, 1.5

Hz, 1 H), 5.90 (ddt, J = 17.2, 10.6, 5.5 Hz, 1 H), 7.24–7.30 (m, 4 H). Se-

.

N

S. Yamazaki et al.

Paper

Synthesis

ed HMBC correlations are between  2.45 (C3-HH), 3.45 (C2-H), 4.14

(C4-H) and  63.38 (C1), between  3.45 (C2-H), 4.14 (C4-H) and 

24.19 (C3), and between  7.22 (Ar-H) and  41.56 (C4).

MS (EI): m/z (%) = 374 (M⁺, 24), 289 (44), 243 (59), 118 (100).

Triethyl (E)-4-(4-Methylphenyl)but-3-ene-1,1,2-tricarboxylate

(4e) (Table 2, Entry 4)

Scale: 0.5 mmol; colorless oil; yield: 90 mg (50%); R_f= 0.6 (hexane/

Et₂O 1:1).

IR (neat): 2983, 1732, 1514, 1369, 1300, 1163, 1032 cm^–1

.

HRMS (EI): m/z calcd for C₂₁H₂₆O₆: 374.1729; found: 374.1730.

¹H NMR (400 MHz, CDCl₃):  = 1.17 (t, J = 7.0 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 2.32 (s, 3 H), 3.86 (dd, J = 10.5, 9.2 Hz,

1 H), 3.97 (d, J = 10.5 Hz, 1 H), 4.10–4.24 (m, 6 H), 6.05 (dd, J = 15.7,

9.2 Hz, 1 H), 6.56 (d, J = 15.7 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 2 H), 7.23 (d,

J = 8.0 Hz, 2 H). Selected NOEs are between  3.86 (C2-H) and  6.56

(C4-H) and between  6.05 (C3-H) and  7.23 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 14.02 (CH₃), 14.09 (CH₃), 14.12

(CH₃), 21.21 (CH₃), 48.94 (CH), 54.25 (CH), 61.40 (CH₂), 61.61 (CH₂),

61.84 (CH₂), 121.70 (CH), 126.47 (CH), 129.28 (CH), 133.45 (C), 135.14

(CH), 137.98 (C), 167.46 (C), 167.73 (C), 171.76 (C).

1,1-Diethyl 2-Isopropyl cis-4-Phenylcyclobutane-1,1,2-tricarb-

oxylate (3l) (Table 2, Entry 17)

Scale: 1.85 mmol; colorless oil; yield: 670 mg (92%); R_f= 0.3 (hexane/

EtOAc 10:1).

IR (neat): 2981, 1735, 1497, 1452, 1375, 1267, 1195, 1111, 1021 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.766 (t, J = 7.1 Hz, 3 H), 1.20 (d, J = 6.3

Hz, 3 H), 1.26 (d, J = 6.3 Hz, 3 H), 1.34 (t, J = 7.1 Hz, 3 H), 2.44 (ddd, J =

11.0, 9.3, 8.7 Hz, 1 H), 3.01 (ddd, J = 11.4, 11.0, 10.3 Hz, 1 H), 3.40 (dd,

J = 10.3, 9.3 Hz, 1 H), 3.66 (dq, J = 10.6, 7.1 Hz, 1 H), 3.77 (dq, J = 10.6,

7.1 Hz, 1 H), 4.16 (dd, J = 11.4, 8.7 Hz, 1 H), 4.26–4.38 (m, 2 H), 5.04

(septet, J = 6.3 Hz, 1 H), 7.18–7.22 (m, 1 H), 7.26–7.29 (m, 2 H), 7.33–

7.35 (m, 2 H). Selected NOEs are between  2.44 (C3-HH) and  3.40

(C2-H), 4.16 (C4-H), between  3.40 (C2-H) and  4.16 (C4-H), and be-

tween  3.01 (C3-HH) and  7.33–7.35 (Ph-H).

MS (EI): m/z (%) = 362 (M⁺, 9.1), 316 (86), 288 (37), 214 (71), 129

(100).

HRMS (EI): m/z calcd for C₂₀H₂₆O₆: 362.1729; found: 362.1727.

1,1-Diethyl 2-Methyl (E)-4-Phenylbut-3-ene-1,1,2-tricarboxylate

¹³C NMR (100.6 MHz, CDCl₃):  = 13.49 (CH₃), 14.14 (CH₃), 21.71

(CH₃), 21.92 (CH₃), 24.06 (CH₂), 40.60 (CH), 41.59 (CH), 61.12 (CH₂),

61.65 (CH₂), 63.33 (C), 68.20 (CH), 127.03 (CH), 127.63 (CH), 128.07

(CH), 138.16 (C), 167.59 (C), 170.80 (C), 171.03 (C). Selected HMBC

correlations are between  2.44 (C3-HH), 3.40 (C2-H), 4.16 (C4-H) and

 63.33 (C1), between  3.40 (C2-H), 4.16 (C4-H) and  24.06 (C3), and

between  7.33–7.35 (Ph-H) and  41.59 (C4).

(4m) (Table 2, Entry 19)

Scale: 1.0 mmol; colorless oil; yield: 248 mg (74%); R_f= 0.6

(hexane/Et₂O 1:1).

IR (neat): 2983, 1735, 1448, 1370, 1294, 1240, 1165, 1030 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 1.18 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1

Hz, 3 H), 3.73 (s, 3 H), 3.91 (dd, J = 10.4, 9.1 Hz, 1 H), 3.99 (d, J = 10.4

Hz, 1 H), 4.11–4.26 (m, 4 H), 6.11 (dd, J = 15.8, 9.1 Hz, 1 H), 6.60 (d, J =

15.8 Hz, 1 H), 7.22–7.35 (m, 5 H). Selected NOEs are between  3.91

(C2-H) and  6.60 (C4-H) and between  6.11 (C3-H) and  7.22–7.35

(Ph-H).

.

MS (EI): m/z (%) = 362 (M⁺, 42), 275 (78), 229 (100).

HRMS (EI): m/z calcd for C₂₀H₂₆O₆: 362.1729; found: 362.1728.

Anal. Calcd for C₂₀H₂₆O₆: C, 66.28; H, 7.23. Found: C, 66.41; H, 7.37.

¹³C NMR (100.6 MHz, CDCl₃):  = 14.00 (CH₃), 14.09 (CH₃), 48.76 (CH),

52.53 (CH₃), 54.18 (CH), 61.66 (CH₂), 61.91 (CH₂), 122.60 (CH), 126.55

(CH), 128.13 (CH), 128.60 (CH), 135.40 (CH), 136.10 (C), 167.37 (C),

167.66 (C), 172.17 (C).

1,1-Diethyl 2-Methyl cis-4-Phenylcyclobutane-1,1,2-tricarboxyl-

ate (3m) (Table 2, Entry 18)

Scale: 0.5 mmol; colorless oil; yield: 133 mg (80%); R_f= 0.5 (hexane/

Et₂O 1:1).

MS (EI): m/z (%) = 334 (M⁺, 7.0), 302 (74), 200 (73), 129 (100).

IR (neat): 2983, 1739, 1449, 1371, 1267, 1196, 1092, 1075 cm^–1

.

HRMS (EI): m/z calcd for C₁₈H₂₂O₆: 334.1416; found: 334.1411.

¹H NMR (400 MHz, CDCl₃):  = 0.775 (t, J = 7.1 Hz, 3 H), 1.35 (t, J = 7.1

Hz, 3 H), 2.46 (ddd, J = 11.3, 9.4, 8.8 Hz, 1 H), 3.03 (ddd, J = 11.3, 11.3,

10.2 Hz, 1 H), 3.46 (dd, J = 10.2, 9.4 Hz, 1 H), 3.65–3.80 (m, 2 H), 3.72

(s, 3 H), 4.17 (dd, J = 11.3, 8.8 Hz, 1 H), 4.31–4.37 (m, 2 H), 7.19–7.23

(m, 1 H), 7.26–7.30 (m, 2 H), 7.33–7.35 (m, 2 H). Selected NOEs are

between  2.46 (C3-HH) and  3.46 (C2-H), 4.17 (C4-H), between 

3.46 (C2-H) and  4.17 (C4-H), and between  3.03 (C3-HH) and 

7.26–7.30 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.44 (CH₃), 14.09 (CH₃), 24.05

(CH₂), 40.28 (CH), 41.72 (CH), 51.92 (CH₃), 61.23 (CH₂), 61.76 (CH₂),

63.27 (C), 127.06 (CH), 127.59 (CH), 128.05 (CH), 137.98 (C), 167.59

(C), 170.60 (C), 171.98 (C). Selected HMBC correlations are between 

2.46 (C3-HH), 3.46 (C2-H), 4.17 (C4-H) and  63.27 (C1), between 

3.46 (C2-H), 4.17 (C4-H) and  24.05 (C3), and between  7.26–7.30

(Ph-H) and  41.72 (C4).

Triethyl 4-Chloro-4-phenylbutane-1,1,2-tricarboxylate (5a) (Table

1, Entry 2)

Scale: 0.5 mmol; colorless oil; yield: 46 mg (24%): dr = 1:1; R_f= 0.2

(hexane/Et₂O 2:1).

IR (neat): 2982, 1735, 1456, 1370, 1176, 1031 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.22 (t, J = 7.1 Hz, 3 H × 0.5), 1.24 (t, J =

7.1 Hz, 3 H × 0.5), 1.274 (t, J = 7.0 Hz, 3 H × 0.5), 1.277 (t, J = 7.1 Hz, 3 H

× 0.5), 1.281 (t, J = 7.1 Hz, 3 H × 0.5), 2.25 (ddd, J = 14.6, 10.7, 2.8 Hz, 1

H × 0.5), 2.38 (ddd, J = 14.1, 9.2, 4.3 Hz, 1 H × 0.5), 2.42 (ddd, J = 14.6,

10.4, 3.3 Hz, 1 H × 0.5), 2.59 (ddd, J = 14.1, 9.6, 6.3 Hz, 1 H × 0.5), 2.93

(ddd, J = 9.6, 8.6, 4.3 Hz, 1 H × 0.5), 3.51 (ddd, J = 10.4, 7.8, 2.8 Hz, 1 H

× 0.5), 3.75 (d, J = 8.6 Hz, 1 H × 0.5), 3.82 (d, J = 7.8 Hz, 1 H × 0.5), 4.07–

4.26 (m, 6 H), 4.99 (dd, J = 9.2, 6.3 Hz, 1 H × 0.5), 5.08 (dd, J = 10.7, 3.3

Hz, 1 H × 0.5), 7.28–7.39 (m, 5 H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.99 (CH₃), 14.02 (CH₃), 14.06

(CH₃), 14.08 (CH₃), 14.11 (CH₃), 14.14 (CH₃), 39.60 (CH₂), 40.02 (CH₂),

42.19 (CH), 42.30 (CH), 53.39 (CH), 53.82 (CH), 60.28 (CH), 61.33

(CH₂), 61.70 (CH), 61.86 (CH₂), 61.91 (CH₂), 126.81 (CH), 127.35 (CH),

128.52 (CH), 128.76 (CH), 128.79 (CH), 140.09 (C), 141.37 (C), 167.55

(C), 167.61 (C), 167.66 (C), 167.74 (C), 172.31 (C), 172.44 (C).

MS (EI): m/z (%) = 334 (M⁺, 2.8), 302 (3.5), 275 (27), 229 (42), 104

(100).

HRMS (EI): m/z calcd for C₁₈H₂₂O₆: 334.1416; found: 334.1412.

O

S. Yamazaki et al.

Paper

Synthesis

MS (EI): m/z (%) = 386 (M⁺, 1.1), 384 (M⁺, 3.2), 339 (6.3), 246 (6.3), 173

MS (EI): m/z (%) = 356 (M⁺, 35), 354 (M⁺, 99), 336 (18), 280 (28), 236

(82), 127 (100).

(100).

HRMS (EI): m/z calcd for C₁₉H₂₅ClO₆: 384.1340, 386.1310; found:

HRMS (EI): m/z calcd for C₁₇H₁₉ClO₆: 354.0870, 356.0841; found:

384.1338, 386.1315.

354.0873, 356.0861.

Triethyl 4-Chloro-4-(4-nitrophenyl)butane-1,1,2-tricarboxylate

(5h) (Table 2, Entry 8)

Triethyl 4,4-Diphenylbut-3-ene-1,1,2-tricarboxylate (8) (Scheme

2)

Scale: 0.5 mmol; colorless oil; yield: 76 mg (35%): dr = 5:1; R_f= 0.2

SnCl₄(1.0 equiv), r.t. 1 h; scale: 0.5 mmol; colorless oil; yield: 202 mg

(hexane/Et₂O 2:1).

(95%); R_f= 0.4 (hexane/Et₂O 2:1).

IR (neat): 2984, 1734, 1608, 1526, 1350, 1177, 1030 cm^–1

.

IR (neat): 2982, 1732, 1445, 1369, 1299, 1239, 1175, 1154, 1031 cm^–1

.

¹H NMR (400 MHz, CDCl₃) (major isomer):  = 1.26–1.31 (m, 9 H),

2.20 (ddd, J = 14.1, 10.9, 2.5 Hz, 1 H), 2.45 (ddd, J = 14.1, 10.2, 2.9 Hz, 1

H), 3.51 (ddd, J = 10.2, 6.8, 2.5 Hz, 1 H), 3.87 (d, J = 6.8 Hz, 1 H), 4.14–

4.31 (m, 6 H), 5.19 (dd, J = 10.9, 2.9 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 2 H),

8.22 (d, J = 8.8 Hz, 2 H).

¹³C NMR (100.6 MHz, CDCl₃) (major isomer):  = 14.08 (CH₃), 14.13

(CH₃), 39.66 (CH₂), 41.82 (CH), 53.56 (CH), 60.24 (CH), 61.57 (CH₂),

61.96 (CH₂), 62.04 (CH₂), 124.06 (CH), 127.91 (CH), 147.79 (C), 148.28

(C), 167.56 (C), 167.64 (C), 172.10 (C).

¹H NMR (400 MHz, CDCl₃):  = 1.14 (t, J = 7.1 Hz, 3 H), 1.19 (t, J = 7.1

Hz, 3 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.94–4.22 (m, 8 H), 5.97 (dd, J = 8.5,

2.1 Hz, 1 H), 7.19–7.29 (m, 7 H), 7.32–7.41 (m, 3 H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.95 (CH₃), 13.98 (CH₃), 14.11

(CH₃), 45.44 (CH), 54.34 (CH), 61.41 (CH₂), 61.59 (CH₂), 61.71 (CH₂),

121.93 (CH), 127.74 (CH), 127.77 (CH), 127.87 (CH), 128.21 (CH),

128.28 (CH), 129.96 (CH), 138.61 (C), 141.96 (C), 147.09 (C), 167.43

(C), 167.66 (C), 171.74 (C).

MS (EI): m/z (%) = 424 (M⁺, 51), 378 (91), 286 (80), 191 (100).

HRMS (EI): m/z calcd for C₂₅H₂₈O₆: 424.1886; found: 424.1885.

Anal. Calcd for C₂₅H₂₈O₆: C, 70.74; H, 6.65. Found: C, 70.45; H, 6.69.

MS (EI): m/z (%) = 431 (M⁺, 0.7), 429 (M⁺, 2.1), 384 (13), 246 (54), 200

(91), 127 (100).

HRMS (EI): m/z calcd for C₁₉H₂₄ClNO₈: 429.1190, 431.1161; found:

429.1187, 431.1168.

Triethyl 4,4-Diphenylcyclobutane-1,1,2-tricarboxylate (9)

(Scheme 2)

Diethyl cis-2-(2-Oxo-5-phenyltetrahydrofuran-3-yl)malonate (6a)

(Table 1, Entry 8)

SnCl₄(1.0 equiv), –78 °C, 3 h; scale 0.5 mmol; colorless oil; yield: 133

mg (62%); R_f= 0.4 (hexane/Et₂O 2:1).

Scale: 0.5 mmol; colorless oil; yield: 40 mg (25%); R_f= 0.3 (hexane/Et₂O

1:1).

IR (neat): 2982, 1732, 1602, 1496, 1446, 1368, 1295, 1184, 1078, 1025

cm^–1

.

IR (neat): 2984, 1778, 1737, 1459, 1372, 1305, 1273, 1227, 1164,

¹H NMR (400 MHz, CDCl₃):  = 0.841 (t, J = 7.1 Hz, 3 H), 0.959 (t, J = 7.1

Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H), 3.13 (dd, J = 11.5, 9.8 Hz, 1 H), 3.53

(dd, J = 11.5, 11.4 Hz, 1 H), 3.68–3.99 (m, 4 H), 4.14 (qd, J = 7.1, 1.1 Hz,

2 H), 4.22 (dd, J = 11.4, 9.8 Hz, 1 H), 7.14–7.26 (m, 6 H), 7.31–7.38 (m,

4 H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.39 (CH₃), 13.67 (CH₃), 14.24

(CH₃), 35.24 (CH₂), 40.44 (CH), 54.39 (C), 60.94 (CH₂), 61.33 (CH₂),

61.44 (CH₂), 67.38 (C), 126.45 (CH), 126.98 (CH), 127.11 (CH), 128.06

(CH), 128.08 (CH), 128.21 (CH), 142.83 (C), 145.41 (C), 168.58 (C),

168.70 (C), 171.98 (C). Selected HMBC correlations are between  3.13

(C3-HH), 4.22 (C2-H) and  67.38 (C1) and between  7.14–7.26 (Ph-

H) and  54.39 (C4).

1096, 1029 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.27 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.1

Hz, 3 H), 2.39 (ddd, J = 12.7, 12.5, 10.7 Hz, 1 H), 2.78 (ddd, J = 12.7, 8.6,

6.1 Hz, 1 H), 3.42 (ddd, J = 12.5, 8.6, 5.9 Hz, 1 H), 3.95 (d, J = 5.9 Hz, 1

H), 4.19–4.29 (m, 4 H), 5.41 (d, J = 10.7, 6.1 Hz, 1 H), 7.33–7.43 (m, 5

H). Selected NOEs are between  3.42 (C3-H) and  2.78 (C4-HH), 5.41

(C5-H) and between  2.39 (C4-HH) and  7.33–7.43 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 14.4 (CH₃), 14.07 (CH₃), 35.04 (CH₂),

41.30 (CH), 50.90 (CH), 62.07 (CH₂), 80.14 (CH), 126.01 (CH), 128.79

(CH), 138.66 (C), 167.21 (C), 167.67 (C), 175.70 (C).

MS (EI): m/z (%) = 320 (M⁺, 38), 203 (37), 189 (49), 173 (41), 129

(100).

MS (EI): m/z (%) = 424 (M⁺, 43), 378 (100).

HRMS (EI): m/z calcd for C₁₇H₂₀O₆: 320.1260; found: 320.1260.

HRMS (EI): m/z calcd for C₂₅H₂₈O₆: 424.1886; found: 424.1887.

Diethyl cis-2-[5-(4-Chlorophenyl)-2-oxotetrahydrofuran-3-

yl]malonate (6b) (Table 2, Entry 12)

Triethyl (E)-4-Phenylpent-3-ene-1,1,2-tricarboxylate (12) and Tri-

ethyl 4-Phenylpent-4-ene-1,1,2-tricarboxylate (13)

Scale: 0.5 mmol; colorless oil; yield: 96 mg (54%); R_f= 0.3 (hexane/

Et₂O 1:1).

Temperature: r.t.; scale: 0.5 mmol; colorless oil; yield: 145 mg (80%);

ratio 12/13 2:1; R_f= 0.2 (hexane/Et₂O 2:1).

IR (neat): 2983, 1779, 1732, 1495, 1372, 1274, 1163, 1092, 1015 cm^–1

.

IR (neat): 2983, 1737, 1445, 1369, 1301, 1174, 1029 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.27 (t, J = 7.1 Hz, 3 H), 1.30 (t, J = 7.1

Hz, 3 H), 2.37 (ddd, J = 12.7, 12.5, 10.7 Hz, 1 H), 2.77 (ddd, J = 12.7, 8.7,

6.1 Hz, 1 H), 3.40 (ddd, J = 12.5, 8.7, 5.7 Hz, 1 H), 3.97 (d, J = 5.7 Hz, 1

H), 4.19–4.28 (m, 2 H), 5.38 (dd, J = 10.7, 6.1 Hz, 1 H), 7.36–7.37 (m, 4

H). Selected NOEs are between  3.40 (C3-H) and  2.77 (C4-HH), 5.38

(C5-H) and between  2.37 (C4-HH) and  7.36–7.37 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 14.07 (CH₃), 14.11 (CH₃), 34.89

(CH₂), 41.17 (CH), 50.75 (CH), 62.16 (CH₂), 79.36 (CH), 127.47 (CH),

129.05 (CH), 134.66 (C), 137.28 (C), 167.22 (C), 167.66 (C), 175.53 (C).

¹H NMR (400 MHz, CDCl₃):  = peaks for 12: 1.16–1.29 (m, 9 H), 2.17

(d, J = 1.4 Hz, 3 H), 3.96 (d, J = 10.6 Hz, 1 H), 3.97–4.03 (m, 1 H), 4.10–

4.26 (m, 6 H), 5.60 (dq, J = 10.6, 1.4 Hz, 1 H), 7.24–7.39 (m, 5 H); sepa-

rated peaks for 13:  = 2.84–2.86 (m, 2 H), 3.21 (ddd, J = 9.4, 8.3, 6.3

Hz, 1 H), 3.73 (d, J = 9.4 Hz, 1 H), 5.09 (d, J = 1.0 Hz, 1 H), 5.32 (d, J = 1.4

Hz, 1 H).

¹³C NMR (100.6 MHz, CDCl₃):  = peaks for 12 and 13: 14.02 (CH₃),

14.08 (CH₃), 14.12 (CH₃), 14.18 (CH₃), 16.64 (CH₂), 36.13 (CH₂), 43.53

(CH), 45.21 (CH), 53.59 (CH), 54.25 (CH), 60.80 (CH₂), 61.34 (CH₂),

P

S. Yamazaki et al.

Paper

Synthesis

61.68 (CH₂), 61.76 (CH₂), 61.89 (CH₂), 115.70 (CH₂), 121.09 (CH),

126.03 (CH), 126.35 (CH), 127.58 (CH), 127.83 (CH), 128.34 (CH),

128.45 (CH), 139.83 (C), 141.21 (C), 142.83 (C), 144.86 (C), 167.66 (C),

167.85 (C), 167.94 (C), 168.04 (C), 171.82 (C), 172.90 (C).

7.35 (m, 2 H), 7.56–7.59 (m, 2 H). Selected NOEs are between  3.11

(C3-HH) and  4.30 (C2-H) and between  3.67 (C3-HH) and  7.56–

7.59 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.44 (CH₃), 14.18 (CH₃), 14.22

(CH₃), 39.54 (CH₂), 40.11 (CH), 61.13 (CH₂), 61.85 (CH₂), 62.29 (CH₂),

62.61 (C), 68.87 (C), 125.74 (CH), 128.37 (CH), 128.59 (CH), 143.11

(C), 166.28 (C), 167.62 (C), 171.07 (C). Selected HMBC correlations are

between  3.11 (C3-HH), 4.30 (C2-H) and  68.87 (C1) and between 

7.56–7.59 (Ph-H) and  62.61 (C4).

MS (EI): m/z (%) = 362 (M⁺, 7.7), 316 (25), 224 (83), 129 (100).

HRMS (EI): m/z calcd for C₂₀H₂₆O₆: 362.1729; found: 362.1728.

Diethyl 2-[(3R,5S) and (3S,5R)-5-Methyl-2-oxo-5-phenyltetra-

hydrofuran-3-yl]malonate (14a) (Scheme 3)

MS (CI): m/z = 429 ([M + 1]⁺), 427 ([M + 1]⁺).

HRMS (CI): m/z [M + H]⁺calcd for C₁₉H₂₄BrO₆: 427.0756, 429.0736;

Temperature: –78 °C; scale: 1.0 mmol; colorless oil; yield: 122 mg

(36%); R_f= 0.4 (hexane/Et₂O 1:1).

found: 427.0760, 429.0742.

IR (neat): 2982, 1770, 1738, 1447, 1372, 1300, 1224, 1029 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.18 (t, J = 7.1 Hz, 3 H), 1.29 (t, J = 7.1

Hz, 3 H), 1.72 (s, 3 H), 2.46 (dd, J = 12.7, 11.9 Hz, 1 H), 2.72 (dd, J =

12.7, 9.0 Hz, 1 H), 3.54 (ddd, J = 11.9, 9.0, 6.2 Hz, 1 H), 3.88 (d, J = 6.2

Hz, 1 H), 4.08–4.20 (m, 2 H), 4.25 (q, J = 7.1 Hz, 2 H), 7.27–7.31 (m, 1

H), 7.34–7.43 (m, 4 H). Selected NOEs are between  3.54 (C3-H), and

 1.72 (5-CH₃), 2.72 (C4-HH), between  1.72 (5-CH₃) and  2.72 (C4-

HH), and between  2.46 (C4-HH) and  7.34–7.43 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.91 (CH₃), 14.03 (CH₃), 28.39

(CH₃), 39.47 (CH₂), 40.40 (CH), 51.35 (CH), 62.05 (CH₂), 85.19 (C),

124.03 (CH), 127.71 (CH), 128.60 (CH), 144.74 (C), 167.11 (C), 167.69

(C), 175.14 (C).

1,1-Diethyl 2-Isopropyl (2R,4S)- and (2S,4R)-4-Bromo-4-phenyl-

cyclobutane-1,1,2-tricarboxylate (16d) (Table 3, Entry 2)

Scale: 5.0 mmol; pale yellow oil; yield: 1.29 g (59%); R_f= 0.2 (hexane/

EtOAc 10:1).

IR (neat): 2982, 1720, 1449, 1370, 1255, 1106 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.829 (t, J = 7.1 Hz, 3 H), 1.18 (d, J = 6.2

Hz, 3 H), 1.23 (d, J = 6.2 Hz, 3 H), 1.44 (t, J = 7.1 Hz, 3 H), 3.10 (dd, J =

12.6, 9.4 Hz, 1 H), 3.66 (dd, J = 12.6, 11.0 Hz, 1 H), 3.79–3.91 (m, 2 H),

4.28 (dd, J = 11.0, 9.4 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2 H), 4.99 (septet, J =

6.2 Hz, 1 H), 7.23–7.27 (m, 1 H), 7.31–7.35 (m, 2 H), 7.57–7.59 (m, 2

H). Selected NOEs are between  3.10 (C3-HH) and  4.28 (C2-H) and

between  3.66 (C3-HH) and  7.57–7.59 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.35 (CH₃), 14.18 (CH₃), 21.61

(CH₃), 21.75 (CH₃), 39.50 (CH₂), 40.21 (CH), 61.75 (CH₂), 62.16 (CH₂),

62.65 (C), 68.63 (CH), 68.82 (C), 125.72 (CH), 128.31 (CH), 128.54

(CH), 143.14 (C), 166.25 (C), 167.56 (C), 170.55 (C). Selected HMBC

correlations are between  3.10 (C3-HH), 4.28 (C2-H) and  68.82 (C1)

and between  7.57–7.59 (Ph-H) and  62.65 (C4).

MS (ESI): m/z = 357 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺calcd for C₁₈H₂₂O₆Na: 357.1314; found:

357.1314 .

Diethyl 2-[(3R,4S,5S)- and (3S,4R,5R)-4-Methyl-2-oxo-5-phenyl-

tetrahydrofuran-3-yl]malonate (14b) (Scheme 3)

Temperature: –76 °C; scale: 0.5 mmol; colorless oil; yield: 121 mg

(72%); R_f= 0.1 (hexane/Et₂O 2:1).

MS (CI): m/z = 443 ([M + 1]⁺), 441 ([M + 1]⁺).

HRMS (CI): m/z [M + H]⁺calcd for C₂₀H₂₆BrO₆: 441.0913, 443.0892;

IR (neat): 2983, 1780, 1734, 1458, 1373, 1176, 1028 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.10 (d, J = 6.4 Hz, 3 H), 1.29 (t, J = 7.1

Hz, 3 H), 1.30 (t, J = 7.1 Hz, 3 H), 2.71 (ddq, J = 11.5, 9.6, 6.4 Hz, 1 H),

3.05 (dd, J = 11.5, 4.7 Hz, 1 H), 3.97 (d, J = 4.7 Hz, 1 H), 4.20–4.32 (m, 4

H), 4.84 (d, J = 9.6 Hz, 1 H), 7.34–7.44 (m, 5 H). Selected NOEs are be-

tween  3.05 (C3-H) and  1.10 (C4-CH₃), 4.84 (C5-H),  4.84 (C5-H)

and  1.10 (C4-CH₃), and between  2.71 (C4-H) and  7.34–7.44 (Ph-

H).

¹³C NMR (100.6 MHz, CDCl₃):  = 14.04 (CH₃), 15.27 (CH₃), 42.32 (CH),

47.73 (CH), 50.09 (CH), 62.00 (CH₂), 86.85 (CH), 126.81 (CH), 128.73

(CH), 129.01 (CH), 137.42 (C), 167.40 (C), 167.64 (C), 175.42 (C).

found: 441.0905, 443.0885.

1,1-Diethyl 2-Methyl (2R,4S) and (2S,4R)-4-Bromo-4-phenyl-

cyclobutane-1,1,2-tricarboxylate (16e) (Table 3, Entry 3)

Scale: 0.5 mmol; pale yellow oil; yield: 72 mg (34%); R_f= 0.5 (hexane/

Et₂O 1:1).

IR (neat): 2983, 1738, 1447, 1257, 1019 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.870 (t, J = 7.1 Hz, 3 H), 1.45 (t, J = 7.1

Hz, 3 H), 3.11 (dd, J = 12.7, 9.4 Hz, 1 H), 3.68 (s, 3 H), 3.68 (dd, J = 12.7,

10.8 Hz, 1 H), 3.85 (q, J = 7.1 Hz, 2 H), 4.32 (dd, J = 10.8, 9.4 Hz, 1 H),

4.41–4.53 (m, 2 H), 7.24–7.28 (m, 1 H), 7.31–7.35 (m, 2 H), 7.56–7.58

(m, 2 H). Selected NOEs are between  3.11 (C3-HH) and  4.32 (C2-H)

and between  3.68 (C3-HH) and  7.56–7.58 (Ph-H).

MS (EI): m/z (%) = 334 (M⁺, 6.3), 290 (8.5), 244 (13), 217 (15), 171 (18),

127 (100).

HRMS (EI): m/z calcd for C₁₈H₂₂O₆: 334.1416; found: 334.1413.

¹³C NMR (100.6 MHz, CDCl₃):  = 13.50 (CH₃), 14.21 (CH₃), 39.50

(CH₂), 40.05 (CH), 52.19 (CH₃), 61.95 (CH₂), 62.37 (CH₂), 62.51 (C),

68.89 (C), 125.72 (CH), 128.41 (CH), 128.59 (CH), 143.01 (C), 166.28

(C), 167.60 (C), 171.52 (C). Selected HMBC correlations are between 

3.11 (C3-HH), 4.32 (C2-H) and  68.89 (C1) and between  7.56–7.58

(Ph-H) and  62.51 (C4).

Triethyl (2R,4S)- and (2S,4R)-4-Bromo-4-phenylcyclobutane-1,1,2-

tricarboxylate (16a) (Table 3, Entry 1)

Scale: 0.5 mmol; pale yellow oil; yield: 118 mg (55%); R_f= 0.2 (hex-

ane/EtOAc 1:1).

IR (neat): 2982, 1737, 1448, 1369, 1256, 1189, 1081, 1024 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.850 (t, J = 7.1 Hz, 3 H), 1.22 (t, J = 7.1

Hz, 3 H), 1.45 (t, J = 7.1 Hz, 3 H), 3.11 (dd, J = 12.5, 9.4 Hz, 1 H), 3.67

(dd, J = 12.5, 10.9 Hz, 1 H), 3.82–3.88 (m, 2 H), 4.10–4.19 (m, 2 H), 4.30

(dd, J = 10.9, 9.4 Hz, 1 H), 4.43–4.49 (m, 2 H), 7.24–7.28 (m, 1 H), 7.31–

MS (CI): m/z = 415 ([M + 1]⁺), 413 ([M + 1]⁺).

HRMS (CI): m/z [M + H]⁺calcd for C₁₈H₂₂BrO₆: 413.0600; found:

413.0589.

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S. Yamazaki et al.

Paper

Synthesis

Triethyl (2R,4S)- and (2S,4R)-4-Chloro-4-(4-methylphenyl)cyclo-

HRMS (CI): m/z [M + H]⁺calcd for C₁₉H₂₄BrO₆: 427.0756, 429.0736;

butane-1,1,2-tricarboxylate (16b_Cl) (Table 3, Entry 7)

found: 427.0758, 429.0744 .

Scale: 0.57 mmol; colorless crystals; yield: 45 mg (20%); R_f= 0.1

(hexane/EtOAc 10:1); mp 105–107 °C (hexane).

IR (KBr): 2979, 1744, 1518, 1446, 1371, 1227, 1038 cm^–1

Triethyl 4-Oxo-4-phenylbutane-1,1,2-tricarboxylate (18) (Table 3,

Entry 6)

.

Scale: 0.5 mmol; pale yellow oil; yield: 34 mg (19%); R_f= 0.1 (hexane/

EtOAc 10:1).

¹H NMR (400 MHz, CDCl₃):  = 0.894 (t, J = 7.1 Hz, 3 H), 1.22 (t, J = 7.1

Hz, 3 H), 1.42 (t, J = 7.1 Hz, 3 H), 2.33 (s, 3 H), 2.93 (dd, J = 12.3, 9.4 Hz,

1 H), 3.62 (dd, J = 12.3, 10.9 Hz, 1 H), 3.87 (q, J = 7.1 Hz, 2 H), 4.10–4.18

(m, 2 H), 4.23 (dd, J = 10.9, 9.4 Hz, 1 H), 4.44 (q, J = 7.1 Hz, 2 H), 7.14

(d, J = 8.3 Hz, 2 H), 7.46 (d, J = 8.3 Hz, 2 H). Selected NOEs are between

 2.93 (C3-HH) and  4.23 (C2-H) and between  3.62 (C3-HH) and 

7.46 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.51 (CH₃), 14.20 (CH₃), 14.23

(CH₃), 21.27 (CH₃), 38.02 (CH₂), 39.90 (CH), 61.09 (CH₂), 61.82 (CH₂),

62.15 (CH₂), 68.60 (C), 70.65 (C), 125.94 (CH), 129.21 (CH), 138.45 (C),

138.67 (C), 166.72 (C), 167.35 (C), 171.30 (C). Selected HMBC correla-

tions are between  2.93 (C3-HH), 4.23 (C2-H) and  68.60 (C1) and

between  7.46 (Ar-H) and  70.65 (C4).

IR (neat): 2981, 1735, 1685, 1597, 1449, 1369, 1222, 1177, 1029 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.21 (t, J = 7.1 Hz, 3 H), 1.24 (t, J = 7.1

Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H), 3.33 (dd, J = 18.0, 4.9 Hz, 1 H), 3.63

(dd, J = 18.0, 7.2 Hz, 1 H), 3.85 (ddd, J = 7.2, 6.6, 4.9 Hz, 1 H), 4.01 (d, J =

6.6 Hz, 1 H), 4.11–4.24 (m, 6 H), 7.45–7.49 (m, 2 H), 7.57 (t-like, J = 7.4

Hz, 1 H), 7.96–7.99 (m, 2 H).

¹³C NMR (100.6 MHz, CDCl₃):  = 14.02 (CH₃), 14.04 (CH₃), 37.42

(CH₂), 39.61 (CH), 52.37 (CH), 61.42 (CH₂), 61.81 (CH₂), 61.83 (CH₂),

128.15 (CH), 128.66 (CH), 133.35 (CH), 136.50 (C), 168.10 (C), 168.11

(C), 172.18 (C), 197.28 (C).

MS (EI): m/z (%) = 364 (M⁺, 2.9), 318 (59), 105 (100).

MS (EI): m/z (%) = 396 (M⁺, 1.4), 361 (4.9), 323 (43), 277 (44), 152

(100).

HRMS (EI): m/z calcd for C₁₉H₂₄O₇: 364.1522; found: 364.1517.

HRMS (EI): m/z calcd for C₂₀H₂₅ClO₆: 396.1340, 198.1310; found:

396.1359, 398.1324.

(Z)-N-Benzyl-4-phenylbut-3-en-1-amine (20Za); Typical Proce-

dure

A solution of benzaldehyde (0.211 g, 2.0 mmol) and (Z)-4-phenylbut-

3-en-1-amine³²(296 mg, 2.0 mmol) in MeOH (3.5 mL) was heated un-

der reflux for 30 min, followed by the portionwise addition of NaBH₄

(114 mg, 3.0 mmol) in ice-cooled bath. The mixture was stirred over-

night at r.t. Excess NaBH₄was quenched by the addition of acetone

(0.73 mL) The mixture was concentrated and the residue dissolved in

CH₂Cl₂and water. The organic layer was washed with water, dried

(Na₂SO₄), and concentrated. The residue was purified by column chro-

matography (silica gel, hexane/Et₂O) to give 20Za as a colorless oil;

yield: 258 mg (54%); R_f= 0.1 (hexane/Et₂O 1:1).

Triethyl (Z)-4-Chloro-4-phenylbut-3-ene-1,1,2-tricarboxylate

(17_Cl) (Table 3, Entry 5)

Scale: 0.5 mmol; pale yellow oil; yield: 122 mg (64%); R_f= 0.6

(hexane/Et₂O 1:1).

IR (neat): 2983, 1735, 1446, 1370, 1175, 1031 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.24 (t, J = 7.2 Hz, 3 H), 1.26 (t, J = 7.1

Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 4.02 (d, J = 8.6 Hz, 1 H), 4.14–4.29 (m,

6 H), 4.48 (dd, J = 10.0, 8.6 Hz, 1 H), 6.21 (d, J = 10.0 Hz, 1 H), 7.33–7.39

(m, 3 H), 7.54–7.58 (m, 2 H). Selected NOEs are between  6.21 (C3-H)

and  7.54–7.58 (Ph-H).

IR (neat): 3304, 3024, 2923, 2816, 1494, 1453, 1120, 1028 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.49 (br s, 1 H), 2.53–2.57 (m, 2 H),

2.76 (t, J = 6.9 Hz, 2 H), 3.77 (s, 2 H), 5.66 (dt, J = 11.6, 7.2 Hz, 1 H), 6.50

(d, J = 11.6 Hz, 1 H), 7.20–7.36 (m, 10 H). Selected NOEs are between 

5.66 (C3-H) and  6.50 (C4-H) and between  2.50 (C2-H₂) and  7.20–

7.36 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 29.30 (CH₂), 49.20 (CH₂), 53.88

(CH₂), 126.72 (CH), 126.97 (CH), 128.15 (CH), 128.23 (CH), 128.44

(CH), 128.82 (CH), 130.20 (CH), 130.55 (CH), 137.49 (C), 140.40 (C).

¹³C NMR (100.6 MHz, CDCl₃):  = 14.05 (CH₃), 14.12 (CH₃), 45.59 (CH),

53.48 (CH), 61.72 (CH₂), 61.86 (CH₂), 61.96 (CH₂), 120.96 (CH), 126.82

(CH), 128.44 (CH), 129.28 (CH), 137.33 (C), 137.62 (C), 167.40 (C),

167.56 (C), 170.73 (C).

MS (EI): m/z (%) = 384 (M⁺, 5.9), 382 (M⁺, 15), 336 (94), 273 (94), 149

(100).

HRMS (EI): m/z calcd for C₁₉H₂₃ClO₆: 382.1183, 384.1154; found:

382.1184, 384.1162.

MS (EI): m/z (%) = 237 (M⁺, 0.9), 120 (95), 91 (100).

Triethyl (Z)-4-Bromo-4-phenylbut-3-ene-1,1,2-tricarboxylate

HRMS (EI): m/z calcd for C₁₇H₁₉N: 237.1517; found: 237.1520.

(17_Br) (Table 3, Entry 6)

Scale: 0.5 mmol; pale yellow oil; yield: 93 mg (44%); R_f= 0.3 (hexane/

(Z)-N-Benzyl-4-(4-chlorophenyl)but-3-en-1-amine (20Zb)

From (Z)-4-(4-chlorophenyl)but-3-en-1-amine³³(1.5 mmol); pale

yellow oil; yield: 264 mg (65%); R_f= 0.2 (hexane/Et₂O 1:1).

EtOAc 10:1).

IR (neat): 2981, 1737, 1445, 1370, 1239, 1176, 1031 cm^–1

.

IR (neat): 3025, 2897, 2817, 1491, 1454, 1091, 1013 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.25 (t, J = 7.2 Hz, 3 H), 1.27 (t, J = 7.2

Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 4.02 (d, J = 8.4 Hz, 1 H), 4.17–4.25 (m,

6 H), 4.43 (dd, J = 9.8, 8.4 Hz, 1 H), 6.29 (d, J = 9.8 Hz, 1 H), 7.32–7.37

(m, 3 H), 7.50–7.53 (m, 2 H). Selected NOEs are between  6.29 (C3-H)

and  7.50–7.53 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 14.09 (CH₃), 14.11 (CH₃), 14.15

(CH₃), 48.36 (CH), 53.40 (CH), 61.77 (CH₂), 61.93 (CH₂), 62.00 (CH₂),

124.96 (CH), 127.90 (CH), 128.41 (CH), 129.25 (CH), 130.43 (C),

139.24 (C), 167.41 (C), 167.53 (C), 170.51 (C).

¹H NMR (400 MHz, CDCl₃):  = 1.49 (br s, 1 H), 2.50 (dtd, J = 7.0, 7.0,

1.8 Hz, 2 H), 2.74 (t, J = 7.0 Hz, 2 H), 3.76 (s, 2 H), 5.67 (dt, J = 11.7, 7.2

Hz, 1 H), 6.42 (d, J = 11.7 Hz, 1 H), 7.19–7.32 (m, 9 H). Selected NOEs

are between  5.67 (C3-H) and  6.42 (C4-H) and between  2.50 (C2-

H₂) and  7.19–7.32 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 29.27 (CH₂), 49.00 (CH₂), 53.86

(CH₂), 126.98 (CH), 128.10 (CH), 128.36 (CH), 128.44 (CH), 129.34

(CH), 130.07 (CH), 130.92 (CH), 132.42 (C), 135.87 (C), 140.31 (C).

MS (CI): m/z = 429 ([M + 1]⁺), 427 ([M + 1]⁺).

MS (CI): m/z = 272 ([M + 1]⁺).

R

S. Yamazaki et al.

Paper

Synthesis

HRMS (CI): m/z [M + H]⁺calcd for C₁₇H₁₉ClN: 272.1206, 174.1177;

found: 272.1201, 274.1176.

1,6-trans-6,7-cis-3-Benzyl-2-oxo-7-phenyl-3-azabicyclo[4.2.0]-

octane-8,8-dicarboxylate (23a) (Table 4, Entry 10)

Scale: 0.42 mmol; colorless oil; yield: 64 mg (35%); R_f= 0.3 (hexane/

1,6-cis-6,7-trans-3-Benzyl-2-oxo-7-phenyl-3-azabicyclo[4.2.0]-

Et₂O 1:2).

octane-8,8-dicarboxylate (22a) (Table 4, Entry 4)

IR (neat): 2980, 1727, 1671, 1604, 1496, 1268, 1098, 1035 cm^–1

.

Scale: 0.47 mmol; colorless oil; yield: 110 mg (50%); R_f= 0.2 (hexane/

EtOAc 3:1).

¹H NMR (400 MHz, CDCl₃):  = 0.849 (t, J = 7.1 Hz, 3 H), 1.33 (t, J = 7.1

Hz, 3 H), 1.90 (dddd, J = 12.5, 12.1, 8.5, 8.5 Hz, 1 H), 2.23 (dddd, J =

12.1, 5.5, 4.6, 4.3 Hz, 1 H), 2.66 (d, J = 12.7 Hz, 1 H), 3.27 (dddd, J =

12.7, 12.5, 11.1, 4.3 Hz, 1 H), 3.39–3.42 (m, 2 H), 3.82–3.97 (m, 2 H),

4.03 (d, J = 11.1 Hz, 1 H), 4.26 (dq, J = 10.7, 7.1 Hz, 1 H), 4.39 (d, J = 14.8

Hz, 1 H), 4.40 (dq, J = 10.7, 7.1 Hz, 1 H), 4.78 (d, J = 14.8 Hz, 1 H), 7.21–

7.37 (m, 10 H). Selected NOEs are between  3.27 (C6-H) and  7.21–

7.37 (Ph-H), and between  2.66 (C1-H) and  4.03 (C7-H). Atom num-

bering is shown in Table 4.

¹³C NMR (100.6 MHz, CDCl₃):  = 13.63 (CH₃), 14.13 (CH₃), 29.19

(CH₂), 35.91 (CH), 45.78 (CH), 47.67 (CH₂), 49.22 (CH₂), 52.12 (CH),

61.35 (CH₂), 61.81 (CH₂), 62.74 (C), 127.31 (CH), 127.59 (CH), 128.15

(CH), 128.20 (CH), 128.66 (CH), 137.04 (C), 137.70 (C), 166.72 (C),

168.99 (C), 170.35 (C). Selected HMBC correlations are between  3.27

(C6-H), 2.66 (C1-H), 4.03 (C7-H) and  62.74 (C8), between  2.66 (C1-

H) and  35.91 (C6), between  2.66 (C1-H), 4.03 (C7-H) and  29.19

(C5), and between  7.21–7.37 (Ph-H) and  52.12 (C7).

IR (KBr): 2980, 2937, 1726, 1646, 1496, 1452, 1367, 1260, 1207, 1082,

1031 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.05 (t, J = 7.1 Hz, 3 H), 1.36 (t, J = 7.1

Hz, 3 H), 1.98 (dddd, J = 13.0, 6.8, 2.6, 2.6 Hz, 1 H), 2.57 (dddd, J = 13.0,

12.7, 9.2, 7.4 Hz, 1 H), 3.16 (dddd, J = 12.7, 10.0, 9.6, 6.8 Hz, 1 H), 3.25–

3.28 (m, 2 H), 3.67 (d, J = 10.0 Hz, 1 H), 3.97–4.14 (m, 2 H), 4.31–4.44

(m, 3 H), 4.43 (d, J = 9.6 Hz, 1 H), 4.87 (d, J = 14.8 Hz, 1 H), 7.17–7.33

(m, 10 H). Selected NOEs are between  3.16 (C6-H) and  3.67 (C1-H),

4.43 (C7-H), and between  3.67 (C1-H) and  4.43 (C7-H). Atom num-

bering is shown in Table 4.

¹³C NMR (100.6 MHz, CDCl₃):  = 13.79 (CH₃), 14.15 (CH₃), 23.70

(CH₂), 34.98 (CH), 40.26 (CH), 44.80 (CH), 46.02 (CH₂), 50.18 (CH₂),

61.65 (CH₂), 61.88 (CH₂), 62.31 (C), 126.38 (CH), 127.21 (CH), 127.30

(CH), 128.07 (CH), 128.20 (CH), 128.53 (CH), 137.04 (C), 137.84 (C),

167.88 (C), 168.78 (C), 171.71 (C). Selected HMBC correlations are be-

tween  3.16 (C6-H), 3.67 (C1-H), 4.43 (C7-H) and  62.31 (C8), be-

tween  3.67 (C1-H) and  34.98 (C6), between  3.67 (C1-H), 4.43

(C7-H) and  23.70 (C5), and between  7.17–7.33 (Ph-H) and  44.80

(C7).

MS (EI): m/z (%) = 435 (M⁺, 5.6), 199 (22), 84 (100).

HRMS (EI): m/z calcd for C₂₆H₂₉NO₅: 435.2046; found: 435.2047.

1,6-trans-6,7-cis-3-Benzyl-7-(4-chlorophenyl)-2-oxo-3-azabicyclo-

[4.2.0]octane-8,8-dicarboxylate (23b) (Table 4, Entry 11)

MS (EI): m/z (%) = 435 (M⁺, 1.4), 246 (15), 148 (31), 105 (100).

HRMS (EI): m/z calcd for C₂₆H₂₉NO₅: 435.2046; found: 435.2047.

Scale: 0.62 mmol; pale yellow oil; yield: 80 mg (28%); R_f= 0.2

(hexane/Et₂O 1:2).

1,6-cis-6,7-trans-3-Benzyl-7-(4-chlorophenyl)-2-oxo-3-azabi-

cyclo[4.2.0]octane-8,8-dicarboxylate (22b) (Table 4, Entry 6)

IR (neat): 2981, 1728, 1671, 1494, 1270, 1095 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.922 (t, J = 7.1 Hz, 3 H), 1.33 (t, J = 7.1

Hz, 3 H), 1.90 (dddd, J = 12.4, 12.1, 8.6, 8.6 Hz, 1 H), 2.22 (dddd, J =

12.1, 6.3, 4.3, 4.1 Hz, 1 H), 2.66 (d, J = 12.7 Hz, 1 H), 3.22 (dddd, J =

12.7, 12.4, 11.1, 4.3 Hz, 1 H), 3.37–3.42 (m, 2 H), 3.86–4.01 (m, 3 H),

4.27 (dq, J = 10.6, 7.1 Hz, 1 H), 4.39 (dq, J = 10.6, 7.1 Hz, 1 H), 4.39 (d,

J = 14.7 Hz, 1 H), 4.76 (d, J = 14.7 Hz, 1 H), 7.24–7.37 (m, 9 H). Selected

NOEs are between  3.22 (C6-H) and  7.24–7.37 (Ar-H), and between

 2.66 (C1-H) and  3.86–4.01 (C7-H, overlapped).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.73 (CH₃), 14.12 (CH₃), 29.07

(CH₂), 36.06 (CH), 45.73 (CH), 47.55 (CH₂), 49.25 (CH₂), 51.52 (CH),

61.53 (CH₂), 61.91 (CH₂), 62.57 (C), 127.37 (CH), 128.15 (CH), 128.34

(CH), 128.68 (CH), 129.01 (CH), 133.16 (C), 135.66 (C), 137.63 (C),

166.60 (C), 168.81 (C), 170.26 (C). Selected HMBC correlations are be-

tween  3.22 (C6-H), 2.66 (C1-H), 3.86–4.01 (C7-H) and  62.57 (C8),

between  2.66 (C1-H) and  36.06 (C6), between  2.66 (C1-H), 3.86–

4.01 (C7-H) and  29.07 (C5), and between  7.24–7.37 (Ar-H) and 

51.52 (C7).

Scale: 0.45 mmol; colorless oil; yield: 115 mg (55%); R_f= 0.1 (hexane/

EtOAc 2:1).

IR (neat): 2980, 1732, 1651, 1494, 1454, 1367, 1269, 1082, 1015 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.09 (t, J = 7.1 Hz, 3 H), 1.36 (t, J = 7.0

Hz, 3 H), 1.95 (ddt, J = 12.5, 6.8, 2.5 Hz, 1 H), 2.55 (ddt, J = 12.5, 12.5,

8.4 Hz, 1 H), 3.15 (dddd, J = 12.5, 10.0, 9.6, 6.8 Hz, 1 H), 3.26 (dd, J =

8.4, 2.5 Hz, 2 H), 3.67 (d, J = 10.0 Hz, 1 H), 3.99–4.15 (m, 2 H), 4.30–

4.44 (m, 4 H), 4.86 (d, J = 14.8 Hz, 1 H), 7.13–7.17 (m, 2 H), 7.22–7.32

(m, 7 H). Selected NOEs are between  3.15 (C6-H) and  3.67 (C1-H),

4.30–4.44 (C7-H, overlapped), and between  3.67 (C1-H) and  4.30–

4.44 (C7-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.88 (CH₃), 14.16 (CH₃), 23.65

(CH₂), 34.88 (CH), 40.24 (CH), 44.32 (CH), 45.97 (CH₂), 50.23 (CH₂),

61.84 (CH₂), 62.03 (CH₂), 62.30 (C), 127.38 (CH), 128.21 (CH), 128.28

(CH), 128.59 (CH), 128.66 (CH), 132.32 (C), 136.43 (C), 136.97 (C),

167.70 (C), 168.67 (C), 171.60 (C). Selected HMBC correlations are be-

tween  3.15 (C6-H), 3.67 (C1-H), 4.30–4.44 (C7-H) and  62.30 (C8),

between  3.67 (C1-H) and  34.88 (C6), between  3.67 (C1-H), 4.30–

4.44 (C7-H) and  23.65 (C5), and between  7.22–7.32 (Ar-H) and 

44.32 (C7).

MS (EI): m/z (%) = 471 (M⁺, 25), 469 (M⁺, 68), 318 (56), 199 (100).

HRMS (EI): m/z calcd for C₂₆H₂₈ClNO₅: 469.1656, 471.1627; found:

469.1657, 471.1641.

MS (EI): m/z (%) = 471 (M⁺, 6.0), 469 (M⁺, 16), 187 (100).

1,7-trans-7,8-cis-3-Benzyl-2-oxo-8-phenyl-3-azabicyclo[5.2.0]-

HRMS (EI): m/z calcd for C₂₆H₂₈ClNO₅: 469.1656, 471.1627; found:

nonane-9,9-dicarboxylate (25) (Scheme 5)

469.1649, 471.1641.

Scale: 0.68 mmol; pale yellow oil; yield: 128 mg (42%); R_f= 0.5

(hexane/EtOAc 1:1).

IR (neat): 2981, 2931, 1732, 1652, 1455, 1366, 1302, 1096, 1029 cm^–1

.

S

S. Yamazaki et al.

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃):  = 0.966 (t, J = 7.1 Hz, 3 H), 1.37 (t, J = 7.1

Hz, 3 H), 1.41–1.47 (m, 2 H), 1.76–1.80 (m, 1 H), 2.21–2.25 (m, 1 H),

3.19–3.28 (m, 2 H), 3.37 (d, J = 11.3 Hz, 1 H), 3.45 (dd, J = 15.5, 10.6 Hz,

1 H), 3.65 (d, J = 10.4 Hz, 1 H), 3.93–4.01 (m, 2 H), 4.31–4.40 (m, 2 H),

4.41 (d, J = 14.7 Hz, 1 H), 4.73 (d, J = 14.7 Hz, 1 H), 7.19–7.34 (m, 8 H),

7.40 (d, J = 7.7 Hz, 2 H).

3.04 (C4-HH), 3.31 (C4-HH), 3.72 (C1-H), 1.34 (6-CH₃) and  82.58

(C6), and between  3.04 (C4-HH), 3.31 (C4-HH), 3.72 (C1-H), 1.34 (6-

CH₃) and  39.44 (C5).

MS (EI): m/z (%) = 435 (M⁺, 30), 276 (38), 84 (100).

HRMS (EI): m/z calcd for C₂₆H₂₉NO₅: 435.2046; found: 435.2047.

¹³C NMR (100.6 MHz, CDCl₃):  = 13.71 (CH₃), 14.17 (CH₃), 27.64

(CH₂), 34.28 (CH₂), 39.11 (CH), 48.99 (CH), 49.14 (CH₂), 49.77 (CH),

51.37 (CH₂), 59.90 (C), 61.07 (CH₂), 61.61 (CH₂), 126.76 (CH), 127.28

(CH), 127.35 (CH), 128.08 (CH), 128.34 (CH), 128.57 (CH), 137.95 (C),

138.29 (C), 168.11 (C), 171.57 (C), 171.69 (C).

28c-ax (Table 5, Entry 5)

Scale: 0.5 mmol; colorless crystals; yield: 184 mg (73%); R_f= 0.5

(hexane/EtOAc 1:1); mp 156.0–157.0 °C.

IR (KBr): 2983, 1745, 1725, 1685, 1437, 1334, 1117 cm^–1

.

¹H NMR (400 MHz, CD₂Cl₂):  = 0.990 (t, J = 7.1 Hz, 3 H), 1.38 (t, J = 7.1

Hz, 3 H), 1.43–1.50 (m, 2 H), 1.77–1.82 (m, 1 H), 2.23–2.26 (m, 1 H),

3.20 (dddd, J = 11.3, 11.1, 10.4, 3.5 Hz, 1 H), 3.26 (dd, J = 15.4, 5.8 Hz, 1

H), 3.40 (d, J = 11.1 Hz, 1 H), 3.48 (dd, J = 15.4, 10.6 Hz, 1 H), 3.65 (d, J =

10.4 Hz, 1 H), 3.87–3.99 (m, 2 H), 4.34 (q, J = 7.1 Hz, 2 H), 4.43 (d, J =

14.8 Hz, 1 H), 4.67 (d, J = 14.8 Hz, 1 H), 7.20–7.37 (m, 8 H), 7.41 (d, J =

8.0 Hz, 2 H). Selected NOEs are between  3.20 (C7-H) and  7.41 (Ph-

H), and between  3.40 (C1-H) and  3.65 (C8-H). Atom numbering is

shown in Scheme 5.

¹³C NMR (100.6 MHz, CD₂Cl₂):  = 13.87 (CH₃), 14.30 (CH₃), 27.92

(CH₂), 34.58 (CH₂), 39.60 (CH), 49.23 (CH), 49.58 (CH₂), 50.00 (CH),

51.58 (CH₂), 60.14 (C), 61.21 (CH₂), 61.87 (CH₂), 126.94 (CH), 127.55

(CH), 128.30 (CH), 128.44 (CH), 128.84 (CH), 138.53 (C), 139.10 (C),

168.58 (C), 171.79 (C), 172.04 (C). Selected HMBC correlations are be-

tween  3.40 (C1-H), 3.65 (C8-H) and  60.14 (C9), between  3.40

(C1-H), 3.65 (C8-H) and  34.58 (C6), between  3.40 (C1-H) and 

39.60 (C7), and between  7.41 (Ph-H) and  50.00 (C8).

¹H NMR (400 MHz, CDCl₃):  = 1.21 (t, J = 7.1 Hz, 3 H), 1.26 (d, J = 7.2

Hz, 3 H), 1.36 (t, J = 7.1 Hz, 3 H), 2.74 (dddd, J = 13.6, 10.1, 8.1, 5.6 Hz,

1 H), 3.15–3.32 (m, 4 H), 4.12 (dq, J = 10.7, 7.1 Hz, 1 H), 4.28 (dq, J =

10.7, 7.1 Hz, 1 H), 4.29 (d, J = 15.0 Hz, 1 H), 4.35–4.48 (m, 2 H), 4.77 (d,

J = 15.0 Hz, 1 H), 7.27–7.37 (m, 6 H), 7.50 (dd, J = 8.2, 1.4 Hz, 1 H), 7.66

(s, 1 H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.79 (CH₃), 14.07 (CH₃), 18.29

(CH₃), 34.69 (CH), 35.43 (CH), 43.90 (CH), 46.55 (CH₂), 46.60 (CH₂),

60.64 (C), 62.26 (CH₂), 62.81 (CH₂), 123.96 (q, J_CF= 272 Hz, C), 124.82

(q, J_CF= 3.8 Hz, CH), 127.61 (CH), 127.92 (q, J_CF= 4.6 Hz, CH), 128.21

(CH), 128.77 (CH), 128.88 (q, J_CF= 33 Hz, C), 130.62 (CH), 134.25 (C),

136.68 (C), 146.03 (C), 167.85 (C), 170.23 (C), 171.63 (C).

¹⁹F NMR (376.3 MHz, CDCl₃):  = –62.85.

¹H NMR (400 MHz, C₆D₆):  = 0.741 (d, J = 7.0 Hz, 3 H), 0.918 (t, J = 7.1

Hz, 3 H), 1.05 (t, J = 7.1 Hz, 3 H), 2.51–2.54 (m, 1 H), 2.57–2.68 (m, 2

H), 2.74–2.78 (dd, J = 7.4, 7.4 Hz, 1 H), 3.32 (d, J = 13.1 Hz, 1 H), 3.85

(dq, J = 10.7, 7.1 Hz, 1 H), 3.93 (d, J = 14.9 Hz, 1 H), 4.07 (dq, J = 10.7,

7.1 Hz, 1 H), 4.11–4.24 (m, 2 H), 4.83 (d, J = 14.9 Hz, 1 H), 6.73 (d, J =

8.0 Hz, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 7.16–7.19 (m, 2 H), 7.28 (dd, J =

8.2, 1.2 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 2 H), 8.14 (br s, 1 H). Selected NOEs

are between  0.741 (4–CH₃) and  3.32 (C9a-H), 2.57–2.68 (C3–HH,

overlapped), and between  2.74–2.78 (C3-HH) and  2.57–2.68 (C3a-

H). Atom numbering is shown in Table 5.

MS (EI): m/z (%) = 449 (M⁺, 39), 250 (24), 91 (100).

HRMS (EI): m/z calcd for C₂₇H₃₁NO₅: 449.2202; found: 449.2201.

Diethyl 1,5-cis-5,6-cis-3-Benzyl-6-methyl-2-oxo-6-phenyl-3-aza-

bicyclo[3.3.0]heptane-7,7-dicarboxylate (27a); Typical Procedure

(Table 5, Entry 2)

¹³C NMR (100.6 MHz, C₆D₆):  = 13.66 (CH₃), 13.90 (CH₃), 17.81 (CH₃),

34.70 (CH), 35.52 (CH), 44.04 (CH), 46.11 (CH₂), 46.40 (CH₂), 60.98 (C),

To a solution of 1,1,2-ethenetricarboxylic acid 1,1-diethyl ester (19)

[prepared from 1,1-diethyl 2-tert-butyl ethenetricarboxylate (272

mg, 1 mmol) upon treatment with TFA (4 mL)] in DMF (0.8 mL) were

added (E)-3-phenylbut-2-en-1-amine (26a; 2.24 g, 1 mmol) in DMF

(0.8 mL), Et₃N (0.14 mL, 102 mg, 1 mmol), HOBt (270 mg, 2.2 mmol),

and EDCI (199 mg, 1 mmol) at 0 °C. The mixture was stirred for 1 h at

0 °C, and was allowed to warm to r.t. and stirred for 20 h. The mixture

was diluted with CH₂Cl₂. The organic phase was washed with sat. aq

NaHCO₃solution, 2 M aq citric acid, sat. aq NaHCO₃, and water, dried

(Na₂SO₄), and evaporated in vacuo. The residue was purified by col-

umn chromatography (silica gel, hexane/EtOAc) to give 27a as a pale

yellow viscous oil; yield: 214 mg (49%); R_f= 0.8 (hexane/EtOAc 1:4).

62.03 (CH₂), 62.61 (CH₂), 124.72 (q, J_CF= 3.8 Hz, CH), 124.83 (q, J_CF

=

272 Hz, C), 127.62 (CH), 128.34 (CH), 128.85 (q, J_CF= 32 Hz, C), 128.86

(CH), 130.88 (CH), 135.26 (C), 137.77 (C), 146.78 (C), 167.77 (C),

170.29 (C), 170.94 (C). Selected HMBC correlations are between 

2.74–2.78 (C3-HH), 2.57–2.68 (C3a-H, C3-HH), 2.51–2.54 (C4-H), and

 44.04 (C9a), between  2.51–2.54 (C4-H), 3.32 (C9a-H), 2.57–2.68

(C3-HH), 2.74–2.78 (C3-HH) and  35.52 (C3a), and between  3.32

(C9a-H), 2.57–2.68 (C3a-H) and  60.98 (C9).

MS (EI): m/z (%) = 503 (M⁺, 89), 400 (57), 91 (100).

HRMS (EI): m/z calcd for C₂₇H₂₈F₃NO₅: 503.1920; found: 503.1923.

IR (neat): 2983, 1699, 1621, 1495, 1444, 1375, 1262, 1092, 1079 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.30 (t, J = 7.1 Hz, 3 H), 1.33 (t, J = 7.0

Hz, 3 H), 1.34 (s, 3 H), 2.87 (ddd, J = 8.2, 7.4, 4.0 Hz, 1 H), 3.04 (dd, J =

10.4, 4.0 Hz, 1 H), 3.31 (dd, J = 10.4, 7.4 Hz, 1 H), 3.72 (d, J = 8.2 Hz, 1

H), 4.13–4.31 (m, 4 H), 4.36 (d, J = 14.5 Hz, 1 H), 4.47 (d, J = 14.5 Hz, 1

H), 7.25–7.38 (m, 10 H). Selected NOEs are between  2.87 (C5-H) and

 7.25–7.38 (Ph-H), 3.72 (C1-H). Atom numbering is shown in Table 5.

¹³C NMR (100.6 MHz, CDCl₃):  = 14.42 (CH₃), 15.02 (CH₃), 21.29

(CH₃), 39.44 (CH), 39.79 (CH), 45.38 (CH₂), 46.71 (CH₂), 59.81 (CH₂),

64.53 (CH₂), 79.56 (C), 82.58 (C), 125.04 (CH), 127.82 (CH), 128.22

(CH), 128.73 (CH), 136.04 (C), 142.66 (C), 161.30 (C), 166.73 (C),

172.59 (C). Selected HMBC correlations are between  2.87 (C5-H),

3.04 (C4-HH), 3.72 (C1-H) and  172.59 (C2), between  2.87 (C5-H),

28d-eq (Table 5, Entry 8)

Scale: 0.5 mmol; pale yellow viscous oil; yield: 147 mg (60%); R_f= 0.2

(hexane/EtOAc 1:1).

IR (KBr): 3111, 2964, 1737, 1677, 1518, 1346, 1253, 1175, 1037 cm^–1

¹H NMR (400 MHz, CDCl₃):  = 1.26 (t, J = 7.1 Hz, 3 H), 1.33 (d, J = 6.6

Hz, 3 H), 1.39 (t, J = 7.1 Hz, 3 H), 2.20 (dddd, J = 13.1, 11.1, 9.8, 7.6 Hz,

1 H), 2.97 (dq, J = 11.1, 6.6 Hz, 1 H), 3.07 (dd, J = 9.8, 9.2 Hz, 1 H), 3.10

(d, J = 13.1 Hz, 1 H), 3.52 (dd, J = 9.2, 7.6 Hz, 1 H), 4.16 (dq, J = 10.7, 7.1

Hz, 1 H), 4.30–4.52 (m, 3 H), 4.39 (d, J = 14.8 Hz, 1 H), 4.68 (d, J = 14.8

Hz, 1 H), 7.28–7.38 (m, 5 H), 7.50 (d, J = 8.8 Hz, 1 H), 8.13 (dd, J = 8.8,

.

T

S. Yamazaki et al.

Paper

Synthesis

2.5 Hz, 1 H), 8.27 (d, J = 2.5 Hz, 1 H). Selected NOEs are between  1.33

(4-CH₃) and  2.20 (C3a-H), 3.52 (C3-HH), between  2.97 (C4-H) and

 3.10 (C9a-H), and between  2.20 (C3a-H) and  3.52 (C3-HH).

(C), 127.23 (CH), 127.76 (CH), 128.10 (CH), 128.17 (CH), 128.29 (CH),

128.41 (CH), 128.52 (CH), 128.57 (CH), 128.63 (CH), 128.83 (CH),

128.85 (CH), 128.89 (CH), 129.04 (CH), 129.40 (CH), 134.25 (CH),

134.66 (C), 134.90 (CH), 135.16 (C), 135.37 (C), 135.93 (C), 137.22 (C),

137.61 (C), 162.80 (C), 162.89 (C), 164.16 (C), 164.23 (C), 164.29 (C),

164.33 (C).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.92 (CH₃), 14.13 (CH₃), 18.77

(CH₃), 38.94 (CH), 39.15 (CH), 46.54 (CH₂), 49.47 (CH), 49.63 (CH₂),

60.97 (C), 62.55 (CH₂), 63.17 (CH₂), 122.95 (CH), 125.93 (CH), 127.72

(CH), 128.23 (CH), 128.59 (CH), 128.82 (CH), 136.01 (C), 136.49 (C),

146.35 (C), 148.25 (C), 167.71 (C), 170.00 (C), 171.31 (C). Selected

HMBC correlations are between  3.07 (C3-HH), 3.52 (C3-HH), 2.97

(C4-H) and  49.47 (C9a), between  3.10 (C9a-H), 3.07 (C3-HH), 3.52

(C3-HH) and  39.15 (C3a), and between  3.10 (C9a-H), 8.27 (C8-H)

and  60.97 (C9).

MS (EI): m/z (%) = 501 (M⁺, 13), 499 (M⁺, 12), 420 (11), 332 (20), 300

(28), 91 (100).

HRMS (EI): m/z calcd for C₂₅H₂₆BrNO₅: 499.0994, 501.0974; found:

499.0994, 501.0963.

32 (Table 6, Entry 2)

MS (EI): m/z (%) = 480 (M⁺, 100), 377 (43), 91 (71).

Scale: 1 mmol; pale yellow viscous oil; yield: 242 mg (48%); R_f= 0.4

HRMS (EI): m/z calcd for C₂₆H₂₈N₂O₇: 480.1897; found: 480.1900.

(hexane/EtOAc 1:1).

IR (neat): 2980, 1731, 1701, 1445, 1366, 1261, 1034 cm^–1

.

29 (Table 5, Entry 9)

¹H NMR (400 MHz, CDCl₃):  = 1.26 (t, J = 7.1 Hz, 3 H), 1.38 (t, J = 7.1

Hz, 3 H), 3.11–3.18 (m, 1 H), 3.20–3.25 (m, 1 H), 3.61 (d, J = 11.9 Hz, 1

H), 3.66 (dd, J = 8.9, 8.9 Hz, 1 H), 4.02 (dq, J = 10.7, 7.1 Hz, 1 H), 4.21

(dq, J = 10.7, 7.1 Hz, 1 H), 4.26 (d, J = 14.7 Hz, 1 H), 4.38–4.52 (m, 2 H),

4.80 (d, J = 10.7 Hz, 1 H), 4.82 (d, J = 14.7 Hz, 1 H), 7.25–7.36 (m, 8 H),

7.68–7.71 (m, 1 H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.70 (CH₃), 13.98 (CH₃), 40.28 (CH),

46.96 (CH₂), 48.29 (CH), 52.03 (CH₂), 52.57 (CH), 60.79 (C), 62.19

(CH₂), 62.68 (CH₂), 127.48 (CH), 127.56 (CH), 128.31 (CH), 128.36

(CH), 128.45 (CH), 128.57 (CH), 134.36 (C), 134.54 (C), 136.02 (C),

168.66 (C), 169.44 (C), 171.83 (C).

¹H NMR (400 MHz, C₆D₆):  = 0.771 (t, J = 7.0 Hz, 3 H), 1.08 (t, J = 7.1

Hz, 3 H), 2.71 (dddd, J = 12.1, 10.2, 8.8, 6.8 Hz, 1 H), 3.04 (dd, J = 9.4,

6.8 Hz, 1 H), 3.25 (dd, J = 9.4, 8.8 Hz, 1 H), 3.59 (d, J = 12.1 Hz, 1 H),

3.63 (dq, J = 10.7, 7.0 Hz, 1 H), 3.95 (dq, J = 10.7, 7.0 Hz, 1 H), 4.18 (d,

J = 14.7 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 4.53 (d, J = 14.7 Hz, 1 H), 4.86

(d, J = 10.2 Hz, 1 H), 7.02–7.18 (m, 7 H), 7.47 (d-like, J = 7.4 Hz, 1 H),

7.69 (d, J = 7.0 Hz, 1 H). Selected NOEs are between  2.71 (C3a-H) and

 3.59 (C9a-H), 3.25 (C3-HH) and 4.86 (C4-H). Atom numbering is

shown in Table 6.

¹³C NMR (100.6 MHz, C₆D₆):  = 13.70 (CH₃), 14.00 (CH₃), 40.67 (CH),

47.11 (CH₂), 48.55 (CH), 52.11 (CH₂), 53.32 (CH), 61.24 (C), 62.06

(CH₂), 62.66 (CH₂), 127.63 (CH), 128.40 (CH), 128.56 (CH), 128.71

(CH), 128.76 (CH), 128.78 (CH), 135.31 (C), 136.97 (C), 168.91 (C),

169.57 (C), 171.42 (C). Selected HMBC correlations are between  4.86

(C4-H), 3.04 (C3-HH), 3.25 (C3-HH), 3.59 (C9a-H) and  40.67 (C3a), 

3.59 (C9a-H), 7.69 (C5-H) and  53.32 (C4), and between  3.59 (C9a-

H), 7.47 (C8-H) and  61.24 (C9).

Scale: 0.5 mmol; colorless crystals; yield: 263 mg (85%); R_f= 0.4

(hexane/EtOAc 1:1); mp 148.0–149.0 °C.

IR (KBr): 2992, 2978, 1736, 1686, 1530, 1349, 1195, 1024 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.18 (t, J = 7.1 Hz, 3 H), 1.27 (t, J = 7.1

Hz, 3 H), 1.49 (s, 3 H), 3.18 (dd, J = 4.5, 4.5 Hz, 1 H), 3.35 (ddd, J = 8.8,

4.5, 3.5 Hz, 1 H), 3.51 (dd, J = 10.6, 3.5 Hz, 1 H), 3.69 (dd, J = 10.6, 8.8

Hz, 1 H), 3.70 (d, J = 4.5 Hz, 1 H), 3.90 (dq, J = 10.7, 7.1 Hz, 1 H), 4.10

(dq, J = 10.7, 7.1 Hz, 1 H), 4.13–4.23 (m, 3 H), 4.72 (d, J = 14.5 Hz, 1 H),

7.15 (d, J = 8.4 Hz, 1 H), 7.22–7.24 (m, 2 H), 7.30–7.36 (m, 4 H), 7.42

(ddd, J = 8.4, 7.1, 1.0 Hz, 1 H), 7.61 (dd, J = 8.6, 8.2 Hz, 1 H), 7.92 (d, J =

8.4 Hz, 1 H), 7.97 (d-like, J = 8.6 Hz, 1 H), 8.25 (ddd, J = 8.2, 2.0, 1.0 Hz,

1 H), 8.34 (dd, J = 2.0, 1.9 Hz, 1 H). Selected NOEs are between  3.18

(C3-H), 3.51 (C5-HH) and  1.49 [C(CH₃)(Ar)O], between  3.35 (C4-H),

and  3.70 [CH(CO₂Et)₂], 3.69 (C5-HH), and between 3.18 (C3-H) and 

7.97, 8.34 (Ar-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.89 (CH₃), 13.94 (CH₃), 18.79

(CH₃), 43.58 (CH), 43.90 (CH), 46.99 (CH₂), 47.03 (CH₂), 52.18 (CH),

61.84 (CH₂), 61.94 (CH₂), 93.87 (C), 108.77 (CH), 120.32 (CH), 122.28

(CH), 124.01 (CH), 124.74 (CH), 127.93 (CH), 128.53 (CH), 128.62

(CH), 128.76 (CH), 129.33 (C), 129.61 (CH), 133.44 (CH), 135.48 (C),

141.44 (C), 142.55 (C), 148.08 (C), 167.56 (C), 167.80 (C), 171.68 (C).

Selected HMBC correlations are between  3.51 (C5-HH), 3.69 (C5-

HH), 3.18 (C3-H) and  171.68 (C2), between  3.51 (C5-HH), 3.69 (C5-

HH), 3.18 (C3-H) and  43.58 (C4), and between  3.51 (C5-HH), 3.69

(C5-HH), 3.18 (C3-H), 3.35 (C4-H), and  93.87 (C(CH₃)(Ar)O).

MS (EI): m/z (%) = 615 (M⁺, 1.4), 570 (1.8), 481 (65), 91 (100).

HRMS (EI): m/z calcd for C₂₃H₃₃N₂O₈: 615.2329; found: 615.2327.

MS (EI): m/z (%) = 501 (M⁺, 12), 499 (M⁺, 12), 420 (10), 346 (50), 300

(100).

31E (Table 6, Entry 1)

HRMS (EI): m/z calcd for C₂₅H₂₆BrNO₅: 499.0994, 501.0974; found:

Scale: 1 mmol; pale yellow oil; yield: 378 mg (75%); R_f= 0.6

499.0990, 501.0978.

(hexane/EtOAc 1:1).

IR (neat): 2982, 1731, 1650, 1444, 1256, 1205, 1069, 1022 cm^–1

.

Transformation of 31E to 32 (Table 6, Entry 3)

¹H NMR (400 MHz, CDCl₃) (2 rotamers, ratio 1:1):  = 1.29 (t, J = 7.1

Hz, 3 H × 0.5), 1.30 (t, J = 7.1 Hz, 3 H × 0.5), 1.32 (t, J = 7.2 Hz, 3 H ×

0.5), 1.37 (t, J = 7.1 Hz, 3 H × 0.5), 3.80 (d, J = 7.0 Hz, 2 H × 0.5), 3.93 (d,

J = 7.0 Hz, 2 H × 0.5), 4.24–4.33 (m, 2 H × 0.5 + 1 H × 0.5), 4.38 (q, J =

7.1 Hz, 1 H × 0.5), 4.38 (s, 2 H × 0.5), 4.52 (s, 2 H × 0.5), 6.16 (t, J = 7.0

Hz, 1 H × 0.5), 6.22 (t, J = 7.0 Hz, 1 H × 0.5), 6.91–6.94 (m, 2 H × 0.5),

6.99–7.01 (m, 2 H × 0.5), 7.19–7.35 (m, 9 H). Selected NOEs are be-

tween  3.80, 3.93 (C1-H₂) and  7.19–7.35 (Ph-H).

To a solution of 31E (483 mg, 0.97 mmol) in benzene (2 mL) was add-

ed Et₃N (0.135 mL, 99 mg, 0.97 mmol). The mixture was stirred at 80

°C for 16 h. The mixture was concentrated under reduced pressure.

The residue was purified by column chromatography (silica gel,

hexane/Et₂O) to give 32 (324 mg, 67%).

Reaction of 31E with SnBr₄(Table 6, Entry 9)

¹³C NMR (100.6 MHz, CDCl₃):  = 13.97 (CH₃), 14.04 (CH₃), 14.06

(CH₃), 14.09 (CH₃), 44.20 (CH₂), 46.49 (CH₂), 47.96 (CH₂), 51.48 (CH₂),

62.01 (CH₂), 62.07 (CH₂), 62.23 (CH₂), 62.29 (CH₂), 125.10 (C), 125.63

To a solution of 1a (628 mg, 1.25 mmol) in CH₂Cl₂(1 mL) was added a

solution of SnBr₄(548 mg, 1.25 mmol) in CH₂Cl₂(1 mL) at 0 °C. The

mixture was allowed to warm to r.t. and stirred for 18 h. Water was

U

S. Yamazaki et al.

Paper

Synthesis

added to the mixture at 0 °C. The mixture was extracted with CH₂Cl₂

and the organic phase was washed with sat. aq NaHCO₃solution,

dried (Na₂SO₄), and evaporated in vacuo. The residue was purified by

column chromatography (silica gel, hexane/EtOAc) to give 33b (320

mg, 51%) and 34 (217 mg, 30%).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.44 (CH₃), 14.08 (CH₃), 37.91 (CH),

44.01 (CH), 47.21 (CH₂), 47.27 (CH₂), 61.61 (CH₂), 62.53 (CH₂), 66.32

(C), 75.97 (C), 126.49 (CH), 127.76 (CH), 128.33 (CH), 128.63 (CH),

128.66 (CH), 128.80 (CH), 135.75 (C), 141.02 (C), 165.06 (C), 168.00

(C), 170.46 (C). Selected HMBC correlations are between  4.06 (C5-H)

and  170.46 (C2), and between  4.06 (C5-H) and  44.01 (C1).

MS (EI): m/z (%) = 457 (M⁺, 15), 455 (M⁺, 32), 420 (81), 256 (67), 173

33b

(82), 91 (100).

Colorless crystals; R_f= 0.3 (hexane/EtOAc 1:1); mp 127.5–128.0 °C.

IR (KBr): 2981, 1757, 1726, 1694, 1478, 1422, 1227, 1028 cm^–1

.

HRMS (EI): m/z calcd for C₂₅H₂₆ClNO₅: 455.1500, 457.1470; found:

455.1505, 457.1502.

¹H NMR (400 MHz, CDCl₃):  = 0.933 (t, J = 7.1 Hz, 3 H), 1.41 (t, J = 7.1

Hz, 3 H), 3.56 (d, J = 8.0 Hz, 1 H), 3.59–3.65 (m, 2 H), 3.75 (dq, J = 10.7,

7.1 Hz, 1 H), 3.85–3.93 (m, 2 H), 4.11 (d, J = 14.5 Hz, 1 H), 4.37–4.50

(m, 2 H), 4.91 (d, J = 14.5 Hz, 1 H), 7.20–7.35 (m, 8 H), 7.43 (d-like, J =

7.8 Hz, 2 H). Selected NOEs are between  3.85–3.93 (C5-H, over-

lapped) and  7.43 (Ph-H). Atom numbering is shown in Table 6.

35a (Table 6, Entry 10)

Scale: 1.0 mmol; pale yellow crystals; yield: 408 mg (74%); R_f= 0.3

(hexane/Et₂O 1:2); mp 65–67 °C (hexane/EtOAc).

IR (KBr): 2982, 1731, 1701, 1444, 1261, 1193, 1029 cm^–1

.

¹³C NMR (100.6 MHz, CDCl₃):  = 13.50 (CH₃), 14.10 (CH₃), 38.58 (CH),

44.27 (CH), 47.24 (CH₂), 49.88 (CH₂), 61.69 (CH₂), 62.59 (CH₂), 66.40

(C), 70.22 (C), 126.20 (CH), 127.77 (CH), 128.35 (CH), 128.44 (CH),

128.65 (CH), 128.87 (CH), 135.72 (C), 142.90 (C), 165.43 (C), 167.85

(C), 170.38 (C). Selected HMBC correlations are between  3.85–3.93

(C5-H), 3.56 (C1-H), 3.59–3.65 (C4-HH) and  170.38 (C2), and be-

tween  3.85–3.93 (C5-H), 3.59–3.65 (C4-HH) and  44.27 (C1).

¹H NMR (400 MHz, CDCl₃):  = 1.25 (t, J = 7.1 Hz, 3 H), 1.34 (t, J = 7.1

Hz, 3 H), 2.73 (dd, J = 9.4, 9.3 Hz, 1 H), 2.88 (dd, J = 9.4, 7.3 Hz, 1 H),

2.92–3.02 (m, 1 H), 3.18 (d, J = 13.3 Hz, 1 H), 4.16 (dq, J = 10.7, 7.1 Hz,

1 H), 4.17 (d, J = 14.8 Hz, 1 H), 4.31–4.46 (m, 3 H), 4.46 (d, J = 14.8 Hz,

1 H), 5.98 (d, J = 9.6 Hz, 1 H), 7.09–7.11 (m, 2 H), 7.22–7.28 (m, 3 H),

7.36–7.40 (m, 1 H), 7.43–7.51 (m, 5 H), 7.96 (d, J = 7.4 Hz, 1 H), 8.01

(d, J = 8.2 Hz, 1 H). Selected NOEs are between  5.98 (C4-H) and 

3.18 (C9a-H), 2.73 (C3-HH) and between  2.73 (C3-HH) and  3.18

(C9a-H).

MS (EI): m/z (%) = 501 (M⁺, 4.5), 499 (M⁺, 4.5), 420 (81), 373 (100).

HRMS (EI): m/z calcd for C₂₅H₂₆BrNO₅: 499.0994, 501.0974; found:

499.0994, 501.0981.

¹³C NMR (100.6 MHz, CDCl₃):  = 13.95 (CH₃), 14.10 (CH₃), 38.19 (CH),

46.31 (CH₂), 48.18 (CH), 48.81 (CH₂), 60.20 (C), 62.43 (CH₂), 62.86

(CH₂), 89.56 (CH), 108.38 (CH), 120.55 (CH), 125.04 (CH), 127.60 (CH),

127.83 (C), 128.02 (CH), 128.66 (CH), 128.69 (CH), 128.70 (CH),

128.90 (CH), 129.49 (CH), 130.59 (CH), 132.51 (C), 135.50 (C), 135.95

(C), 143.47 (C), 167.68 (C), 169.87 (C). Selected HMBC correlations are

between  2.88 (C3-HH) and  48.18 (C9a), between  3.18 (C9a-H),

2.73 (C3-HH), 2.88 (C3-HH), 5.98 (C4-H) and  38.19 (C3a), and be-

tween  3.18 (C9a-H) and  60.20 (C9).

Anal. Calcd for C₂₅H₂₆BrNO₅: C, 60.01; H, 5.24; N, 2.80; Br, 15.97.

Found: C, 60.16; H, 5.28; N, 2.68; Br, 15.83.

34

Pale yellow oil; R_f= 0.6 (hexane/EtOAc 1:1).

IR (neat): 2982, 1754, 1681, 1486, 1444, 1257, 1178, 1030 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.26 (t, J = 7.2 Hz, 3 H), 1.27 (t, J = 7.2

Hz, 3 H), 3.17 (br, 1 H), 3.43 (br, 1 H), 3.51–3.55 (m, 3 H), 4.06–4.14

(m, 1 H), 4.17–4.25 (m, 3 H), 4.47 (d, J = 14.8 Hz, 1 H), 4.51 (d, J = 14.8

Hz, 1 H), 7.24–7.37 (m, 8 H), 7.70–7.73 (m, 2 H). Selected NOEs are

between  3.43 (C3-H) and  7.70–7.73 (Ph-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.96 (CH₃), 14.02 (CH₃), 46.88

(CH₂), 47.33 (CH), 50.86 (CH₂), 51.18 (CH), 52.46 (CH), 61.68 (CH₂),

61.78 (CH₂), 76.35 (C), 127.57 (CH), 128.27 (CH), 128.53 (CH), 128.67

(CH), 129.72 (CH), 135.56 (C), 142.13 (C), 167.68 (C), 167.96 (C),

171.69 (C).

MS (EI): m/z (%) = 554 (M⁺, 2.8), 435 (8.5), 420 (61), 213 (73), 91 (100).

HRMS (EI): m/z calcd for C₃₁H₃₀N₄O₆: 554.2165; found: 554.2157.

35b (Table 6, Entry 14)

Scale: 0.5 mmol; colorless crystals; yield: 131 mg (44%); R_f= 0.2

(hexane/Et₂O 1:2); mp 122–123 °C (EtOAc).

IR (KBr): 2985, 1731, 1699, 1484, 1444, 1259, 1200, 1022 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.27 (t, J = 7.1 Hz, 3 H), 1.37 (t, J = 7.1

Hz, 3 H), 2.71 (dd, J = 9.7, 9.4 Hz, 1 H), 2.85 (dd, J = 9.4, 7.4 Hz, 1 H),

2.88–2.98 (m, 1 H), 3.16 (d, J = 13.5 Hz, 1 H), 4.16 (d, J = 14.7 Hz, 1 H),

4.19 (dd, J = 10.7, 7.1 Hz, 1 H), 4.34–4.46 (m, 3 H), 4.46 (d, J = 14.7 Hz,

1 H), 5.92 (d, J = 9.6 Hz, 1 H), 7.08–7.10 (m, 2 H), 7.23–7.28 (m, 3 H),

7.37–7.49 (m, 5 H), 7.90 (d, J = 8.6 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H).

Selected NOEs are between  5.92 (C4-H) and  3.16 (C9a-H), 2.71

(C3-HH) and between  2.71 (C3-HH) and  3.16 (C9a-H).

¹³C NMR (100.6 MHz, CDCl₃):  = 13.95 (CH₃), 14.08 (CH₃), 38.12 (CH),

46.31 (CH₂), 48.09 (CH), 48.65 (CH₂), 60.04 (C), 62.71 (CH₂), 63.20

(CH₂), 88.98 (CH), 108.21 (CH), 120.64 (CH), 125.15 (CH), 127.67 (CH),

127.76 (C), 128.02 (CH), 128.74 (CH), 128.84 (CH), 129.30 (CH),

129.98 (CH), 130.51 (CH), 131.50 (C), 135.51 (C), 135.81 (C), 137.20

(C), 143.44 (C), 167.14 (C), 169.40 (C), 169.50 (C). Selected HMBC cor-

relations are between  2.85 (C3-HH) and  48.09 (C9a), between 

3.16 (C9a-H), 2.71 (C3-HH), 2.85 (C3-HH), 5.92 (C4-H) and  38.12

(C3a), and between  3.16 (C9a-H) and  60.04 (C9).

MS (FAB): m/z = 580, 582, 584 ([M + H]⁺), 602, 604, 606 ([M + Na]⁺).

HRMS (FAB): m/z [M

+

H]⁺calcd for C₂₅H₂₈Br₂NO₅: 580.0334,

582.0314, 584.0293 found: 580.0330, 582.0317, 584.0313; m/z [M +

Na]⁺calcd for C₂₅H₂₇Br₂NO₅Na: 602.0154, 604.0133, 606.0113; found:

602.0163, 604.0140, 606.0134.

33a (Table 6, Entry 8)

Using SnCl₄; scale: 1.3 mmol; colorless crystals; yield: 344 mg (43%);

ratio 33a (X = Cl)/33b (X = Br) 4.4:1; R_f= 0.3 (hexane/EtOAc 1:1).

IR (KBr): 2992, 2896, 1758, 1736, 1683, 1607, 1425, 1228, 1071, 1028

cm^–1

.

¹H NMR (400 MHz, CDCl₃) (for major 33a):  = 0.895 (t, J = 7.2 Hz, 3 H),

1.39 (t, J = 7.1 Hz, 3 H), 3.52–3.63 (m, 3 H), 3.71 (dq, J = 10.7, 7.2 Hz, 1

H), 3.86 (dq, J = 10.7, 7.2 Hz, 1 H), 4.06 (ddd, J = 7.4, 7.4, 0.8 Hz, 1 H),

4.23 (d, J = 14.4 Hz, 1 H), 4.34–4.48 (m, 2 H), 4.77 (d, J = 14.4 Hz, 1 H),

7.23–7.32 (m, 8 H), 7.45–7.47 (m, 2 H). Selected NOEs are between 

4.06 (C5-H) and  7.45–7.47 (Ph-H).

MS (EI): m/z (%) = 588 (M⁺, 0.4), 454 (11), 247 (17), 91 (100).

V

S. Yamazaki et al.

Paper

Synthesis

HRMS (EI): m/z calcd for C₃₁H₂₉ClN₄O₆: 588.1776, 590.1746; found:

588.1766, 590.1767.

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16. (b) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103,

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Anal. Calcd for C₃₁H₂₉ClN₄O₆: C, 63.21; H, 4.96; N, 9.51. Found: C,

63.28; H, 4.88; N, 9.54.

35c (Table 6, Entry 15)

Scale: 0.5 mmol; colorless crystals; yield: 51 mg (18%); R_f= 0.2

(hexane/Et₂O 1:5); mp 75–76 °C (hexane/EtOAc).

IR (KBr): 2979, 2928, 1752, 1735, 1701, 1437, 1262 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.25 (t, J = 7.0 Hz, 3 H), 1.35 (t, J = 7.1

Hz, 3 H), 2.41 (s, 3 H), 2.72 (dd, J = 9.4, 9.3 Hz, 1 H), 2.87 (dd, J = 9.3,

7.3 Hz, 1 H), 2.91–2.98 (m, 1 H), 3.17 (d, J = 13.3 Hz, 1 H), 4.16 (d, J =

14.6 Hz, 1 H), 4.17 (dq, J = 10.7, 7.0 Hz, 1 H), 4.31–4.46 (m, 3 H), 4.46

(d, J = 14.6 Hz, 1 H), 5.94 (d, J = 9.4 Hz, 1 H), 7.08–7.11 (m, 2 H), 7.22–

7.30 (m, 5 H), 7.36–7.41 (m, 1 H), 7.43–7.45 (m, 2 H), 7.81 (d, J = 7.8

Hz, 1 H), 8.00 (d, J = 8.2 Hz, 1 H). Selected NOEs are between  5.94

(C4-H) and  3.17 (C9a-H), 2.72 (C3-HH) and between  2.72 (C3-HH)

and  3.17 (C9a-H).

(6) (a) Hu, J.-L.; Feng, L.-W.; Wang, L.; Xie, Z.; Tang, Y.; Li, X. J. Am.

Chem. Soc. 2016, 138, 13151. (b) Parsons, A. T.; Johnson, J. S.

J. Am. Chem. Soc. 2009, 131, 14202. (c) Baar, M. R.; Ballesteros,

P.; Roberts, B. W. Tetrahedron Lett. 1986, 27, 2083. (d) Yamazaki,

S.; Tanaka, M.; Inoue, T.; Morimoto, N.; Kumagai, H.; Yamamoto,

K. J. Org. Chem. 1995, 60, 6546. (e) De-Nanteuil, F.; Waser, J.

Angew. Chem. Int. Ed. 2013, 52, 9009.

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J. Org. Chem. 1988, 53, 4859. (b) Ballesteros, P.; Roberts, B. W.

Org. Synth. Coll. Vol. 7 1990; 142.

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Ukai, T.; Mikata, Y. J. Org. Chem. 2010, 75, 5216. (b) Yamazaki, S.;

Takebayashi, M.; Miyazaki, K. J. Org. Chem. 2010, 75, 1188.

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2009, 7, 655. (d) Morikawa, S.; Yamazaki, S.; Tsukada, M.;

Izuhara, S.; Morimoto, T.; Kakiuchi, K. J. Org. Chem. 2007, 72,

6459. (e) Yamazaki, S.; Iwata, Y. J. Org. Chem. 2006, 71, 739.

(f) Yamazaki, S.; Ueda, K.; Fukushima, Y.; Ogawa, A.; Kakiuchi, K.

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Fujinami, K.; Mikata, Y. RSC Adv. 2012, 2, 8095.

¹³C NMR (100.6 MHz, CDCl₃):  = 13.95 (CH₃), 14.10 (CH₃), 21.40

(CH₃), 38.30 (CH), 46.32 (CH₂), 48.31 (CH), 48.87 (CH₂), 60.17 (C),

62.39 (CH₂), 62.81 (CH₂), 89.62 (CH), 108.42 (CH), 120.54 (CH), 125.00

(CH), 127.60 (CH), 127.89 (C), 128.04 (CH), 128.53 (CH), 128.63 (CH),

128.70 (CH), 129.59 (C), 129.88 (CH), 130.87 (CH), 135.37 (C), 136.00

(C), 139.58 (C), 143.48 (C), 167.79 (C), 169.94 (C), 169.98 (C). Selected

HMBC correlations are between  2.87 (C3-HH) and  48.31 (C9a), be-

tween  3.17 (C9a-H), 2.72 (C3-HH), 2.87 (C3-HH), 5.94 (C4-H) and 

38.30 (C3a), and between  3.17 (C9a-H) and  60.17 (C9).

MS (ESI): m/z = 591 [M + Na]⁺.

HRMS (ESI): m/z [M + Na]⁺calcd for C₃₂H₃₂N₄O₆Na: 591.2220; found:

591.2216.

Funding Information

This work was supported by the Ministry of Education, Culture,

Sports, Science, and Technology (MEXT) and Japan Society for the

Promotion of Science (JSPS) (KAKENHI Grant Number JP26410048).

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(9) (a) Srisiri, W.; Padias, A. B.; Hall, H. K. Jr. J. Org. Chem. 1994, 59,

5424. (b) Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K.

O. Jr.; Ray, J. E. J. Org. Chem. 1994, 59, 6567. (c) Murphy, W. S.;

Neville, D. Tetrahedron Lett. 1996, 37, 9397. (d) Wang, L.; Lv, J.;

Li, S.; Luo, S. Org. Lett. 2017, 19, 3366.

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52, 10639. (b) Qin, Y.; Lv, J.; Luo, S.; Cheng, J.-P. Org. Lett. 2014,

16, 5032.

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(b) Manning, W. B. Tetrahedron Lett. 1979, 20, 1661. (c) Zheng,

M.; Wu, F.; Chen, K.; Zhu, S. Org. Lett. 2016, 18, 3554.

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Acknowledgment

This work was partly supported by Nanotechnology Platform Program

of MEXT. The computations were performed at the Research Center

for Computational Science, Okazaki, Japan. We thank Ms. Y. Yamamoto,

Mr. A. Hirose, Mr. M. Sawada and Ms. M. Yamamoto (Nara University

of Education) for experimental help.

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0040-1706547. Su

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Inter-and Intramolecular Cycloaddition Reactions of Ethenetricarboxylates with Styrenes and Halostyrenes

DOI: 10.1055/s-0040-1706547

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Article abstract of DOI:10.1055/s-0040-1706547

Full text of DOI:10.1055/s-0040-1706547

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