Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides catalyzed by chiral Lewis acids-Scope and limitations of diazo and olefinic substrates

Tetrahedron 66 (2010) 3070–3089

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Tetrahedron

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Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides

catalyzed by chiral Lewis acidsdScope and limitations of diazo and oleﬁnic

substrates

,

a

Hiroyuki Suga ^a, Satoshi Higuchi , Motoo Ohtsuka , Daisuke Ishimoto , Tadashi Arikawa ,

*

Yuta Hashimoto ^a, Shunta Misawa ^a, Teruko Tsuchida ^a, Akikazu Kakehi ^a, Toshihide Baba ^b

^aDepartment of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380-8553, Japan

^bDepartment of Environmental Chemistry & Engineering, Interdisciplinary Graduate School of Science & Engineering, Tokyo Institute of Technology, G1-14,

4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 5 January 2010

Received in revised form 26 January 2010

Accepted 27 January 2010

Available online 10 February 2010

High enantioselectivities (94–96% ee) were obtained for the inverse electron-demand 1,3-dipolar cyclo-

additions between cyclohexyl vinyl ether and 2-benzopyrylium-4-olate generated via Rh₂(OAc)₄-cata-

lyzed decomposition of o-methoxycarbonyl-a-diazoacetophenone. The reactions were effectively

catalyzed by Eu(OTf)₃, Ho(OTf)₃, or Gd(OTf)₃complexes (10 mol %) of chiral 2,6-bis[(4S,5S)-4,5-diphenyl-

2-oxazolinyl]pyridine. The reactions with the other electron-rich dipolarophiles such as allyl alcohol, 2,3-

dihydrofuran, and butyl-tert-butyldimethylsilylketene acetal showed moderate enanantioselectivities

(60–73% ee). Good to high enantioselectivities (73–97% ee) were also obtained for the cycloadditions

between 3-acyl-2-benzopyrylium-4-olates, generated from methyl 2-(2-diazo-1,3-dioxoalkyl)benzoates

and butyl or cyclohexyl vinyl ethers, in the presence of binaphthyldiimine (BINIM)–Ni(II) complexes

(10 mol %). Under similar conditions, the reaction between methyl 2-(2-diazo-1,3-dioxohexyl)benzoate

and 2,3-dihydrofuran was highly endo-selective, and moderately enantioselective (70% ee). For the BINIM–

Ni(II)-catalyzed reactions of cyclohexyl vinyl ether, the use of an epoxyindanone as the 3-acyl-2-benzo-

pyrylium-4-olate precursor revealed that the chiral Lewis acid can function as a catalyst for asymmetric

induction. The scope of the cyclic carbonyl ylides was extended to those generated from 1-diazo-2,5-

pentanedione derivatives, which were reacted with butyl or TBS vinyl ether and catalyzed using the

(4S,5S)-Pybox-4,5-Ph₂–Lu(OTf)₃complex to give good levels of asymmetric inductions (75–84% ee).

Keywords:

1,3-Dipolar cycloaddition

Carbonyl ylide

Chiral Lewis acid

Asymmetric synthesis

Metal catalyst

Diazocarbonyl compound

1. Introduction

a different approachdrare earth metal complexes of chiral 2,6-

(oxazolinyl)-pyridine (Pybox)¹⁰were employed as chiral Lewis

Tandem Rh(II)-catalyzed intramolecular carbonyl ylide forma-

tion followed by 1,3-dipolar cycloaddition of -diazocarbonyl

acids to catalyze the enantioselective cycloadditions between 2-

benzopyrylium-4-olate and electron-deﬁcient carbonyl and oleﬁnic

dipolarophiles. We have recently reported on the ﬁrst successful

examples of chiral Lewis acid-catalyzed inverse electron-demand

cycloadditions between 2-benzopyrylium-4-olates and vinyl ether

derivatives with high levels of asymmetric induction.¹¹In this

paper, we describe the full account of our investigations on the

inverse electron-demand cycloadditions of cyclic carbonyl ylides,

along with the scope and limitations of our methodology with

a

compounds with dipolarophiles,¹which can efﬁciently provide

epoxy-bridged complex polycyclic products in a one-pot reaction

(Scheme 1), has been applied toward the syntheses of various

biologically important oxygen-containing polycyclic natural prod-

ucts, such as brevicomin,²zaragozic acids,³komaroviquinone,⁴

polygalolides,⁵pseudolaric acid A,⁶and aspidophytine⁷(Fig. 1). To

improve the asymmetric synthesis of optically active oxygen-

containing polycyclic compounds, Hodgson⁸and Hashimoto⁹

have independently developed a highly enantioselective variant

of this methodology featuring a chiral Rh(II)-associated carbonyl

ylide in the transition state. In contrast, our laboratory has pursued

R

O

R

O

A

B

A

B

MLn

- N₂

O

CHN₂

n

O

n

O

MLn

O

M = Cu, Rh

Cyclic carbony ylide

Carbenoid

A

B:

C C,

C

O,

C

N

* Corresponding author. Tel.: þ81 26 269 5392; fax: þ81 26 269 5424.

E-mail address: sugahio@shinshu-u.ac.jp (H. Suga).

Scheme 1.

doi:10.1016/j.tet.2010.01.095

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3071

O

(+)-exo-Brevicomin

H

Ph

O

OH

O

OAc

O

Me

R

OMe

Me

(+)-Komaroviquinone

HO₂C

OH

(+)-Zaragozic acid C

O

Ph

O

Me

CO₂H

OH

H

MeO

O

OH

(-)-Polygalolides

A: R = H, B: R = OMe

Figure 1. Naturally occurring epoxy-bridged polycyclic compounds.

regards to the several electron-rich oleﬁnic dipolarophiles and di-

azo substrates as the carbonyl ylide precursors. It is important to

note that the range of diazo substrates have been extended to in-

clude several 1-diazo-2,5-pentanedione derivatives with good

levels of asymmetric induction. Insights into the mechanism of the

Rh(II)- and chiral Lewis acid catalysts, using the corresponding

epoxyindanone as the carbonyl ylide precursor, are also presented.

inﬂuence of the ionic radius of the lanthanoid metals on the

enantio- and diastereoselectivities, and the yields of the cyclo-

adducts are shown in Table 1 (entries 1–9) and Figure 3. Although

strong correlations were not observed (Fig. 3), lanthanoid triﬂates

that exhibited higher enantioselectivities generally corresponded

to higher yields. Good enantioselectivities (81–85% ee) were

obtained for reactions involving Eu(OTf)₃, Gd(OTf)₃, Ho(OTf)₃

Er(OTf)₃, and Tm(OTf)₃. The nature of the lanthanoid triﬂates,

however, did not signiﬁcantly affect the diastereoselectivities. In

regards to the R group of the vinyl ether (entries 3 and 10–14),

a series of (4S,5S)-Pybox-Ph₂–Eu(III)-catalyzed reactions in CH₂Cl₂

(commercial grade) under reﬂuxing conditions revealed that

a cyclohexyl substituent (entry 14) gave the highest enantio- (95%

ee)¹²and diastereoselectivities (endo/exo¼88:12).¹³Interestingly,

both enantioselectivity and yield were reduced when dried and

puriﬁed CH₂Cl₂(via distillation over CaCl₂, then CaH₂) (entry 15)

was used as the reaction solventdthe enantioselectivity and yield,

however, were restored by the addition of MeOH (10 mol %) to the

dried and puriﬁed CH₂Cl₂(entries 16 and 17). Similarly, extremely

high enantioselectivities were obtained for the cyclohexyl vinyl

ether reactions in commercial CH₂Cl₂using Gd(III)- and Ho(III)-

complexes (entries 18 and 19, respectively).

2. Results and discussion

2.1. Reaction of o-methoxycarbonyl-a-diazoacetophenone

with vinyl ethers

Initially, we examined the reaction between butyl vinyl ether

(2a) and o-methoxycarbonyl- -diazoacetophenone (1), as a pre-

a

cursor of 2-benzopyrylium-4-olate, in the presence of chiral Lewis

acids that were prepared from 2,6-bis[(4S,5S)-4,5-diphenyl-1,3-

oxazolin-2-yl]pyridine ((4S,5S)-Pybox-4,5-Ph₂, Fig. 2) and lantha-

noid triﬂates (Scheme 2). The reaction was carried out by adding

a solution of diazoacetophenone 1 to vinyl ether 2a and Rh₂(OAc)₄

(2 mol %) in reﬂuxing CH₂Cl₂over a period of 1 h in the presence of

the (4S,5S)-Pybox-4,5-Ph₂–lanthanoid metal complex (10 mol %),

which was prepared in advance by mixing the ligand and the cor-

responding triﬂates in THF for 2 h followed by drying in vacuo. The

2.2. Reaction of o-methoxycarbonyl-a-diazoacetophenone

with other electron-rich dipolarophiles

X

To investigate the scope of the electron-rich dipolarophiles for

diazo substrate 1, reactions were carried out using mono-

substituted oleﬁns 4–9 in the presence of Pybox-Ph₂–Eu(III)

(10 mol %) (Scheme 3, Table 2). In contrast to the alkyl vinyl ethers,

TBS vinyl ether (4), which possesses a slightly weaker electron-

releasing character, was somewhat unreactive under similar

conditions, afforded the endo-cycloadduct in a low yield and

enantioselectivity (entry 1). Accordingly, weak electron-releasing

oleﬁns such as vinyl propanoate (5), 1-pentene (6), and allyl butyl

ether (7) did not afford the corresponding cycloadducts. Surpris-

ingly, allyl alcohol (8), which presumably possesses an electron-

releasing character similar to that of allyl butyl ether (7), was

reactive in the presence of the (4S,5S)-Pybox-Ph₂–Eu(III) catalyst in

N

O

N

R²

N

R¹

R¹= i-Pr, R²= H : (S,S)-Pybox-i-Pr

X

R

¹= Ph, R²= H : (S,S)-Pybox-Ph

¹= Ph, R²= Ph : (4S,5S)-Pybox-4,5-Ph₂

(R)-BINIM-2QN: X=H

(R)-BINIM-4Me-2QN: X=Me

(R)-BINIM-4(3,5-Xylyl)-2QN: X=Xylyl

Figure 2. Structures of chiral Pybox and BINIM ligands.

MeO

OMe

O

OR

2a - f

CO₂Me

Rh₂(OAc)₄

O

+

O

OR

CHN₂

Chiral

Lewis acid

O

1

endo-3a - f

exo-3a - f

2-benzopyrylium-4-olate

a: R = Bu

b: R = Et

c: R = Bn

d: R = p-MeOC₆H₄CH₂

e: R = t-Bu

f: R = Cyclohexyl

Scheme 2.

3072

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

Table 1

Reactions between diazoacetophenone 1 and oleﬁns 2a–f catalyzed by chiral (4S,5S)-Pybox-4,5-Ph₂–M(OTf)₃complexes^a

endo:exo^c

ee^d(%)

b

Entry

R

M (Ionic Radius (Å))

Distillation of CH₂Cl₂

Additive

Temp (^ꢀC)

Yield (%)

1

2

3

4

5

6

7

8

Bu

La (1.032)

Sm (0.958)

Eu (0.947)

Gd (0.938)

Tb (0.923)

Ho (0.901)

Er (0.890)

Tm (0.880)

Yb (0.868)

Eu (0.947)

Gd (0.938)

Ho (0.901)

No

Yes

No

Yes

No

None

MeOH (10 mol %)

None

MeOH (10 mol %)

None

Reﬂux

87

74

94

Quant

65

89

97

78

80

92

61

64

91

Quant

63

Quant

99

93

99

76:24

79:21

81:19

79:21

77:23

75:25

83:17

80:20

82:18

87:13

88:12

89:11

90:10

88:12

51

59

81

85

67

85

84

81

67

83

61

79

88

95

69

96

95

94

96

9

Bu

Et

Bn

10

11

12

13

14

15

16

17^g

18

19

PMB^e

t-Bu

Cy^f

None

a

The reactions were carried out by adding a solution of 1 in CH₂Cl₂to a suspension of 2a–f, Rh₂(OAc)₄(2 mol %), MS 4 Å, and Pybox–M(OTf)₃complexes (10 mol %) in CH₂Cl₂

under reﬂux over a period of 1 h.

b

Yes: CH₂Cl₂was dried and puriﬁed by distillation with CaCl₂, then CaH₂. No: commercially available CH₂Cl₂was used without further puriﬁcations.

c

Determined by ¹H NMR.

d

Enantiomeric excess of the endo-adduct was determined using chiral HPLC.

p-Methoxybenzyl.

Cyclohexyl.

e

f

g

A mixture of 1 and 2f in CH₂Cl₂was added over a period of 1 h.

CH₂Cl₂under reﬂux conditions to exclusively afford the endo-

cycloadduct in a 32% yield with moderate enantioselectivity (entry

2). Moreover, the yield and enantioselectivity were improved (59%

and 51% ee, respectively) when the reaction was carried out in

reﬂuxing CHCl₃(entry 3).

agreement with that observed for the reaction of electron-deﬁcient

oleﬁnic dipolarophiles such as 3-acryloyl-2-oxazolidinone.

Next, reactions were carried using other electron-releasing

oleﬁns such as substituted alkenyl ethers, 2,3-dihydrofuran (13),

methoxypropene (14), and silylketene acetal 15 (Scheme 4, Table 3).

In the case of 13, the (4S,5S)-Pybox-Ph₂–Eu(III)-catalyzed

(10 mol %) reaction in CH₂Cl₂under reﬂux conditions gave only the

endo-cycloadduct in a high yield with 59% ee (entry 1). Upon fur-

ther investigations using different temperatures and solvents, the

enantioselectivity was improved (66% ee, entry 2) using toluene as

the solvent and 45 ^ꢀC as the reaction temperature. Investigations

involving various lanthanoid triﬂates revealed that the combina-

tion of Yb(OTf)₃with (4S,5S)-Pybox-Ph₂afforded the highest

enantioselectivity (67% ee, entry 3).¹⁴Interestingly, although the

(4S,5S)-Pybox-Ph₂–Eu(III)-catalyzed reaction of methoxypropene

(14) resulted in a low yield and stereoselectivity (entry 4), the re-

action of silylketene acetal 15 in reﬂuxing CH₂Cl₂afforded the

cycloadduct as a mixture of diastereomers (72:28) with a total yield

of 54% and ee values of 27% and 53% (major and minor di-

astereomers, respectively) (entry 5). The enatioselectivities of

(4S,5S)-Pybox-Ph₂–Lu(III)-catalyzed reaction were somewhat im-

proved using a reaction temperature of 45 ^ꢀC in CHCl₃(entry 7). It is

interesting to note that the use of (S,S)-Pybox-Ph and (S,S)-Pybox-i-

Pr as ligands caused a switch of the major diastereomer with dia-

stereoselectivity of up to 76:24 (entries 8 and 9). Moreover, upon

a survey of reaction solvents, the use of toluene gave the highest

enantioselectivites (about 70% ee) without causing a signiﬁcant loss

in the diastereoselectivity (entries 10–12).

100

80

60

40

20

0

100

85

1.05

1

97

84

94

81

89

85

87

80

81

78

74

59

67

65

0.95

0.9

67

Ionic Radius

51

52

62

(

)

Å

58

Yield (%)

54

50

ee (%)

0.85

0.8

0.75

La

Sm Eu

Gd

Tb

Ho Er

Tm Yb

Figure 3. Relationship between the ionic radius of the lanthanoid metals and the

enantio- or diastereoselectivities for the reaction between diazoacetophenone 1 and

oleﬁn 2a catalyzed by chiral (4S,5S)-Pybox-4,5-Ph₂–M(OTf)₃complexes.

Next, the relationship between the lanthanoid metals on the

enantioselectivities and yields in reﬂuxing CHCl₃were examined.

As shown in Figure 4, the yields varied between 36% and 88%, and

did not exhibit any strong correlations to the ionic radii. Although

the use of the Eu(OTf)₃, Gd(OTf)₃, and Ho(OTf)₃complexes exhibi-

ted higher enantioselectivities than that of other lanthanoid tri-

ﬂates, the maximum enantioselectivity was merely 55% ee

(Ho(OTf)₃, entry 4). Subsequent investigations revealed that the

addition of basic inorganic salts (10–30 mol %) in combination with

the (4S,5S)-Pybox-Ph₂–Ho(III) catalyst improved the enantiose-

lectivity (up to 60% ee) with reasonable yields (entries 5–7).²⁷The

(4S,5S)-Pybox-Ph₂–Eu(III)-catalyzed reaction of styrene (9) in

CH₂Cl₂under reﬂux conditions afforded the alternate regio-isomer

with a yield of 22% as a mixture of the exo:endo diastereomers with

low enantioselectivity (entry 8). The regioselectivity was in good

2.3. Reaction of methyl 2-(2-diazo-1,3-dioxoalkyl)benzoates

with vinyl esters

To investigate the generality of our methodology on other diazo

a⁰

compounds (Table 4), butyl vinyl ether (2a) was reacted with a, -

dicarbonyl diazo substrate 19, which was prepared from diazo-

acetophenone 1 according to the procedure reported by Padwa.⁴To

date, catalysts involving various combinations of chiral Pybox

ligands and lanthanoid triﬂates have yet to afford satisfactory

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3073

MeO

OMe

O

Chiral

Lewis acid

CO₂Me

CHN₂

O

Rh₂(OAc)₄

O

R

10: R = OTBS

R

11: R = CH₂OH

O

endo

O

4: R = OTBS

1

2-benzopyrylium-4-olate

5: R =

O

C

O

Pr

MeO

Ph

6: R = Bu

7: R = CH₂OBu

8: R = CH₂OH

9: R = Ph

O

+

O

exo-12

endo-12

Scheme 3.

Table 2

Reactions between diazoacetophenone 1 and oleﬁns 4, 8, and 9 catalyzed by chiral (4S,5S)-Pybox-4,5-Ph₂–M(OTf)₃complexes^a

Entry

R⁰(4, 8, 9)

M (Ionic radius (Å))

Solvent

Temp (^ꢀC)

Additive (mol %)

Yield (%)

ee^b(%)

c

1

2

3

4

5

6

7

8

OTBS (4)

Eu (0.947)

Ho (0.901)

Eu (0.947)

CH₂Cl₂

Reﬂux

MeOH (10)

None

K₂CO₃(30)

LiF (30)

13

32

59

70

61

73

66

17

45

51

55

60

59

c

CH₂OH (8)

Ph (9)

CH₂Cl₂

CHCl₃

CH₂Cl₂

NaOAc (10)

MeOH (10)

58

22 (69:31)^d

10, 20^e

a

The reactions were carried out by adding a solution of 1 in CH₂Cl₂to a suspension of oleﬁns 4–9, Rh₂(OAc)₄(2 mol %), MS 4 Å, and Pybox–M(OTf)₃complexes (10 mol %)

over a period of 1 h.

b

Enantiomeric excess of the endo-adduct was determined using chiral HPLC.

Dried and puriﬁed by distillation with CaCl₂and then CaH₂.

Diastereomeric ratio.

c

d

e

Enantiomeric excess of the adducts were determined using chiral HPLC (Major, Minor).

resulted in lowering the enantioselectivity (entry 7), which was

recovered to that of commercial CH₂Cl₂by the addition of MeOH

100

80

60

40

20

0

1.05

1

(10 mol %) (entries 8 and 9). Subsequently, the BINIM-4Me-2QN–

Ni(II) catalyst was employed for the reactions of several diazo

compounds 20–27 with vinyl ethers 2c or 2d to give the corre-

sponding adducts with good to excellent enantioselectivities (en-

tries 10–18). Among diazo compounds 19–27, those that possess

substrates with bulky acyl substituents exhibited relatively higher

enantioselectivities (entries 12, and 16).

88

50

80

41

70

55

65

59

51

55

51

41

48

16

0.95

0.9

44

Ionic Radius

( Å)

36

25

45

Yield (%)

ee (%)

150.85

2.4. Asymmetric induction using epoxyindanone as

a carbonyl ylide precursor

La Sm Eu Gd Tb Ho Er Tm Yb Lu

-22

0.8

-20

-40

Padwa reported that, in the presence of Rh₂(OAc)₄, carbonyl

ylides that are generated from a,a

⁰-dicarbonyl diazo compounds

0.75

Figure 4. Relationship between the ionic radius of the lanthanide metals and the

enantioselectivities and yields for the reaction between diazoacetophenone 1 and

oleﬁn 8 catalyzed by chiral (4S,5S)-Pybox-4,5-Ph₂–M(OTf)₃complexes.

in the absence of dipolarophiles cyclize to the corresponding

epoxyindanones that, upon heating, revert to the carbonyl ylides.⁴

Accordingly, diazo compound 23 was cyclized, under similar

conditions, to epoxyindanone B as the precursor of carbonyl ylide

A. As a note, the reaction also afforded a small amount of 3,4-

dihydro-1H-2-benzopyran-1,4-dione derivative as an impurity.

Under reﬂux conditions (CH₂Cl₂) without slow addition of sub-

strates, however, (R)-BINIM-4Me-2QN–Ni(II)-catalyzed reaction

between diazo substrate 23 and vinyl ether 2f required a relatively

long reaction time (22 h) affording the endo-adduct (61% yield)

with merely 9% ee. In contrast, slow addition (over a period of 1 h)

of epoxyindanone B into a solution of vinyl ether 2f and the Ni(II)

catalyst in dry CH₂Cl₂under reﬂux conditions gave endo-cyclo-

adduct 32f (60% yield) with 86% ee (Scheme 5). Under the con-

ditions, however, the reaction did not proceed to completion, in

which unreacted epoxyindanone B was readily hydrolyzed to the

3,4-dihydro-1H-2-benzopyran-1,4-dione derivative during chro-

matographic separation of cycloadduct 32f. Our results suggest

enantioselectivities.¹⁵However, we have achieved good enantio-

selectivities (up to 73% ee) with extremely high endo selectivity

(Table 4, entries 1–3) using

a chiral catalyst consisting of

Ni(ClO₄)₂$6H₂O and optically active binaphthyldiimine (BINIM) li-

gand (Fig. 2).¹⁶Raising the temperature for the reactions of 19 in

CH₂Cl₂under reﬂux conditions increased the enantioselectivities to

92% ee,¹²using the (R)-BINIM-4Me-2QN–Ni(II) complex as the

Lewis acid (entry 4). Under similar conditions, high enantiose-

lectivity was also obtained for the reaction with cyclohexyl vinyl

ether (2f, entry 6)dhowever, a slightly lower enantioselectivity

was observed for the reaction with benzyl vinyl ether (2c, entry 5).

Similar to the reaction of diazo substrate 1, the use of dried and

puriﬁed CH₂Cl₂(distillation with CaCl₂, then CaH₂) as the solvent

3074

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

R³

MeO

H

OMe

O

Chiral

R³

R²

H

CO₂Me

CHN₂

O

Lewis acid

OR¹

R²

Rh₂(OAc)₄

+

O

OR¹

R²

O

OR¹

O

1

R³

Me

OMe

16 - 18

OTBS

OBu

O

13

14

Scheme 4.

15

Table 3

Reactions between diazoacetophenone 1 and oleﬁns 13–15 catalyzed by chiral (4S,5S)-Pybox-4,5-Ph₂–M(OTf)₃complexes^a

Entry

Oleﬁn

M (Å)^b

Pybox

Solvent

Temp (^ꢀC)

Yield (%) (Products)

dr

ee (%)^c

Former

Latter

>99:1^e

47:53

28:72

42:58

46:54

64:36

76:24

74:26

72:28

59

66

67

d

1

2

3

4

5

6

7

8

13

14

15

Eu (0.947)

Yb (0.868)

Eu (0.947)

Lu (0.861)

Pybox-Ph₂

Pybox-Ph

Pybox-i-Pr

CH₂Cl₂

Reﬂux

45

Reﬂux

45

98 (16)

96 (16)

86 (16)

23 (17)

54 (18)

41 (18)

36 (18)

29 (18)

24 (18)

68 (18)

63 (18)

49 (18)

Toluene

d

CH₂Cl₂

15

53

56

67

58

65

72

70

12

27

26

42

44

56

55

73

72

f

CH₂Cl₂

f

CH₂Cl₂

CHCl₃

9

10

11

12

Toluene

Toluene^g

Toluene^h

45

a

The reactions were carried out by adding a solution of 1 to a suspension of oleﬁns 13–15, Rh₂(OAc)₄(2 mol %), MS 4 Å, and Pybox–M(OTf)₃complexes (10 mol %,

5.0ꢁ10^ꢂ3M calculated from total volume of the solvent used) over a period of 1 h.

b

Ionic radius.

c

Enantiomeric excess of the adduct was determined using chiral HPLC.

Commercially available CH₂Cl₂was used without further puriﬁcations.

Only the endo-adduct was obtained.

d

e

f

Dried and puriﬁed CH₂Cl₂was used with MeOH (10 mol %) as an additive.

g

2.5ꢁ10^ꢂ3M for Pybox-i-Pr-Lu(OTf)₃.

h

10.0ꢁ10^ꢂ3M for Pybox-i-Pr-Lu(OTf)₃.

that the asymmetric induction is effectively catalyzed by the (R)-

BINIM-4Me-2QN–Ni(II) complex, and without the participation of

Rh₂(OAc)₄, which may be involved only in the generation of the

carbonyl ylides for reactions of diazocarbonyl compounds as

substrates. It should be noted that the use of commercial grade

CH₂Cl₂as a solvent lowered not only yield (40%) but also enan-

tioselectivity (65% ee) in the reaction of epoxyindanone B as

a carbonyl ylide precursor. This result indicates that commercial

grade CH₂Cl₂or MeOH as an additive in puriﬁed CH₂Cl₂probably

did not play an effective role for improvement of yield and

enantioselectivity in the chiral Lewis acid-catalyzed cycloaddition

step of carbonyl ylides, which were generated from diazocarbonyl

compounds. As mentioned above, Hodgson⁸and Hashimoto⁹

showed that Rh(II)-associated species could participate in the

transition state of the cycloadditions of carbonyl ylides. However,

compared with a free carbonyl ylide, the Rh(II)-associated car-

bonyl ylide would not easily coordinate with a chiral Lewis acid for

activation on a basis of frontier orbital theory. Considering from

these facts, one possibility for the effect of MeOH as an additive or

commercial grade CH₂Cl₂is that it can be attributed to the pre-

sumed coordination of the chiral Lewis acid to the carbonyl ylide

via dissociation of the Rh-associated species to a free carbonyl

ylide. The unusual dependence between the selectivity and the

reaction temperature (raising the temperature increased the

enantioselectivity, Table 4, entries 3 vs 4) may be also attributed to

the dissociation of the Rh-associated species in the reaction of

diazo substrates as carbonyl ylide precursors.

2.5. Reaction of methyl 2-(2-diazo-1,3-dioxohexyl)benzoate

with other electron-rich dipolarophiles

To investigate the range of electron-rich dipolarophiles as diazo

substrate 19, reactions were carried out using mono-substituted

oleﬁns 4–9 and disubstituted alkenyl ethers 13–15 and 37

(Scheme 6, Table 5). In comparison to those from diazo compound

1, carbonyl ylides that were generated from diazo compound 19

exhibited somewhat different reactivities toward the dipolaro-

philes. In the case of TBS vinyl ether (4, entry 2), the yield of the

(4S,5S)-Pybox-Ph₂–Eu(OTf)₃–catalyzed reaction with diazo com-

pound 19 was higher (68%) than that with diazo substrate 1 but

with similar low enantioselectivity. For vinyl propanoate (5), 1-

pentene (6), allyl butyl ether (7), and styrene (9) (entries 3–7), the

(R)-BINIM-4Me-2QN–Ni(II)-catalyzed reactions did afford the cor-

responding cycloadducts, but in very low yields with only slight

asymmetric induction. For allylic alcohol (8), the Ni(II)-complex

catalyzed reaction with diazo diketone 19, unlike that with diazo

compound 1, did not give the cycloadduct. For 2,3-dihydrofuran

(13), the reaction with diazo substrate 19 afforded only the endo-

cycloadduct in high yieldsdmoreover, upon a survey of solvents

and temperatures, CHCl₃at 40 or 45 ^ꢀC was found as optimal re-

action conditions affording moderate enantioselectivity (70% ee,

entries

8 and 9). In the case of silyketene acetal 15, its

decomposition occurred as the main process under (R)-BINIM-

4Me-2QN–Ni(II)-catalyzed conditions, to afford the cycloadduct in

low yields with little asymmetric induction. Finally, in the cases of

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3075

Table 4

Reactions of

a

,a

⁰-dicarbonyl diazo compounds 19–27 with oleﬁns 2a, 2c, and 2f catalyzed by (R)-BINIM–Ni(II) complexes^a

MeO

OMe

Chiral

CO₂Me

N₂

Lewis acid

Rh₂(OAc)₄

O

OR

R'

OR

O

2a 2f

or

O

19 - 27

a: R = Bu

endo-28a

endo-

c

: R = Bn

28f 36f

-

f: R = Cyclohexyl

Entry

BINIM ligand

2QN

19–27 (R⁰)

Oleﬁn

Temp (^ꢀC)

Product

Yield (%)

ee^b(%)

1

19 (Pr)

2a

2c

2f

2c

2f

rt

28a

28c

28f

29f

30c

30f

31f

32f

33f

34f

35f

36f

78

86

99

76

96

85

80

86

77

85

96

87

82

66

78

85

87

59

42

73

92

79

93

90

94

93

73

90

97

93

88

84

96

92

77

2

3

4

5

4(3,5-Xylyl)-2QN

4Me-2QN

19 (Pr)

rt

Reﬂux

6

7^c

8^d

9^e

10

11

12

13

14

15

16

17

18

20 (Et)

21 (i-Pr)

22 (Bu)

23 (i-Bu)

24 (Pentyl)

25 (Cyclohexyl)

26 (Bn)

27 (PhCH₂CH₂)

a

The reactions were carried out by adding a solution of 19–27 in CH₂Cl₂(commercial grade without further puriﬁcations) to a suspension of 2a or 2f, Rh₂(OAc)₄(2 mol %),

MS 4 Å, and BINIM–Ni(II) complexes (10 mol %) over a period of 1 h.

b

Enantiomeric excess of endo-adduct was determined by chiral HPLC.

Dried and puriﬁed CH₂Cl₂by distillation with CaCl₂, then CaH₂was used.

The reaction was carried out in dried and puriﬁed CH₂Cl₂with MeOH (10 mol %) as an additive.

The reaction was carried out by adding a solution of 19 and 2f over a period of 1 h in dried and puriﬁed CH₂Cl₂with MeOH (10 mol %) as an additive.

c

d

e

a

-substituted vinyl ethers, higher enantioselectivity (44% ee) was

2.6. Reaction of 1-diazo-2,5-pentandione derivatives with

vinyl ethers

obtained in CH₂Cl₂under reﬂux conditions for the relatively bulky

vinyl ether 37 (entry 12) compared to that of vinyl ether 14 (entry

10).

To further investigate the scope of our methodology for other

diazo compounds, the reaction between diazo diketone 47 and

OMe

CO₂Me

Cy: Cyclohexyl

N₂

Rh₂(OAc)₄

O

OCy

O

23

Slow addition

(1 h)

O

2f

A

Rh₂(OAc)₄

rt

92% Yield

82% Yield

88% ee

(R)-BINIM-4M-2QN-Ni(II)

(10 mol%)

O

OMe

Reflux in CH₂Cl₂

O

+

O

B

O

97 : 3

Slow addition (1 h)

(R)-BINIM-4M-2QN-Ni(II)

MeO

(10 mol%)

OMe

O

2f

OCy

O

OCy

60% Yield

86% ee

Reflux

O

in CH₂Cl₂

O

A

Scheme 5.

3076

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

R²

O

MeO

OMe

H

Chiral

R²

R¹

R

Pr

H

CO₂Me

N₂

Lewis acid

R

Rh₂(OAc)₄

O

+

O

R¹

Pr

R¹

O

R

O

R²

4: R = OTBS, R¹= R²= H

19

¹= R²= H

5: R = O

C

O

Pr,

R

6: R = Bu, R¹= R²= H

7: R = CH₂OBu, R¹= R²= H

8: R = CH₂OH, R¹= R²= H

9: R = Ph, R¹= R²= H

Ph

Me

OMe

14

OTBS

OBu

O

OBu

13

37

15

Scheme 6.

butyl vinyl ether (2a) was examined (Scheme 7, Table 6). First,

catalysts were prepared from Eu(OTf)₃and three types of Pybox

ligands (Fig. 2). Next, to the solutions of these Pybox–Eu(III) com-

plexes, along with vinyl ether 2a (2 equiv) and Rh₂(OAc)₄, in CH₂Cl₂

at 23 ^ꢀC was added diazo diketone 47 over a period of 1 h (entries

1–3). In contrast to the reaction of 2-benzopyryrium-4-olate gen-

Gd(OTf)₃or Tb(OTf)₃with (4S,5S)-Pybox-Ph₂as the ligand (Fig. 5).

For the (4S,5S)-Pybox-Ph₂–Tm(III)-catalyzed reactions (entries 4, 5,

9, and 10), a reaction temperature of 30 ^ꢀC was found to give the

highest enantioselectivity (75% ee). The yield and enantioselectivity

were improved by modifying the procedure in which a mixture of

diazo diketone 47 and vinyl ether 2a was added to Rh₂(OAc)₄and

the (4S,5S)-Pybox-Ph₂–Tm(III) complex in CH₂Cl₂over a period of

1 h (entry 6). In the case of the (4S,5S)-Pybox-Ph₂–Lu(III)-catalyzed

reaction (entry 12), the exo-selectivity was also improved by adding

a mixture of diazo diketone 47 and vinyl ether 2a. Again, it is

noteworthy that, for the reactions of both Tm(OTf)₃and Lu(OTf)₃

(entries 7 and 13, respectively), enantioselectivities were reduced

when dried and puriﬁed CH₂Cl₂(via distillation with CaCl₂, then

CaH₂) was used as the solvent. In the case of the (4S,5S)-Pybox-Ph₂–

Lu(III)-catalyzed reactions, higher enantioselectivities were not

obtained by raising the reaction temperature (entries 17 and

18)dthe maximum enantioselectivity (78% ee) was observed at

23 ^ꢀC (entry 12). Finally, the optimal enantioselectivity (82% ee) and

exo-selectivity (92:8) was achieved using the (4S,5S)-Pybox-Ph₂–

Lu(III) complex in dried and puriﬁed CH₂Cl₂with MeOH (10 mol %)

as an additive (entry 14). It is interesting to note that increasing the

catalyst loading (20%, entry 15; and 50%, entry 16) resulted in lower

enantioselectivities.

erated from o-methoycarbonyl-a-diazoacetophenone (1), which

gave the endo-cycloadduct with a high diastereoselectivity, the

reactions of diazo diketone 47 selectively formed the exo-cyclo-

adduct.¹⁷Among the three Pybox–Eu(III) complexes, the catalyst

involving the (4S,5S)-Pybox-Ph₂ligand exhibited the highest

enantioselectivity (60% ee, exo), which was comparable to that of

the reaction with diazoacetophenone 1. Upon a survey of various

lanthanoid metals (Fig. 5, three metals (Eu, Tm, and Lu) are shown

in Table 6), catalysts that involve Tm (67% ee) and Lu (77% ee)

(entries 4 and 11, respectively) exhibited higher enantioselectivities

than those of other lantanoid metals. Maximum exo-selectivity

(exo:endo¼92:8 (84% de)) was observed for reactions that employ

Table 5

Reactions of diazo compound 19 with oleﬁns 4–9, 13–15, and 37 catalyzed by the

(R)-BINIM-4Me-2QN–Ni(II) complex^a

Entry Oleﬁns Solvent Temp (^ꢀC) Product Yield (%) dr^b

ee^c(%)

Investigations of the R⁰-substituent of the vinyl ethers (Scheme

8, Table 7, entries 1–6), with the (4S,5S)-Pybox-Ph₂–Lu(III) complex

as the catalyst, demonstrated that the enantioselectivity of butyl

vinyl ether (2a) was higher than those of tert-butyl or cyclohexyl

vinyl ethers (2e or 2f, respectively), which was in contrast to the

Major Minor

>99:1^e

6

d

1

4

5

6

7

9

13

14

15

37

CH₂Cl₂Reﬂux

38

39

40

41

42

43

44

45

46

44

68

2

9

1

d

2^g

3

CH₂Cl₂Reﬂux

>99:1^e19

CH₂Cl₂Reﬂux

>99:1^e

1

4

d

4

5

CH₂Cl₂Reﬂux

reactions of o-methoycarbonyl-a-diazoacetophenone (1). Re-

CH₂Cl₂Reﬂux

>99:1^eNDⁱ

90:10 10^f

89:11 7^f

>99:1^e70

61:39 30

d

markably, TBS vinyl ether (4) gave the exo-cycloadduct exclusively,

in a reasonable yield and with good enantioselectivity (82% ee). To

investigate the R-substituent of the diazo compounds (Scheme 8,

Table 7, entries 7–11), diazo diketones 48–52 were reacted with

vinyl ether 2a in the presence of (4S,5S)-Pybox-Ph₂–Lu(III) complex

to afford the corresponding cycloadducts with good enantiose-

lectivities (75–84% ee) and high exo-selectivities (92:8 to >99:1).

6

CHCl₃

Reﬂux

9

7^h

8

CH₂Cl₂Reﬂux

38

95

98

85

12

68

d

CHCl₃

40

45

9

d

10

11

12

CH₂Cl₂Reﬂux

17

d

CH₂Cl₂Reﬂux

74:26

2

NDⁱ

44

d

CH₂Cl₂Reﬂux

74:26 44

a

The reactions were carried out by adding a solution of 1 to a suspension of

oleﬁns 4–9, 13–15, or 37, Rh₂(OAc)₄(2 mol %), MS 4 Å, and (R)-BINIM-4Me-2QN–

Ni(II) complex (10 mol %), which was prepared from (R)-BINIM-4Me-2QN and

Ni(ClO₄)₂6H₂O, over a period of 1 h.

b

Diastereomer ratio.

Enantiomeric excess of adducts was determined by chiral HPLC.

Commercially available CH₂Cl₂was used without further puriﬁcations.

Only the endo-adduct was obtained.

Enantiomeric excess of the major diastereomer.

(4S,5S)-Pybox-Ph₂–Eu(OTf)₃(10 mol %) was used for the chiral Lewis acid.

Ni(BF₄)₂6H₂O was used for the preparation of the (R)-BINIM-4Me-2QN–Ni(II)

Me

c

Me

2a

Rh₂(OAc)₄

OBu

d

(2 mol%)

(2 equiv)

O

CHN₂

O

e

O

OBu

Pybox-M(OTf)₃

(10 mol%)

23 ^oC in CH₂Cl₂

f

O

g

O

47

h

exo-53a

complex.

i

Scheme 7.

Not determined.

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3077

Table 6

Reactions of diazo compound 47 with vinyl ether 2a catalyzed by the chiral Pybox–M(OTf)₃complexes^a

Entry

Pybox^b

M (Å)^c

Add. Conditions^d

Solvent

Temp (^ꢀC)

Yield (%)

exo:endo^e

ee^f(%)

1

2

3

4

5

6

7

8

i-Pr

Ph

Eu (0.947)

Tm (0.880)

Lu (0.861)

A

B

A

B

CH₂Cl₂

23

30

35

Reﬂux

23

30

35

79

68

63

68

60

71

70

68

55

65

57

68

70

64

53

62

63

64

81:19

84:16

88:12

91:9

90:10

95:5

90:10

86:14

89:11

90:10

92:8

90:10

94:16

87:13

89:11

16

43

60

67

75

76

65

68

53

77

78

65

82

75

64

73

72

Ph₂

g

CH₂Cl₂

Toluene^k

CH₂Cl₂

9

10

11

12

13

14

15ⁱ

16^j

17

18

g

CH₂Cl₂

h

CH₂Cl₂

h

CH₂Cl₂

h

CH₂Cl₂

a

The reactions were carried out by adding a solution of the substrates in CH₂Cl₂(commercial grade without further puriﬁcations) to a suspension of Rh₂(OAc)₄(2 mol %), MS

4 Å, and Pybox–M(OTf)₃complexes (10 mol %) over a period of 1 h.

b

Ph₂: (4S,5S)-Pybox-Ph₂, i-Pr: (S,S)-Pybox-i-Pr, Ph: (S,S)-Pybox-Ph.

Ionic radius.

A: The reaction was carried out by adding a solution of 47 to a suspension of 2a, the catalyst, and MS 4 Å over a period of 1 h. B: The reaction was carried out by adding

c

d

a solution of 47 and 2a to a suspension of the catalyst and MS 4 Å over a period of 1 h.

e

Determined by ¹H NMR.

f

Enantiomeric excess of the exo-adduct was determined by ¹H NMR after conversion to the corresponding acetal in the reaction with (R,R)-hydrobenzoin.

g

Dried and puriﬁed CH₂Cl₂(via distillation with CaCl₂, then CaH) was used.

The reaction was carried out in dried and puriﬁed CH₂Cl₂with MeOH (10 mol %) as an additive.

20 mol % catalyst was used.

50 mol % catalyst was used.

h

i

j

k

Dried and puriﬁed toluene (typical procedures) was used.

2.7. Reaction of 1-diazo-2,5-hexandione with other

electron-rich dipolarophiles

2.8. Absolute conﬁguration of cycloadduct exo-53f

Cycloadduct exo-53f was converted to the corresponding

acetal via reaction with (R,R)-hydrobenzoin in the presence of

PPTS in toluene under reﬂux conditions using a Dean–Stark trap

(Scheme 10). Recrystallization from hexane gave a single crystal

of the acetal (mp 147–148 ^ꢀC) that consisted of a single di-

astereomer (>99% de, determined by 400 MHz ¹H NMR). Struc-

tural analysis of the crystal using X-ray crystallography showed

that all the asymmetric carbons of the corresponding cyclo-

adduct exo-53f possess the (R)-conﬁguration (Fig. 6). These

results suggests that the coordination between the (4S,5S)-

Pybox-Ph₂–Lu(OTf)₃complex and the carbonyl ylide effectively

shields the approach of vinyl ether 2f from the upper side, and

hence, the formation of cycloadduct exo-53f, with (R)-conﬁgu-

rations at all three stereocenters (Fig. 7), involves an approach of

vinyl ether 2f from the lower side with an exo-orientation.

Previously, X-ray analysis of the (4S,5S)-Pybox-Ph₂–La(OTf)₃

complex has shown that the La metal possesses nine coordination

sites and includes four hydrates.¹⁸Moreover, the number of the

coordination sites may vary according to the type of the lanthanoid

metal. Because the Pybox–lantanoid triﬂate complexes could pos-

sess multi-coordination sites, the exact arrangement of the car-

bonyl ylide coordinated to the Pybox–lanthanoid complexes that

shields the upper side could not be easily estimated at this point.

However, a similar facial shielding behavior would also explain the

efﬁcient asymmetric induction of the reactions between 2-benzo-

pyrylium-4-olate and vinyl ethers.

Reactions between diazo substrate 47 and other electron-rich

dipolarophiles were evaluated under similar conditions using the

(4S,5S)-Pybox-Ph₂–Lu(OTf)₃complex as the catalyst (Scheme 9,

Table 8). Although the reactions of a-substituted vinyl ethers 14 and

15 exhibited slight asymmetric inductions (entry 1 and 2, re-

spectively), the reaction with styrene (9) afforded the endo-cyclo-

adduct exclusively with 80% ee (entry 3), albeit with a yield of

merely 3%.

3. Conclusion

We have successfully developed the inverse-electron-demand

dipole-LUMO/dipolarophile-HOMO-controlled cycloaddition re-

actions of cyclohexyl or butyl vinyl ethers toward carbonyl

Figure 5. Relationship between the ionic radii and the enantio- and diaster-

eoselectivities and the yields for the reaction of diazo compound 47 with vinyl ether 2a

catalyzed by the chiral (4S,5S)-Pybox-4,5-Ph₂–M(OTf)₃complexes.

3078

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

R

O

2a - c,

Rh₂(OAc)₄

(2 mol%)

OR'

2e - f, 4

(2 equiv)

O

CHN₂

O

OR'

Pybox-Ph₂-Lu(OTf)₃

(10 mol%)

O

exo

MeOH (10 mol%)

47: R =Me

48: R = Et

49: R = i-Pr

50: R = t-Bu

51: R = Bn

52: R = Ph

23 ^oC in CH₂Cl₂

53: R = Me

54: R = Et

55: R = i-Pr

56: R = t-Bu

57: R = Bn

58: R = Ph

a: R' = Bu

b: R' = Et

c: R' = Bn

e: R' = t-Bu

f: R' = Cyclohexyl

59: R = Me, R' = TBS

Scheme 8.

Table 7

Table 8

Reactions of diazo compounds 47–52 with vinyl ethers 2a–c, 2e and 2f, and 4 cat-

alyzed by the (4S,5S)-Pybox-Ph₂–Lu(OTf)₃complex^a

Reactions of diazo compound 47 with oleﬁns 14, 15, and 9 catalyzed by the (4S,5S)-

Pybox-Ph₂–Lu(OTf)₃complexes^a

Entry R (Diazo substrates) R⁰(Oleﬁns)

Products Yield (%) exo:endo^bee^c(%)

Enrty

Oleﬁns

Products

Yield (%)

dr^b

ee^c(%)

1

2

3

4

5

6

7

8

Me (47)

Et (48)

i-Pr (49)

t-Bu (50)

Bn (51)

Ph (52)

Bu (2a)

Et (2b)

Bn (2c)

t-Bu (2e)

53a

53b

53c

53e

64

52

59

56

82

54

61

76

73

71

75

92:8

>99:1

95:5

82

71

1

2

3

14

15

9

60

61

62

27

61

3

81:19^d

63:37^d

>99:1^f

22

ND^e

80^g

60

95:5

74^d

73

a

Cyclohexyl (2f) 53f

89:11

>99:1

92:8

The reactions were carried out by adding a solution of diazo compound 47 and

oleﬁns 14, 15, or 9 to a suspension of Rh₂(OAc)₄(2 mol %), MS 4 Å, (4S,5S)-Pybox-

Ph₂–Lu(OTf)₃complex (10 mol %), and MeOH (10 mol %) over a period of 1 h in dried

and puriﬁed CH₂Cl₂at 23 ^ꢀC.

TBS (4)

Bu (2a)

59

82^d

79

54a

55a

56a

57a

58a

84

b

9

10

11

82

Diastereoselectivity was determined by ¹H NMR.

75^e

78^e

Enantiomeric excess of the major diastereomer was determined by ¹H NMR

c

>99:1

after conversion to the corresponding acetal in the reaction with (R,R)-

hydrobenzoin.

a

The reactions were carried out by adding a solution of diazo compounds 47–52

and vinyl ethers 2a–c, 2e and 2f, or 4 to a suspension of Rh₂(OAc)₄(2 mol %), MS 4 Å,

(4S,5S)-Pybox-Ph₂–Lu(OTf)₃complex (10 mol %), and MeOH (10 mol %) over a period

of 1 h in dried and puriﬁed CH₂Cl₂at 23 ^ꢀC.

d

Major/Minor.

Not determined. [

Only the exo-isomer was obtained.

e

f

25

a

]

þ2.75 (CHCl₃, c 1.0) (Major/Minor¼63:37).

D

g

Determined by chiral HPLC.

b

Determined by ¹H NMR.

c

Enantiomeric excess of the exo-adduct was determined by ¹H NMR after con-

version to the corresponding acetal in the reaction with (R,R)-hydrobenzoin.

d

Determined by ¹H NMR after stereoselective reduction by NaBH₄, followed by

exhibited moderate enanantioselectivities (60–73% ee). The re-

action between methyl 2-(2-diazo-1,3-dioxohexyl)benzoate (19)

and 13 using a BINIM–Ni(II) complex as the chiral Lewis acid also

gave the cycloadduct with high exo-selectivity and moderate

enantioselectivity (70% ee). During studies of the BINIM–Ni(II)-

catalyzed reaction between cyclohexyl vinyl ether and an epox-

yindanone (as the carbonyl ylide precursor), the chiral Lewis acid

conversion to the corresponding (R)-

a

-methoxyphenylacetate ester.

e

Determined by chiral HPLC.

ylides that were generated from o-methoxycarbonyl-a-diazo-

acetophenone (1) or acyl derivatives 19–27 via Rh₂(OAc)₄-cata-

lyzed decomposition. High levels of asymmetric induction

(73–97% ee) were achieved using chiral Pybox–lanthanoid

Pybox-Ph₂-Lu(OTf)₃

(10 mol%)

Me

R²

Me

R²

Me

O

MeOH (10 mol%)

Rh₂(OAc)₄

(2 mol%)

H

R¹

23 ^oC in CH₂Cl₂

O

CHN₂

O

+

O

R

R¹

O

R

47

R²

60 - 62

9: R = Ph, R¹= R²= H

Me

OTBS

OMe

OBu

14

15

Scheme 9.

metal(III) or BINIM–Ni(II) complexes as the chiral Lewis acid

catalysts. The Pybox–lanthanoid metal(III)-catalyzed reactions

between o-methoxycarbonyl-a-diazoacetophenone (1) and

electron-rich dipolarophiles such as allyl alcohol (8), 2,3-dihy-

drofuran (13), and butyl-tert-butyldimethylsilylketene acetal (15)

without the participation of Rh₂(OAc)₄was found to be an ef-

fective catalyst for asymmetric inductions. For the Pybox–lan-

thanoid metal(III)-catalyzed reaction with butyl vinyl ether, the

scope of diazo substrates was extended to include several 1-di-

azo-2,5-pentanedione derivatives (47–52) with good levels of

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3079

Me

4.2. Materials

Me

(R)

HO

Ph

OH

Ph

(R)

PPTS

O

o-Methoxycarbonyl-

a

-diazoacetophenone (1) was prepared by

O

the procedure in the previous paper.²⁰⁰-Dicarbonyl diazo sub-

a,a

Reflux

(R)

O

in Toluene

O

(R)

Ph

strates 19–27⁴and 1-diazo-2,5-alkanedione 47–52^2,21were pre-

pared according to the procedure reported by Padwa. Ethyl vinyl

ether, butyl vinyl ether, tert-butyl vinyl ether, cyclohexyl vinyl ether,

vinyl butyrate, 2,3-dihydrofuran, allyl alcohol, 1-hexene, styrene, 2-

methoxypropene and, Rh₂(OAc)₄were commercially available, and

used without further puriﬁcation. Lanthanoid triﬂates were com-

mercially available, and dried in vacuo at 200 ^ꢀC for 12 h before use.

tert-Butyldimethylsilyl vinyl ether,²²allyl vinyl ether,²³1-(tert-

O

(R)

Ph

exo-53f

> 99% de after recrystallizatiion

Scheme 10.

butyldimethylsilyloxy)-1-butyloxyethylene,²⁴

a

-butoxystyrene,²⁵

and 2,6-Bis(oxazolinyl)pyridines^18,26(Pybox) were prepared by

the procedure in the literatures. Powdered 4 Å molecular sieves

(MS 4 Å) was commercially available (Aldrich) and dried in vacuo at

200 ^ꢀC for 12 h before use. Ni(ClO₄)₂$6H₂O and Ni(BF₄)₂$6H₂O were

commercially available, and used without further puriﬁcation.

Chiral Binaphthyldiimine (BINIM) ligands were prepared by the

procedure reported previously.¹⁶Dichloromethane was commer-

cially available, and used without further puriﬁcation. For puriﬁed

dichloromethane, puriﬁcation was carried out by distillation ﬁrst

from CaCl₂and then CaH₂under argon before used. Toluene, ben-

zene, THF, and 1,4-dioxane were distilled from a sodium benzo-

phenone ketyl still under argon. Chloroform was puriﬁed by

distillation ﬁrst from CaCl₂and then P₂O₅under argon before used.

Figure 6. ORTEP drawing of the acetal prepared from exo-53f and (R,R)-hydrobenzoin.

The Upper Side

O

Me

N

(R)

Me

N

(R)

O

M

O

(R)

O

The Lower Side

exo-53f

O

Figure 7. Proposed approaches for asymmetric induction based on the absolute conﬁguration of exo-53f.

asymmetric induction (75–84% ee). Studies to expand our

4.3. General procedure for the reaction of o-

methoxycarbonyl- -diazoacetophenone (1) with oleﬁns was

exempliﬁed the reaction with cyclohexyl vinyl ether (2f)

methodology to other diazo substrates, while optimizing reaction

conditions to achieve high enantioselectivities are currently

underway.

a

catalyzed by (4S,5S)-Pybox-Ph₂–Eu(III) complex

A solution of 2,6-bis[(4S,5S)-4,5-diphenyl-2-oxazolin-2-yl]pyr-

idine ((4S,5S)-Pybox-Ph₂, 26.1 mg, 0.05 mmol) in THF (1.5 mL) was

added to a solution of Eu(OTf)₃(29.9 mg, 0.05 mmol) in THF (1 mL).

After stirring the mixture for 2 h, the solvent was removed under

reduced pressure and resulting solid was dried in vacuo at room

temperature for 5 h. A solution of Eu(III)–Pybox complex in CH₂Cl₂

(3 mL, commercial grade without further puriﬁcations) was trans-

ferred to a two-necked round-bottomed ﬂask (30 mL) equipped

with reﬂux condenser. After added MS 4 Å (0.5 g), cyclohexyl vinyl

ether (2f) (126 mg, 1.00 mmol), Rh₂(OAc)₄(4.4 mg, 0.01 mmol), and

CH₂Cl₂(1 mL, without puriﬁcation), successively, a solution of

diazoacetophenone 1 (102 mg, 0.50 mmol) in CH₂Cl₂(5 mL, with-

out puriﬁcation) was added over a period of 1 h using a syringe

pump under reﬂux (bath temp 55 ^ꢀC). The syringe was washed with

CH₂Cl₂(1 mL, without puriﬁcation). After removal of MS 4 Å

4. Experimental

4.1. General

Melting points were determined on a melting point apparatus

and are uncorrected. IR spectra were taken with a FTIR spectro-

photometer. ¹H NMR spectra were recorded on a 400 MHz spec-

trometer. Chemical shifts are expressed in parts per million

downﬁeld from tetramethylsilane as an internal standard. ¹³C NMR

spectra were recorded on a 100 MHz spectrometer using broad-

band proton decoupling. Chemical shifts are expressed in parts per

million using the middle resonance of CDCl₃(77.0 ppm) as an in-

ternal standard. For preparative column chromatography, Wakogel

C-300HG was employed. All reactions were carried out under an

argon atmosphere in dried glassware.

3080

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

through Celite, the reaction mixture was ﬁltered through a plug of

silica gel (3 cm) with AcOEt/hexane (1:1, 80 mL) as an eluent. The

solvent was removed in vacuo, and the residue was puriﬁed by

column chromatography (99:1 hexane/AcOEt) to provide a quanti-

tative amount (quant) of endo-3f and exo-3f.

of the integration corresponding to one of the methylene protons at

6 position.

4.3.4. 7-exo-Ethoxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]octan-2-

one (exo-3b). Although exo-3b could not be separated by chro-

matography from a mixture with major endo-3b, it could charac-

4.3.1. 7-endo-Butoxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]octan-

terize by ¹H and ¹³C NMR. ¹H NMR (CDCl₃)

d

1.25 (3H, t, J¼7.1 Hz),

25

2-one (endo-3a). Colorless viscous oil; [

a

]

D

ꢂ77.4 (c 1.00, CHCl₃)

2.32 (1H, dd, J¼13.2, 3.7 Hz), 2.41 (1H, dd, J¼13.2, 7.3 Hz), 3.35–3.60

(endo:exo¼81:19, 85% ee (endo), 62% ee (exo)), IR (neat) 3031, 3009,

(2H, m), 3.98 (1H, dd, J¼3.7, 7.3 Hz), 4.79 (1H, s), 7.42–7.49 (2H, m),

2961, 2874, 1707, 1603, 1458, 1300, 1267, 1163, 1113, 1055,

7.58–7.64 (1H, m), 7.93–7.98 (1H, m); ¹³C NMR (CDCl₃)

d 15.3 (CH₃),

1005 cm^ꢂ1

;

¹H NMR (CDCl₃)

d

0.79 (3H, t, J¼7.3 Hz), 1.15 (2H, sext,

42.2 (CH₂), 52.0 (CH₃), 65.4 (CH₂), 79.7 (CH), 86.6 (CH), 107.4 (C),

122.9 (CH), 126.8 (CH), 128.6 (CH), 129.3 (C), 134.3 (CH), 145.6 (C),

193.5 (C). The enantiomeric excess was determined by HPLC anal-

ysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min,

35 ^ꢀC) t_R¼32.3 min (major), 42.6 min (minor).

J¼7.3 Hz), 1.35 (2H, quint, J¼7.3 Hz), 2.02 (1H, dd, J¼13.4, 2.7 Hz),

2.60 (1H, dd, J¼13.4, 9.8 Hz), 3.27–3.34 (1H, m), 3.45–3.52 (1H, m),

3.46 (3H, s), 4.53 (1H, ddd, J¼2.7, 9.8, 7.1 Hz), 4.96 (1H, d, J¼7.1 Hz),

7.42–7.48 (2H, m), 7.58–7.64 (1H, m), 7.99–8.04 (1H, m); ¹³C NMR

(CDCl₃)

d 13.9 (CH₃), 19.2 (CH₂), 31.6 (CH₂), 42.0 (CH₂), 51.9 (CH₃),

70.7 (CH₂), 76.6 (CH), 83.8 (CH), 106.4 (C), 122.8 (CH), 126.4 (CH),

128.3 (CH), 131.0 (C), 133.6 (CH), 145.1 (C), 192.5 (C); MS (EI) m/z 276

(M^þ), 247, 203, 176, 161, 147, 133, 117, 103, 91, 77, 61, 50, 37, 26, 13;

HRMS (EI) calcd for C₁₆H₂₀O₄(M^þ): 276.1360. Found: 276.1387.

Anal. Calcd for C₁₆H₂₀O₄: C, 69.54; H, 7.30%. Found: C, 69.14; H,

7.70%. The enantiomeric excess was determined by HPLC analysis

(DAICEL Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min,

35 ^ꢀC) t_R¼22.9 min (minor), 45.7 min (major). Relative stereo-

chemistry (endo/exo) of the products could be determined by ¹H

NMR analysis on the basis of a coupling constant between H-1 and

H-7, which reported previously (endo:7.1 Hz, exo:0 Hz).¹⁹The endo/

exo ratio was determined by ¹H NMR analysis (endo:exo¼81:19) on

the basis of the integration corresponding to one of the methylene

protons at 6 position.

4.3.5. 7-endo-Benzyloxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]oct-

25

an-2-one (endo-3c). Colorless viscous oil; [

a

]

ꢂ46.0 (c 0.44,

D

CHCl₃) (endo:exo¼80:20, 61% ee (endo), ND (exo)); IR (neat) 3012,

2947, 1705, 1601, 1454, 1400, 1300, 1153, 1092, 1053, 945, 891,

833 cm^ꢂ1; ¹H NMR (CDCl₃)

d

2.07 (1H, dd, J¼2.9, 13.4 Hz), 2.61 (1H,

dd, J¼9.8, 13.4 Hz), 3.46 (3H, s), 4.38 (1H, d, J¼11.5 Hz), 4.58 (1H, d,

J¼11.5 Hz), 4.65 (1H, ddd, J¼2.9, 7.1, 9.8 Hz), 5.02 (1H, d, J¼7.1 Hz),

7.16–7.30 (5H, m), 7.44–7.48 (2H, m), 7.59–7.63 (1H, m), 8.05–8.07

(1H, m); ¹³C NMR (CDCl₃)

d 41.9 (CH₂), 51.9 (CH₃), 72.4 (CH₂), 75.8

(CH), 83.6 (CH), 106.4 (C), 122.9 (CH), 126.6 (CH), 127.6 (CH), 128.2

(CH), 128.5 (CH), 130.9 (C), 133.8 (CH), 137.0 (C), 145.2 (C), 192.7 (C);

MS (EI) m/z 310 (M^þ), 281, 267, 250, 237, 219, 201, 190, 173, 161, 145,

131, 115, 103, 91, 77, 65, 50, 39, 27, 15, 3; HRMS (EI) calcd for

C₁₉H₁₈O₄(M^þ): 310.1205. Found: 310.1221. The enantiomeric excess

was determined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99

i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼51.5 min (minor),

106.8 min (major). Relative stereochemistry (endo/exo) of the

products could be determined by ¹H NMR analysis on the basis of

a coupling constant between H-1 and H-7, which reported pre-

viously (endo:7.1 Hz, exo:0 Hz).¹⁹The endo/exo ratio was de-

termined by ¹H NMR analysis (endo:exo¼80:20) on the basis of the

integration corresponding to one of the methylene protons at 6

position.

4.3.2. 7-exo-Butoxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]octan-2-

one (exo-3a). Although exo-3a could not be separated by chroma-

tography from a mixture with major endo-3a, it could characterize

by ¹H and ¹³C NMR.¹H NMR (CDCl₃)

d

0.93 (3H, t, J¼7.3 Hz),1.31–1.45

(2H, m),1.55–1.66 (2H, m), 2.31 (1H, dd, J¼13.2, 3.9 Hz), 2.39 (1H, dd,

J¼13.2, 7.3 Hz), 3.37–3.59 (2H, m), 3.55 (3H, s), 3.97 (1H, dd, J¼3.9,

7.3 Hz), 4.78 (1H, s), 7.42–7.48 (2H, m), 7.58–7.64 (1H, m), 7.93–7.97

(1H, m); ¹³C NMR (CDCl₃)

d 14.0 (CH₃), 19.4 (CH₂), 29.7 (CH₂), 31.7

(CH₂), 51.9 (CH₃), 69.7 (CH₂), 79.8 (CH), 86.5 (CH), 107.4 (C), 122.8

(CH),126.7 (CH),128.5 (CH),129.2 (C),134.3 (CH),145.6 (C),193.5 (C).

The enantiomeric excess was determined by HPLC analysis (DAICEL

Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC)

t_R¼39.6 min (minor), 36.4 min (major).

4.3.6. 7-exo-Benzyloxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]octan-

2-one (exo-3c). Although exo-3c could not be separated by chro-

matography from a mixture with major endo-3c, it could charac-

terize by ¹H NMR. ¹H NMR (CDCl₃)

d 2.35–2.44 (2H, m), 3.56 (3H, s),

4.09 (1H, dd, J¼4.4, 6.6 Hz), 4.51 (1H, d, J¼12.0 Hz), 4.66 (1H, d,

J¼12.0 Hz), 4.88 (1H, s), 7.16–7.32 (5H, m), 7.34–7.35 (3H, m), 7.93–

7.95 (1H, m).

4.3.3. 7-endo-Ethoxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]octan-

25

2-one (endo-3b). Colorless viscous oil; [

a

]

ꢂ95.1 (c 1.00, CHCl₃)

D

(endo:exo¼83:17, 83% ee (endo), 67% ee (exo)); IR (neat) 3012, 2980,

1707, 1603, 1458, 1445, 1300, 1267, 1252, 1215, 1165, 1115, 1053,

4.3.7. 5-Methoxy-7-endo-(p-methoxybenzyloxy)-8-oxabenzo[c]bicy-

25

1005 cm^ꢂ1

;

¹H NMR (CDCl₃)

d

1.02 (3H, t, J¼7.1 Hz), 2.02 (1H, dd,

clo[3.2.1]octan-2-one (endo-3d). Colorless viscous oil; [

a

]

ꢂ45.1

D

J¼13.2, 2.7 Hz), 2.63 (1H, dd, J¼13.2, 10.0 Hz), 3.36–3.58 (2H, m),

3.47 (3H, s), 4.55 (1H, ddd, J¼2.7, 10.0, 7.3 Hz), 4.97 (1H, d, J¼7.3 Hz),

7.42–7.49 (2H, m), 7.58–7.64 (1H, m), 7.99–8.06 (1H, m); ¹³C NMR

(c 0.50, CHCl₃) (endo:exo¼82:18, 79% ee (endo), 55% ee (exo)); IR

(neat) 3008, 2951, 2846, 1705, 1608, 1516, 1458, 1296, 1250, 1173,

1045, 883 cm^ꢂ1

;

¹H NMR (CDCl₃)

d

2.04 (1H, dd, J¼2.9, 13.4 Hz),

(CDCl₃)

d

15.0 (CH₃), 42.1 (CH₂), 51.9 (CH₃), 66.3 (CH₂), 76.4 (CH),

2.59 (1H, dd, J¼10.0, 13.4 Hz), 3.46 (3H, s), 3.76 (3H, s), 4.31 (1H, d,

J¼11.2 Hz), 4.51 (1H, d, J¼11.2 Hz), 4.63 (1H, ddd, J¼2.9, 10.0,

7.3 Hz), 5.01 (1H, d, J¼7.3 Hz), 6.79–6.83 (2H, m), 7.10–7.12 (2H, m),

7.42–7.46 (2H, m), 7.58–7.62 (1H, m), 8.05–8.07 (1H, m); ¹³C NMR

83.8 (CH), 106.4 (C), 122.8 (CH), 126.6 (CH), 128.4 (CH), 130.9 (C),

133.7 (CH), 145.2 (C), 192.7 (C); MS (EI) m/z 248 (M^þ), 216, 203, 176,

161, 147, 133, 129, 115, 103, 89, 76, 61, 47, 39, 26, 13; HRMS (EI) calcd

for C₁₄H₁₆O₄(M^þ): 248.1048. Found: 248.1050. Anal. Calcd for

C₁₄H₁₆O₄: C, 67.73; H, 6.50%. Found: C, 67.30; H, 6.62%. The enan-

tiomeric excess was determined by HPLC analysis (DAICEL Chir-

alpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC)

t_R¼23.5 min (minor), 46.9 min (major). Relative stereochemistry

(endo/exo) of the products could be determined by ¹H NMR analysis

on the basis of a coupling constant between H-1 and H-7, which

reported previously (endo:7.3 Hz, exo:0 Hz).¹⁹The endo/exo ratio

was determined by ¹H NMR analysis (endo:exo¼83:17) on the basis

(CDCl₃)

d 41.9 (CH₂), 51.9 (CH₃), 55.3 (CH₃), 72.1 (CH₂), 75.4 (CH),

83.7 (CH), 106.4 (C), 113.7 (CH), 122.9 (CH), 126.6 (CH), 128.4 (CH),

129.1 (C), 129.4 (CH), 130.9 (C), 133.8 (CH), 145.2 (C), 159.1 (C),

192.7 (C); MS (EI) m/z 340 (M^þ), 308, 204, 187, 176, 161, 147, 133,

122, 103, 91, 77, 65, 50, 39, 27, 15, 3. Anal. Calcd for C₂₀H₂₀O₅: C,

70.57; H, 5.92%. Found: C, 70.48; H, 6.00%. The enantiomeric

excess was determined by HPLC analysis (DAICEL Chiralpak OD-3,

1:24 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼25.2 min (minor),

35.6 min (major). Relative stereochemistry (endo/exo) of the

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3081

products could be determined by ¹H NMR analysis on the basis of

a coupling constant between H-1 and H-7, which reported pre-

viously (endo:7.3 Hz, exo:0 Hz).¹⁹The endo/exo ratio was de-

termined by ¹H NMR analysis (endo:exo¼82:18) on the basis of the

integration corresponding to one of the methylene protons at 6

position.

(C),122.8 (CH),126.4 (CH),128.3 (CH),131.1 (C),133.5 (CH),145.1 (C),

192.8 (C); MS (EI) m/z 302 (M^þ), 220, 204, 176, 161, 143, 133, 115,

103, 91, 77, 67, 55, 47, 37, 24,16. Anal. Calcd for C₁₈H₂₂O₄: C, 71.50; H,

7.33%. Found: C, 71.58; H, 7.60%. The enantiomeric excess (endo)

was determined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99

i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼29.4 min (minor),

71.1 min (major). Relative stereochemistry (endo/exo) of the prod-

ucts could be determined by ¹H NMR analysis on the basis of

a coupling constant between H-1 and H-7, which reported pre-

viously (endo:7.3 Hz, exo:0 Hz).¹⁹The endo/exo ratio was de-

termined by ¹H NMR analysis (endo:exo¼88:12) on the basis of the

integration corresponding to one of the methylene protons at 6

position.

4.3.8. 5-Methoxy-7-exo-(p-methoxybenzyloxy)-8-oxabenzo[c]bicy-

clo[3.2.1]octan-2-one (exo-3d). Although exo-3d could not be sep-

arated by chromatography from a mixture with major endo-3d, it

could characterize by ¹H and ¹³C NMR. ¹H NMR (CDCl₃)

d 2.37 (2H,

m), 3.55 (3H, s), 3.79 (3H, s), 4.07 (1H, dd, J¼4.6, 6.3 Hz), 4.44 (1H, d,

J¼11.5 Hz), 4.59 (1H, d, J¼11.5 Hz), 4.86 (1H, s), 6.86–6.88 (2H, m),

7.26–7.28 (2H, m), 7.42–7.62 (3H, m), 7.93–7.95 (1H, m); ¹³C NMR

(CDCl₃)

d

42.0 (CH₂), 52.0 (CH₃), 55.3 (CH₃), 72.1 (CH₂), 75.5 (CH),

4.3.12. 7-exo-Cyclohexyloxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]-

octan-2-one (exo-3f). Although exo-3d could not be separated by

chromatography from a mixture with major endo-3f, it could

78.7 (CH), 106.7 (C), 113.8 (CH), 123.0 (CH), 126.8 (CH), 128.6 (CH),

129.0 (C), 129.4 (CH), 130.9 (C), 134.3 (CH), 145.6 (C), 159.5 (C), 192.8

(C). The enantiomeric excess was determined by HPLC analysis

(DAICEL Chiralpak OD-3, 1:24 i-PrOH/hexane, ﬂow 0.5 mL/min,

35 ^ꢀC) t_R¼28.4 min (minor), 31.0 min (major).

characterize by ¹H and ¹³C NMR. ¹H NMR (CDCl₃)

d 1.00–1.82 (10H,

m), 2.31 (1H, dd, J¼13.2, 3.9 Hz), 2.39 (1H, dd, J¼13.2, 7.3 Hz), 3.32–

3.38 (1H, m), 3.55 (3H, s), 4.14 (1H, dd, J¼3.9, 7.3 Hz), 4.74 (1H, s),

7.40–7.49 (2H, m), 7.57–7.64 (1H, m), 7.93–7.98 (1H, m); ¹³C NMR

4.3.9. 7-endo-tert-Butoxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]-

(CDCl₃) d 24.1 (CH₂), 24.2 (CH₂), 29.7 (CH₂), 32.0 (CH₂), 32.8 (CH₂),

25

octan-2-one (endo-3e). Colorless viscous oil; [

CHCl₃) (endo:exo[87:13, 88% ee (endo), 74% ee (exo)); IR (neat)

a

]

ꢂ112.8 (c 1.00,

42.6 (CH₂), 52.0 (CH₃), 76.9 (CH), 77.2 (CH), 87.8 (CH), 107.4 (C),

122.9 (CH), 126.7 (CH), 128.5 (CH), 129.2 (C), 134.2 (CH), 145.5 (C),

193.6 (C). The enantiomeric excess was determined by HPLC anal-

ysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min,

35 ^ꢀC) t_R¼39.6 min (minor), 36.4 min (major).

D

3021, 2978,1709,1603,1458,1393,1368,1298,1267,1215,1150,1078,

1051, 1028, 1007 cm^ꢂ1; ¹H NMR (CDCl₃)

d 1.09 (9H, s), 1.92 (1H, dd,

J¼13.2, 2.7 Hz), 2.61 (1H, dd, J¼13.2, 9.8 Hz), 3.46 (3H, s), 4.69 (1H,

ddd, J¼2.7, 9.8, 7.6 Hz), 4.77 (1H, d, J¼7.6 Hz), 7.36–7.51 (2H, m),

7.50–7.67 (1H, m), 7.98–8.04 (1H, m); ¹³C NMR (CDCl₃)

d

28.0

4.3.13. 7-endo-(tert-Butyldimethylsilyl)oxy-5-methoxy-8-oxabenzo-

25

(CH₃ꢁ3), 44.1 (CH₂), 51.8 (CH₃), 69.2 (CH), 74.5 (C), 84.9 (CH), 106.5

(C),122.8 (CH),126.5 (CH),128.2 (CH),131.2 (C),133.4 (CH),145.2 (C),

192.6 (C); MS (EI) m/z 276 (M^þ), 261, 221, 203,179,160,145,129,115,

103, 91, 76, 57, 49, 39, 26, 13. Anal. Calcd for C₁₆H₂₀O₄: C, 69.54; H,

7.30%. Found: C, 69.44; H, 7.38%. The enantiomeric excess was de-

termined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/

hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼27.5 min (minor), 64.1 min

(major). Relative stereochemistry (endo/exo) of the products could

be determined by ¹H NMR analysis on the basis of a coupling con-

stant between H-1 and H-7, which reported previously (endo:7.6 Hz,

exo:0 Hz).¹⁹The endo/exo ratio was determined by ¹H NMR analysis

(endo:exo¼87:13) on the basis of the integration corresponding to

one of the methylene protons at 6 position.

[c]bicyclo[3.2.1]octan-2-one (endo-10). Colorless viscous oil; [a]

D

ꢂ32.1 (c 0.17, CHCl₃) (endo:exo¼>99:1, 14% ee (endo)); IR (neat)

3413, 3159, 3070, 2939, 2897, 2858, 1716, 1601, 1462, 1396, 1362,

1292, 1257, 1200, 1161, 1107, 1049, 1011, 960, 899 cm^ꢂ^{1 1}H NMR

;

(CDCl₃)

d

ꢂ0.05 (3H, s), 0.01 (3H, s), 0.67 (9H, s), 1.91 (1H, dd, J¼2.0,

12.9 Hz), 2.58 (1H, dd, J¼8.8, 12.9 Hz), 3.45 (3H, s), 4.81 (1H, d,

J¼7.3 Hz), 4.87 (1H, ddd, J¼2.0, 8.8, 7.3 Hz), 7.41–7.50 (2H, m), 7.57–

7.65 (1H, m), 7.97–8.00 (1H, m); ¹³C NMR (CDCl₃)

d

ꢂ5.0 (CH₃), ꢂ4.9

(CH₃), 17.9 (C), 25.5 (CH₃), 44.9 (CH₂), 51.9 (CH₃), 69.6 (CH), 84.8

(CH), 106.7 (C), 122.9 (CH), 126.3 (CH), 128.3 (CH), 131.5 (C), 133.4

(CH), 144.9 (C), 192.3 (C); MS (EI) m/z 334 (M^þ), 319, 303, 291, 278,

259, 249, 231, 217, 203,189, 177,161, 145, 133, 116,102, 89, 76, 59, 45,

29, 15, 3. Anal. Calcd for C₁₈H₂₆O₄Si: C, 64.64; H, 7.83%. Found: C,

64.38; H, 8.01%. The enantiomeric excess (endo) was determined by

HPLC analysis (DAICEL Chiralpak AD-3, 1:99 i-PrOH/hexane, ﬂow

0.5 mL/min, 35 ^ꢀC) t_R¼14.3 min (minor), 39.9 min (major). Relative

stereochemistry (endo/exo) of the products could be determined by

¹H NMR analysis on the basis of a coupling constant between H-1

and H-7, which reported previously (endo:7.3 Hz).¹⁹

4.3.10. 7-exo-tert-Butoxy-5-methoxy-8-oxabenzo[c]bicyclo[3.2.1]-

octan-2-one (exo-3e). Although exo-3e could not be separated by

chromatography from a mixture with major endo-3e, it could

characterize by ¹H and ¹³C NMR. ¹H NMR (CDCl₃)

d 1.21 (9H, s), 2.28

(1H, dd, J¼13.2, 4.2 Hz), 2.39 (1H, dd, J¼13.2, 7.6 Hz), 3.54 (3H, s),

4.18 (1H, dd, J¼4.2, 7.6 Hz) 4.67 (1H, s), 7.36–7.51 (2H, m), 7.50–7.67

(1H, m), 7.94–7.98 (1H, m); ¹³C NMR (CDCl₃)

d

28.3 (CH₃ꢁ3), 44.1

4.3.14. 7-endo-Hydroxymethyl-5-methoxy-8-oxabenzo[c]bicyclo-

25

(CH₂), 52.1 (CH₃), 72.5 (CH), 74.9 (C), 89.7 (CH), 107.5 (C), 123.0 (CH),

126.8 (CH), 128.5 (CH), 129.3 (C), 134.2 (CH), 145.5 (C), 193.5 (C). The

enantiomeric excess was determined by HPLC analysis (DAICEL

Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC)

t_R¼22.5 min (major), 36.2 min (minor).

[3.2.1]octan-2-one (endo-11). Colorless viscous oil; [

a

]

D

þ113.2 (c

0.65, CHCl₃) (endo:exo¼>99:1, 60% ee (endo)); IR (neat) 3537, 3032,

2993, 2947, 1697, 1601, 1458, 1392, 1296, 1176, 1065, 972, 864 cm^ꢂ1

¹H NMR (CDCl₃)

;

d

1.65 (1H, dd, J¼5.6, 12.9 Hz), 2.49 (1H, dd, J¼11.2,

12.9 Hz), 3.10–3.20 (1H, m), 3.25 (1H, dd, J¼9.5, 11.7 Hz), 3.51 (3H,

s), 3.51 (1H, dd, J¼5.9, 11.7 Hz), 4.92 (1H, d, J¼8.1 Hz), 7.44–7.50 (2H,

4.3.11. 7-endo-Cyclohexyloxy-5-methoxy-8-oxabenzo[c]bicyclo-

m), 7.62–7.67 (1H, m), 8.01–8.04 (1H, m); ¹³C NMR (CDCl₃)

d 36.7

25

[3.2.1]octan-2-one (endo-3f). Colorless viscous oil; [

a

]

D

ꢂ99.9 (c

(CH₂), 41.3 (CH₂), 52.1 (CH₃), 62.3 (CH), 83.4 (CH), 107.0 (C), 122.7

(CH), 126.7 (CH), 128.5 (CH), 130.2 (C), 134.5 (CH), 146.5 (C), 195.7

(C); MS (EI) m/z 234 (M^þ), 219, 203, 189, 178, 171, 161, 145, 133, 115,

104, 91, 83, 76, 63, 57, 49, 39, 31, 15, 3. Anal. Calcd for C₁₃H₁₄O₄: C,

66.66; H, 6.02%. Found: C, 66.48; H, 5.87%. The enantiomeric excess

(endo) was determined by HPLC analysis (DAICEL Chiralpak OD-3,

1:99 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼21.0 min (minor),

22.4 min (major). Relative stereochemistry (endo/exo) of the

products could be determined by ¹H NMR analysis on the basis of

1.00, CHCl₃) (endo:exo¼88:12, 95% ee (endo), 47% ee (exo)); IR (neat)

3021, 2938, 2859, 1707, 1603, 1453, 1300, 1263, 1215, 1161, 1101,

1078, 1053, 1026, 1007 cm^ꢂ1; ¹H NMR (CDCl₃)

d 1.00–1.82 (10H, m),

1.99 (1H, dd, J¼13.2, 2.7 Hz), 2.61 (1H, dd, J¼13.2, 9.8 Hz), 3.22–3.32

(1H, m), 3.50 (3H, s), 4.71 (1H, ddd, J¼2.7, 9.8, 7.3 Hz,), 4.91 (1H, d,

J¼7.3 Hz), 7.40–7.49 (2H, m), 7.57–7.64 (1H, m), 7.98–8.04 (1H, m);

¹³C NMR (CDCl₃)

d 24.0 (CH₂), 24.1 (CH₂), 25.7 (CH₂), 31.7 (CH₂), 32.4

(CH₂), 42.7 (CH₂), 51.8 (CH₃), 73.5 (CH), 77.6 (CH), 84.0 (CH), 106.4

3082

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

a coupling constant between H-1 and H-7, which reported pre-

141.7 (C), 177.2 (C); exo: d 20.8 (CH₂), 47.2 (CH₂), 51.0 (CH₃), 52.3

viously (endo:8.1 Hz).¹⁹

(CH₃), 89.7 (CH), 106.1 (C), 106.2 (C), 122.7 (CH), 126.7 (CH), 128.6

(CH),133.7 (CH),135.6 (C),140.7 (C),176.9 (C); MS (EI) m/z 248 (M^þ),

233, 216, 201,185,177,163,155,148,141,131,128, 115,101, 90, 83, 74,

63, 50, 42, 31, 15. Satisfactory elemental analysis was not obtained.

The enantiomeric excess (endo) was determined by HPLC analysis

(DAICEL Chiralpak AD-3, 1:200 i-PrOH/hexane, ﬂow 0.5 mL/min,

35 ^ꢀC) t_R¼17.2 min (minor), 24.6 min (major). The enantiomeric

excess (exo) was determined by HPLC analysis (DAICEL Chiralpak

AD-3, 1:200 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼18.1 min

(minor), 19.3 min (major).

4.3.15. 5-Methoxy-6-phenyl-8-oxabenzo[c]bicyclo[3.2.1]octan-2-one

25

(12). Mixture of diastereomers, 69:31; Colorless viscous oil; [a]

D

ꢂ7.5 (c 0.12, CHCl₃) (69:31 Mixture of diastereomers, 10% ee (ma-

jor), 20% ee (minor)); IR (neat) 2954, 2862, 1782, 1712, 1604, 1462,

1389, 1257, 1084, 1038, 895 cm^ꢂ^{1 1}H NMR (CDCl₃) Major:

; d 2.00

(1Hꢁ0.69, ddd, J¼2.0, 7.6, 14.2 Hz), 3.04 (1Hꢁ0.69, ddd, J¼9.3, 11.2,

14.2 Hz), 3.49 (3Hꢁ0.69, s), 3.79 (1Hꢁ0.69, dd, J¼7.6, 11.2 Hz), 4.91

(1Hꢁ0.69, dd, J¼2.0, 9.3 Hz), 6.65–6.71 (2Hꢁ0.69, m), 7.04–7.16

(3Hꢁ0.69, m), 7.27–8.09 (4Hꢁ0.69, m); Minor:

d

2.39 (1Hꢁ0.31,

ddd, J¼1.7, 9.3, 14.2 Hz), 2.62 (1Hꢁ0.31, ddd, J¼3.7, 9.3, 14.2 Hz),

3.32 (3Hꢁ0.31, s), 3.38 (1Hꢁ0.31, dd, J¼3.7, 9.3 Hz), 4.96 (1Hꢁ0.31,

dd, J¼1.7, 9.3 Hz), 6.65–6.71 (3Hꢁ0.31, m), 7.04–7.16 (2Hꢁ0.31, m),

4.3.18. 7-Butoxy-7-(tert-butyldimethylsilyl)oxy-5-methoxy-8-oxa-

benzo[c]bicyclo[3.2.1]octan-2-one (18). Mixture of diastereomer,

25

74:26; Pale yellow viscous oil; [

a

]

þ21.3 (c 1.00, CHCl₃) (74:26

D

7.27–8.09 (4Hꢁ0.31, m); ¹³C NMR (CDCl₃) Major:

d

31.5 (CH₂), 51.6

Mixture of diastereomer, 72% ee (major), 55% ee (minor)); IR (neat)

(CH₃), 52.7 (CH), 79.5 (CH), 109.3 (C), 125.9 (CH), 126.7 (CH), 126.8

(CH), 127.7 (CH), 127.9 (CH), 128.7 (CH), 130.4 (C), 133.0 (CH), 136.6

2951, 2866, 1709, 1604, 1462, 1392, 1296, 1261, 1134, 1076 cm^ꢂ1; ¹H

NMR (CDCl₃) Major:

d

0.23 (3Hꢁ0.74, s), 0.26 (3Hꢁ0.74, s), 0.69

(C), 141.2 (C), 194.8 (C); Minor:

d

36.1 (CH₂), 52.3 (CH₃), 53.6 (CH),

(3Hꢁ0.74, t, J¼7.3 Hz), 0.94 (9Hꢁ0.74, s), 1.17–1.25 (2Hꢁ0.74, m),

1.36–1.48 (2Hꢁ0.74, m), 2.39 (1Hꢁ0.74, d, J¼12.9 Hz), 2.50

(1Hꢁ0.74, d, J¼12.9 Hz), 3.27 (1Hꢁ0.74, ddd, J¼6.8, 9.8, 16.1 Hz),

3.50 (3Hꢁ0.74, s), 3.52–3.58 (1Hꢁ0.74, m), 4.64 (1Hꢁ0.74, s), 7.38–

7.45 (2Hꢁ0.74, m), 7.52–7.60 (1Hꢁ0.74, m), 7.95–7.97 (1Hꢁ0.74,

78.9 (CH), 108.6 (C), 123.5 (CH), 126.8 (CH), 127.3 (CH), 127.4 (CH),

128.1 (CH), 128.6 (CH), 129.9 (C), 134.2 (CH), 140.9 (C), 145.5 (C),

194.8 (C); MS (EI) m/z 280 (M^þ), 248, 219, 191, 163, 133, 105, 77, 50,

28, 3. Anal. Calcd for C₁₈H₁₆O₃þH₂O: C, 72.47; H, 6.08%. Found: C,

72.40; H, 6.02%. The enantiomeric excess (major diastereomer) was

determined by HPLC analysis (DAICEL Chiralpak AD-3, 1:200

i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼44.6 min (minor),

88.7 min (major). The enantiomeric excess (minor diastereomer)

was determined by HPLC analysis (DAICEL Chiralpak AD-3, 1:200

i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼69.6 min (minor),

117.2 min (major).

m); Minor:

d

ꢂ0.39 (3Hꢁ0.26, s), 0.04 (3Hꢁ0.26, s), 0.57 (9Hꢁ0.26,

s), 0.95 (3Hꢁ0.26, t, J¼7.3 Hz), 1.36–1.65 (4Hꢁ0.26, m), 2.26

(1Hꢁ0.26, d, J¼13.2 Hz), 2.65 (1Hꢁ0.26, d, J¼13.2 Hz), 3.50

(3Hꢁ0.26, s), 3.52–3.58 (1Hꢁ0.26, m), 3.64 (1Hꢁ0.26, ddd, J¼6.3,

7.1, 9.3 Hz), 4.76 (1Hꢁ0.26, s), 7.38–7.45 (2Hꢁ0.26, m), 7.52–7.60

(1Hꢁ0.26, m), 7.95–7.97 (1Hꢁ0.26, m); ¹³C NMR (CDCl₃) Major:

d

ꢂ3.0 (CH₃), 1.2 (CH₃), 13.8 (CH₃), 18.4 (C), 19.0 (CH₂), 25.9 (CH₃),

31.5 (CH₂), 48.0 (CH₂), 51.7 (CH₃), 63.5 (CH₂), 90.4 (CH), 106.2 (C),

106.9 (C), 122.5 (CH), 126.4 (CH), 128.5 (CH), 130.3 (C), 133.5 (CH),

4.3.16. 6-endo-7-endo-5-Methoxy-8-oxabenzo[c]tetrahydrofuro[3,2-

25

f]bicyclo[3.2.1]octan-2-one (endo-16). Colorless viscous oil; [

a

]

144.5 (C); Minor:

d

ꢂ4.0 (CH₃), ꢂ3.5 (CH₃), 14.1 (CH₃), 18.0 (C), 19.5

D

ꢂ147.1 (c 0.26, CHCl₃) (59% ee (endo)); IR (neat) 2976, 2951, 2890,

(CH₂), 25.3 (CH₃), 32.1 (CH₂), 48.9 (CH₂), 51.7 (CH₃), 63.1 (CH₂), 85.3

(CH), 105.8 (C), 106.4 (C), 122.9 (CH), 126.5 (CH), 128.5 (CH), 130.6

(C), 133.6 (CH), 144.3 (C), 191.0 (C); MS (EI) m/z 406 (M^þ), 391, 377,

349, 333, 317, 305, 289, 275, 261, 247, 231, 217, 203, 189, 177, 159,

145, 129, 115,103, 89, 73, 59, 41, 29, 15, 3. Anal. Calcd for C₂₂H₃₄O₅Si:

C, 64.99; H, 8.43%. Found: C, 64.88; H, 8.52%. The enantiomeric

excess (major) was determined by HPLC analysis (DAICEL Chiralpak

OD-3, 1:200 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼7.8 min

(major), 13.8 min (minor). The enantiomeric excess (minor) was

determined by HPLC analysis (DAICEL Chiralpak OD-3, 1:200 i-

PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼9.1 min (minor), 14.5 min

(major).

2845, 2361, 2340, 1713, 1601, 1456, 1331, 1310, 1290, 1246, 1200,

1169, 1088, 1061, 1044, 1013 cm^ꢂ1; ¹H NMR (CDCl₃)

d 1.42–1.52 (1H,

m), 1.89–2.02 (1H, m), 2.73 (1H, q, J¼8.1 Hz), 3.28 (1H, dt, J¼8.8,

2.4 Hz), 3.45 (3H, s), 3.65 (1H, dt, J¼8.8, 4.4 Hz), 4.91 (1H, d,

J¼7.3 Hz), 5.15 (1H, dd, J¼8.1, 7.3 Hz), 7.43–7.54 (2H, m), 7.61–7.68

(1H, m), 8.03–8.08 (1H, m); ¹³C NMR (CDCl₃)

d 26.6 (CH₂), 52.3

(CH₃), 52.9 (CH), 72.0 (CH₂), 83.1 (CH), 83.7 (CH), 108.4 (C), 125.2

(CH), 126.6, (CH), 129.0 (CH), 132.3 (C), 133.1 (CH), 141.2 (C), 192.1

(C); MS (EI) m/z 246 (M^þ), 217, 202, 187, 173, 161, 148, 139, 128, 115,

102, 91, 76, 63, 55, 47, 35, 24, 13. Anal. Calcd for C₁₄H₁₄O₄: C, 68.28;

H, 5.73%. Found: C, 68.28; H, 5.68%. The enantiomeric excess was

determined by HPLC analysis (DAICEL Chiralpak AD-H, 1:9 i-PrOH/

hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼17.9 min (major), 18.8 min

(minor). Relative stereochemistry (endo/exo) of the products could

be determined by ¹H NMR analysis on the basis of a coupling

constant between H-1 and H-7, which reported previously

(endo:7.3 Hz).¹⁹

4.4. Generalprocedure forthereactionsofa,a

⁰-dicarbonyldiazo

compounds 19–27 with oleﬁns was exempliﬁed the reaction of

methyl 2-(2-diazo-1,3-dioxohexyl)benzoate (19) with butyl vinyl

ether (2a) catalyzed by (R)-BINIM-4Me-2QN–Ni(II) complex

A solution of (R)-BINIM-4Me-2QN (29.5 mg, 0.05 mmol) in

CH₂Cl₂(2.5 mL, without puriﬁcation) was added to a mixture of

powdered MS 4 Å (500 mg) and Ni(ClO₄)₂$6H₂O (18.3 mg,

4.3.17. 5,7-Dimethoxy-7-methyl-8-oxabenzo[c]bicyclo[3.2.1]octan-2-

one (17). Mixture of diastereomer, 47:53 (endo/exo); Colorless

25

viscous oil; [

a]

ꢂ24.0 (c 0.21, CHCl₃) (endo:exo¼47:53, 12% ee

0.05 mmol) in a two-necked round-bottomed ﬂask (30 mL)

D

(endo), 15% ee (exo)); IR (neat) 3066, 2978, 2835, 1705, 1597, 1454,

equipped with reﬂux condenser, and then stirred for 6 h at room

temperature. After added butyl vinyl ether (2a) (100 mg,

1.00 mmol), Rh₂(OAc)₄(4.4 mg, 0.01 mmol) and CH₂Cl₂(1.5 mL,

without puriﬁcation), successively, a solution of diazo compound

19 (137 mg, 0.50 mmol) in CH₂Cl₂(5 mL, without puriﬁcation) was

added over a period of 1 h using a syringe pump under reﬂux (bath

temp 55 ^ꢀC). The syringe was washed with CH₂Cl₂(1 mL, without

puriﬁcation). After removal of MS 4 Å through Celite, the reaction

mixture was ﬁltered through a plug of silica gel (3 cm) with AcOEt/

hexane (1:1, 80 mL) as an eluent. The solvent was removed in

vacuo, and the residue was puriﬁed by column chromatography

1377, 1288, 1149, 1045, 972, 899 cm^ꢂ1; ¹H NMR (CDCl₃) endo:

d

1.16

(3Hꢁ0.47, s), 1.99 (1Hꢁ0.47, d, J¼13.7 Hz), 2.63 (1Hꢁ0.47, dd, J¼1.0,

13.7 Hz), 3.34 (3Hꢁ0.47, s), 3.54 (3Hꢁ0.47, s), 4.71 (1Hꢁ0.47, d,

J¼1.0 Hz), 7.43–7.47 (2Hꢁ0.47, m), 7.58–7.64 (1Hꢁ0.47, m), 7.97–

7.99 (1Hꢁ0.47, m); exo:

d

1.66 (3Hꢁ0.53, s), 2.22 (1Hꢁ0.53, d,

J¼13.2 Hz), 2.26 (1Hꢁ0.53, d, J¼13.2 Hz), 3.13 (3Hꢁ0.53, s), 3.48

(3Hꢁ0.53, s), 4.50 (1Hꢁ0.53, s), 7.43–7.47 (2Hꢁ0.53, m), 7.58–7.64

(1Hꢁ0.53, m), 8.01–8.03 (1Hꢁ0.53, m); ¹³C NMR (CDCl₃) endo:

d

25.2 (CH₂), 47.9 (CH₂), 51.8 (CH₃), 52.0 (CH₃), 87.7 (CH), 110.0 (C),

111.1 (C), 122.5 (CH), 126.6 (CH), 128.4 (CH), 134.3 (CH), 136.7 (C),

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3083

(99:1 hexane/AcOEt) to provide 172 mg (99%) of endo-28a. Relative

stereochmistry (endo/exo) of the products 28a, 28c, 30c, 28f–36f,

38–41, 43, and 44 could be determined by ¹H NMR analysis on the

basis of chemical shifts of H-2 (and a coupling constant between H-

1 and H-2) compared with endo-3a–f, exo-3a–f, endo-10, endo-11,

and endo-16.

AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼13.8 min

(minor), 17.8 min (major).

4.4.4. 7-endo-Cyclohexyloxy-5-methoxy-1-propanoyl-8-oxabenzo[c]-

25

bicyclo[3.2.1]octan-2-one (endo-29f). Colorless viscous oil; [a]

D

þ176.9 (c 0.60, CHCl₃) (73% ee (endo)); ¹H NMR (CDCl₃)

d 0.99–1.78

(10H, m), 1.12 (3H, t, J¼6.6 Hz), 2.03 (1H, dd, J¼1.7, 13.2 Hz), 2.57

(1H, dq, J¼7.1, 18.8 Hz), 2.58 (1H, dd, J¼9.3, 13.2 Hz), 2.80 (1H, dq,

J¼7.1, 18.8 Hz), 3.49 (3H, s), 3.46–3.52 (1H, m), 4.74 (1H, dd, J¼1.7,

9.3 Hz), 7.44–7.48 (2H, m), 7.60–7.64 (1H, m), 7.97–8.00 (1H, m); ¹³C

4.4.1. 1-Butanoyl-7-endo-butoxy-5-methoxy-8-oxabenzo[c]bicyclo-

25

[3.2.1]octan-2-one (endo-28a). Colorless viscous oil; [

a

]

D

þ175.8 (c

1.00, CHCl₃) (92% ee); IR (neat) 3025, 2963, 2936, 2874, 1730, 1701,

1603, 1458, 1404, 1368, 1302, 1269, 1217, 1171, 1101, 1065, 1040,

NMR (CDCl₃)

d 7.3 (CH₃), 23.8 (CH₂), 23.9 (CH₂), 25.9 (CH₂), 31.5

1007 cm^ꢂ1

;

¹H NMR (CDCl₃)

d

0.76 (3H, t, J¼7.3 Hz), 0.95 (3H, t,

(CH₂), 32.3 (CH₂), 32.7 (CH₂), 43.7 (CH₂), 52.1 (CH), 74.9 (CH), 76.5

(CH), 95.6 (C), 106.9 (C), 123.2 (CH), 126.6 (CH), 128.7 (CH), 131.6 (C),

133.7 (CH), 144.1 (C), 189.8 (C), 204.6 (C). Satisfactory elemental

analysis was not obtained. The enantiomeric excess was de-

termined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/

hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼13.5 min (minor), 18.6 min

(major).

J¼7.3 Hz), 1.09 (2H, sext, J¼7.3 Hz), 1.20–1.34 (2H, m), 1.61–1.76

(2H, m), 2.08 (1H, dd, J¼13.2, 1.7 Hz), 2.55 (1H, ddd, J¼6.6, 8.1,

18.3 Hz), 2.60 (1H, dd, J¼13.2, 9.5 Hz), 2.73 (1H, ddd, J¼6.6, 8.1,

18.3 Hz), 3.36 (1H, dt, J¼6.4, 9.5 Hz), 3.50 (1H, dt, J¼6.4, 9.5 Hz),

3.50 (3H, s), 4.55 (1H, dd, J¼1.7, 9.5 Hz), 7.45–7.51 (2H, m), 7.61–

7.66 (1H, m), 7.98–8.02 (1H, m); ¹³C NMR (CDCl₃)

d 13.7 (CH₃), 13.8

(CH₃),16.5 (CH₂), 19.1 (CH₂), 31.5 (CH₂), 41.2 (CH₂), 43.0 (CH₂), 52.0

(CH₃), 70.5 (CH₂), 77.8 (CH), 95.3 (C), 106.7 (C), 123.1 (CH), 126.5

(CH), 128.6 (CH), 131.2 (C), 133.7 (CH), 144.1 (C), 189.3 (C), 203.5 (C);

MS (EI) m/z 346 (M^þ), 303, 246, 231, 186, 175, 161, 147, 129, 117, 103,

91, 71, 61, 49, 39, 26, 13; HRMS (EI) calcd for C₂₀H₂₆O₅(M^þ):

346.1779. Found: 346.1797. Anal. Calcd for C₂₀H₂₆O₅: C, 69.34; H,

7.56%. Found: C, 69.32; H, 7.64%. The enantiomeric excess was

determined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99

i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼13.3 min (minor),

14.2 min (major).

4.4.5. 7-endo-Benzyloxy-5-methoxy-1-(3-methylbutanoyl)-8-

oxabenzo[c]bicyclo[3.2.1]-octan-2-one (endo-30c). Colorless viscous

25

oil; [

a]

þ133.7 (c 0.74, CHCl₃) (90% ee (endo)); IR (neat) 3035,

D

2978, 2943, 1724, 1601, 1458, 1304, 1269, 1173, 1099, 1041, 953,

887 cm^ꢂ^{1 1}H NMR (CDCl₃)

;

d

1.14 (3H, t, J¼6.8 Hz), 1.17 (3H, t,

J¼6.8 Hz), 2.12 (1H, dd, J¼1.7, 13.2 Hz), 2.62 (1H, dd, J¼9.8, 13.2 Hz),

3.08 (1H, quint, J¼6.8 Hz), 3.50 (3H, s), 4.48 (1H, d, J¼12.0 Hz), 4.63

(1H, d, J¼12.0 Hz), 4.60 (1H, dd, J¼1.7, 9.8 Hz), 7.16–7.25 (5H, m),

7.47–7.51 (2H, m), 7.62–7.66 (1H, m), 8.05–8.07 (1H, m); ¹³C NMR

(CDCl₃)

d 18.4 (CH₃), 18.7 (CH₃), 37.9 (CH), 42.9 (CH₂), 52.0 (CH₃),

4.4.2. 1-Butanoyl-7-endo-benzyloxy-5-methoxy-8-oxabenzo[c]-

bicyclo[3.2.1]octan-2-one (endo-28c). Colorless viscous oil; [a]

D

72.0 (CH₂), 77.8 (CH), 96.2 (C), 106.4 (C), 123.2 (CH), 126.9 (CH),

127.3 (CH), 127.8 (CH), 128.0 (CH), 128.8 (CH), 130.9 (C), 134.0 (CH),

137.5 (C), 144.1 (C), 189.1 (C), 207.7 (C); MS (EI) m/z 380 (M^þ), 362,

348, 310, 289, 247, 231, 215, 201, 187, 174, 161, 147, 129, 115, 104, 91,

71, 54, 43, 27, 15, 3. Anal. Calcd for C₂₃H₂₄O₅: C, 72.61; H, 6.36%.

Found: C, 72.55; H, 6.37%. The enantiomeric excess was determined

by HPLC analysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/hexane,

ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼23.2 min (major), 26.8 min (minor).

25

þ114.6 (c 1.00, CHCl₃) (79% ee (endo)); IR (neat) 3012, 2962, 2881,

1724, 1601, 1458, 1362, 1304, 1269, 1215, 1169, 1095, 1041, 930 cm^ꢂ1

¹H NMR (CDCl₃)

;

d

0.95 (3H, t, J¼7.6 Hz), 1.69 (2H, m), 2.13 (1H, dd,

J¼13.4, 2.0 Hz), 2.57 (1H, ddd, J¼6.3, 8.3, 18.5 Hz), 2.61 (1H, dd,

J¼13.4, 10.0 Hz), 2.74 (1H, ddd, J¼6.6, 8.3, 18.5 Hz), 3.49 (3H, s), 4.45

(1H, d, J¼12.0 Hz), 4.58 (1H, d, J¼12.0 Hz), 4.65 (1H, dd, J¼2.0,

10.0 Hz), 7.15–7.27 (5H, m), 7.47–7.51 (2H, m), 7.62–7.66 (1H, m),

8.04–8.06 (1H, m); ¹³C NMR (CDCl₃)

d

13.7 (CH₃), 16.5 (CH₂), 41.3

4.4.6. 7-endo-Cyclohexyloxy-5-methoxy-1-(3-methylbutanoyl)-8-

(CH₂), 42.9 (CH₂), 52.0 (CH₃), 72.0 (CH₂), 77.1 (CH), 95.6 (C), 106.5

(C), 123.2 (CH), 126.7 (CH), 127.3 (CH), 127.7 (CH), 127.9 (CH), 128.7

(CH), 131.0 (C), 133.9 (CH), 137.4 (C), 144.1 (C), 189.5 (C), 203.7 (C);

MS (EI) m/z 380 (M^þ), 367, 330, 320, 310, 300, 289, 276, 262, 250,

230, 217, 201, 186, 176, 164, 152, 120, 109, 90, 78, 51, 24, 13. Anal.

Calcd for C₂₃H₂₄O₅: C, 72.61; H, 6.36%. Found: C, 72.54; H, 6.41%. The

enantiomeric excess was determined by HPLC analysis (DAICEL

Chiralpak AD-H, 0.5:99.5 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC)

t_R¼43.0 min (minor), 72.6 min (major).

oxabenzo[c]bicyclo[3.2.1]-octan-2-one (endo-30f). Colorless viscous

25

oil; [

a

]

þ177.3 (c 1.00, CHCl₃) (88% ee (endo)); IR (neat) 3568, 3021,

D

2936, 2858, 2401, 1728, 1703, 1602, 1415, 1366, 1362, 1269, 1215,

1169, 1169, 1098, 1064, 758, 530 cm^ꢂ1; ¹H NMR (CDCl₃)

d

0.84–1.70

(10H, m), 0.94 (3H, d, J¼6.5 Hz), 0.97 (3H, d, J¼6.8 Hz), 2.06 (1H, dd,

J¼13.2, 1.7 Hz), 2.25 (1H, m), 2.47 (1H, dd, J¼6.5, 17.8 Hz) 2.58 (1H,

dd, J¼13.2, 9.2 Hz), 2.63 (1H, dd, J¼6.8, 17.8 Hz), 3.42–3.54 (1H, m),

3.49 (3H, s), 4.72 (1H, dd, J¼1.7, 9.2 Hz), 7.41–7.52 (2H, m), 7.58–7.67

(1H, m), 7.94–8.03 (1H, m); ¹³C NMR (CDCl₃)

d 22.6 (CH₃), 22.7

(CH₃), 23.7 (CH), 23.7 (CH₂), 23.8 (CH₂), 25.8 (CH₂), 31.5 (CH₂), 32.2

(CH₂), 43.5 (CH₂), 48.1 (CH₂), 52.0 (CH₃), 74.8 (CH), 76.4 (CH), 95.4

(C), 106.8 (C),123.1 (CH), 126.5 (CH), 128.6 (CH), 131.5 (C), 133.6 (CH),

144.1 (C), 189.6 (C), 203.3 (C); MS (EI) m/z 386 (M^þ), 354, 327, 304,

286, 272, 261, 244, 232, 219, 201, 200,187,173,161,147,129,115,103,

85, 69, 57, 39, 26, 13; HRMS (EI) calcd for C₂₃H₃₀O₅(M^þ): 386.2092.

Found: 386.2106. The enantiomeric excess was determined by

HPLC analysis (DAICEL Chiralpak AD-H, 0.5:99.5 i-PrOH/hexane,

ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼14.9 min (minor), 18.0 min (major).

4.4.3. 1-Butanoyl-7-endo-cyclohexyloxy-5-methoxy-8-oxabenzo[c]-

25

bicyclo[3.2.1]octan-2-one (endo-28f). Colorless viscous oil; [a]

D

þ171.4 (c 1.00, CHCl₃) (93% ee (endo)); IR (neat) 3021, 2936, 2859,

1728, 1701, 1603, 1522, 1456, 1362, 1300, 1269, 1215, 1169, 1098,

1063 cm^ꢂ1; ¹H NMR (CDCl₃)

d

0.95 (3H, t, J¼7.3 Hz), 0.99–1.86 (10H,

m), 1.62–1.74 (2H, m), 2.04 (1H, dd, J¼12.9, 1.7 Hz), 2.59 (1H, dd,

J¼12.9, 9.5 Hz), 2.56 (1H, ddd, J¼6.4, 8.1, 18.3 Hz), 2.74 (1H, ddd,

J¼6.6, 7.8, 18.3 Hz), 3.50 (3H, s), 3.44–3.54 (1H, m), 4.74 (1H, dd,

J¼1.7, 9.5 Hz), 7.43–7.51 (2H, m), 7.59–7.66 (1H, m), 7.96–8.03 (1H,

m); ¹³C NMR (CDCl₃)

d

13.8 (CH₃), 16.5 (CH₂), 23.7 (CH₂), 23.9 (CH₂),

4.4.7. 7-endo-Cyclohexyloxy-5-methoxy-1-pentanoyl-8-oxabenzo-

25

25.8 (CH₂), 31.5 (CH₂), 32.3 (CH), 41.2 (CH₂), 43.6 (CH₂), 52.0 (CH₃),

74.8 (CH₂), 76.5 (CH), 95.5 (C), 106.9 (C), 123.2 (CH), 126.5 (CH),

128.6 (CH), 131.5 (C), 133.6 (CH), 144.1 (C), 189.7 (C), 203.8 (C); MS

(EI) m/z 372 (M^þ), 340, 313, 301, 290, 272, 258, 246, 230, 218, 201,

191, 187, 175, 163, 147, 129, 115, 103, 83, 71, 55, 39, 24, 13; HRMS (EI)

calcd for C₂₂H₂₈O₅(M^þ): 372.1935. Found: 372.1953. The enantio-

meric excess was determined by HPLC analysis (DAICEL Chiralpak

[c]bicyclo[3.2.1]octan-2-one (endo-31f). Colorless viscous oil; [a]

D

þ180.5 (c 1.00, CHCl₃) (93% ee (endo)); IR (neat) 3020, 2935, 1728,

1701, 1423, 1302, 1269, 1215, 1168, 1097, 1047, 929, 771, 669 cm^ꢂ1

¹H NMR (CDCl₃)

;

d

0.91 (3H, t, J¼7.3 Hz), 0.95–1.74 (10H, m), 1.34

(2H, m),1.64 (2H, m) 2.03 (1H, dd, J¼1.7, 12.9 Hz), 2.56 (1H, m), 2.58

(1H, dd, J¼9.5, 12.9 Hz), 2.75 (1H, ddd, J¼6.3, 8.3, 18.0 Hz), 3.40–

3.54 (1H, m), 3.50 (3H, s), 4.73 (1H, dd, J¼1.7, 9.5 Hz), 7.42–7.50 (2H,

3084

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

m), 7.59–7.66 (1H, m), 7.95–8.02 (1H, m); ¹³C NMR (CDCl₃)

d

13.9

353, 330, 287, 270, 201, 187, 174, 161, 147, 129, 103, 83, 55, 37, 24;

HRMS (EI) calcd for C₂₅H₃₂O₅(M^þ): 412.2248. Found: 412.2234. The

enantiomeric excess was determined by HPLC analysis (DAICEL

Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC)

t_R¼16.0 min (major), 19.5 min (minor).

(CH₃), 22.2 (CH₂), 23.6 (CH₂), 23.8 (CH₂), 25.1 (CH₂), 25.8 (CH₂), 31.4

(CH₂), 32.2 (CH₂), 38.9 (CH₂), 43.5 (CH₂), 51.9 (CH₃), 74.8 (CH), 76.4

(CH), 95.5 (C), 106.8 (C), 123.1 (CH), 126.4 (CH), 128.5 (CH), 131.4 (C),

133.6 (CH), 144.1 (C), 189.7 (C), 203.9 (C); MS (EI) m/z 386 (M^þ), 354,

327, 304, 286, 272, 260, 244, 231, 218, 201, 200, 187, 173, 161, 147,

129, 115, 103, 83, 71, 57, 37, 26, 13; HRMS (EI) calcd for C₂₃H₃₀O₅

(M^þ): 386.2092. Found: 386.2112. The enantiomeric excess was

determined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/

hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼13.3 min (minor), 17.8 min

(major).

4.4.11. 7-endo-Cyclohexyloxy-5-methoxy-1-(phenylacetyl)-8-

oxabenzo[c]bicyclo[3.2.1]-octan-2-one (endo-35f). Colorless viscous

25

oil; [

a

]

þ165.7 (c 1.00, CHCl₃) (92% ee (endo)); IR (neat) 3020, 2938,

D

1734,1701,1302,1269,1215,1165,1098,1067,1028, 976, 669 cm^ꢂ1; ¹H

NMR (CDCl₃)

d

0.84–1.72 (10H, m), 2.05 (1H, dd, J¼13.1, 1.7 Hz), 2.60

(1H, dd, J¼13.1, 9.5 Hz), 3.41–3.56(1H, m), 3.88(1H, d, J¼17.1 Hz), 4.06

4.4.8. 7-endo-Cyclohexyloxy-5-methoxy-1-(3-methylbutanoyl)-8-

(1H, d, J¼17.1 Hz), 4.75 (1H, dd, J¼1.7, 9.5 Hz), 7.44–7.53 (2H, m), 7.61–

oxabenzo[c]bicyclo[3.2.1]-octan-2-one (endo-32f). Colorless viscous

7.67 (1H, m), 7.96–8.04 (1H, m); ¹³C NMR (CDCl₃)

d 23.6 (CH₂), 23.8

25

oil; [a

]

þ177.3 (c 1.00, CHCl₃) (88% ee (endo)); IR (neat) 3568, 3021,

(CH₂), 25.8 (CH₂), 31.3 (CH₂), 32.2 (CH₂), 43.6 (CH₂), 45.9 (CH₂), 52.1

(CH₃), 74.8 (CH), 76.4 (CH), 95.7 (C), 107.0 (C), 123.2 (CH), 126.5 (CH),

126.7(CH),128.2 (CH),128.6 (CH),129.8(CH),131.4(C),133.2 (C),133.7

(CH), 144.0 (C), 189.5 (C), 201.1 (C); MS (EI) m/z 420 (M^þ), 388, 360,

338, 307, 294, 278, 262, 247, 234, 219, 203,187, 173,160, 147, 129, 104,

91, 77, 55, 37, 24;HRMS (EI) calcd for C₂₆H₂₈O₅(M^þ):420.1935. Found:

420.1942. The enantiomeric excess was determined by HPLC analysis

(DAICEL Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min,

35 ^ꢀC) t_R¼24.2 min (minor), 39.0 min (major).

D

2936, 2858, 2401, 1728, 1703, 1602, 1415, 1366, 1362, 1269, 1215,

1169, 1169, 1098, 1064, 758, 530 cm^ꢂ1; ¹H NMR (CDCl₃)

d

0.84–1.70

(10H, m), 0.94 (3H, d, J¼6.5 Hz), 0.97 (3H, d, J¼6.8 Hz), 2.06 (1H, dd,

J¼13.2, 1.7 Hz), 2.25 (1H, m), 2.47 (1H, dd, J¼6.5, 17.8 Hz) 2.58 (1H,

dd, J¼13.2, 9.2 Hz), 2.63 (1H, dd, J¼6.8, 17.8 Hz), 3.42–3.54 (1H, m),

3.49 (3H, s), 4.72 (1H, dd, J¼1.7, 9.2 Hz), 7.41–7.52 (2H, m), 7.58–7.67

(1H, m), 7.94–8.03 (1H, m); ¹³C NMR (CDCl₃)

d 22.6 (CH₃), 22.7

(CH₃), 23.7 (CH), 23.7 (CH₂), 23.8 (CH₂), 25.8 (CH₂), 31.5 (CH₂), 32.2

(CH₂), 43.5 (CH₂), 48.1 (CH₂), 52.0 (CH₃), 74.8 (CH), 76.4 (CH), 95.4

(C), 106.8 (C),123.1 (CH), 126.5 (CH), 128.6 (CH), 131.5 (C), 133.6 (CH),

144.1 (C), 189.6 (C), 203.3 (C); MS (EI) m/z 386 (M^þ), 354, 327, 304,

286, 272, 261, 244, 232, 219, 201, 200,187,173,161,147,129,115,103,

85, 69, 57, 39, 26, 13; HRMS (EI) calcd for C₂₃H₃₀O₅(M^þ): 386.2092.

Found: 386.2106. The enantiomeric excess was determined by

HPLC analysis (DAICEL Chiralpak AD-H, 0.5:99.5 i-PrOH/hexane,

ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼14.9 min (minor), 18.0 min (major).

4.4.12. 7-endo-Cyclohexyloxy-5-methoxy-1-(3-phenylpropanoyl)-8-

oxabenzo[c]bicyclo[3.2.1]-octan-2-one (endo-36f). Colorless viscous

25

oil; [

a

]

þ135.1 (c 1.00, CHCl₃) (77% ee (endo)); IR (neat) 2935,

D

2859, 1730, 1705, 1602, 1497, 1454, 1362, 1302, 1269, 1215, 1165,

1096, 1046, 754, 700, 505 cm^ꢂ1; ¹H NMR (CDCl₃)

d

0.83–1.84 (10H,

m), 2.03 (1H, dd, J¼13.1, 1.7 Hz), 2.56 (1H, dd, J¼13.1, 9.5 Hz), 2.89

(1H, m), 2.99 (2H, m), 3.07 (1H, m), 3.50 (3H, s), 3.40–3.54 (1H, m),

4.71 (1H, dd, J¼1.7, 9.5 Hz), 7.39–7.53 (2H, m), 7.57–7.66 (1H, m),

4.4.9. 7-endo-Cyclohexyloxy-1-hexanoyl-5-methoxy-8-oxabenzo[c]-

bicyclo[3.2.1]-octan-2-one (endo-33f). Colorless viscous oil; [

7.93–8.01 (1H, m); ¹³C NMR (CDCl₃)

d 23.7 (CH₂), 23.8 (CH₂), 25.8

25

a

]

(CH₂), 29.2 (CH₂), 31.5 (CH₂), 32.3 (CH₂), 41.0 (CH₂), 43.7 (CH₂), 52.1

(CH₃), 74.9 (CH), 76.6 (CH), 95.4 (C), 107.0 (C),123.2 (CH),125.8 (CH),

126.5 (CH), 128.1 (CH), 128.2 (CH), 128.6 (CH), 131.5 (C), 133.7 (CH),

140.8 (C), 144.0, (C)189.7 (C), 202.8 (C); MS (EI) m/z 434 (M^þ), 402,

375, 352, 334, 309, 292, 279, 263, 248, 231, 217, 201, 187, 173, 149,

129, 105, 91, 71, 57, 39, 26, 13; HRMS (EI) calcd for C₂₇H₃₀O₅(M^þ):

434.2092. Found: 434.2104. The enantiomeric excess was de-

termined by HPLC analysis (DAICEL Chiralpak AD-H, 2:98 i-PrOH/

hexane, ﬂow 0.2 mL/min, 35 ^ꢀC) t_R¼44.4 min (minor), 47.1 min

(major).

D

þ154.1 (c 0.80, CHCl₃) (84% ee, (endo)); IR (neat) 3021, 2934, 2859,

1730, 1701,1651, 1603, 1507,1456,1362,1300, 1269, 1215,1167,1098,

1065 cm^ꢂ1; ¹H NMR (CDCl₃)

d

0.89 (3H, t, J¼7.3 Hz), 1.01–1.77 (10H,

m), 1.04, (2H, m), 1.31 (2H, m), 1.65 (2H, m), 2.03 (1H, dd, J¼1.7,

12.9 Hz), 2.56 (1H, ddd, J¼6.3, 8.1, 18.3 Hz), 2.58 (1H, dd, J¼9.3,

12.9 Hz), 2.75 (1H, ddd, J¼6.6, 8.3, 18.3 Hz), 3.49 (3H, s), 3.45–3.52

(1H, m), 4.73 (1H, dd, J¼1.7, 9.3 Hz), 7.44–7.48 (2H, m), 7.60–7.64

(1H, m), 7.96–8.00 (1H, m); ¹³C NMR (CDCl₃)

d 14.1 (CH₃), 22.6

(CH₂), 22.8 (CH₂), 23.8 (CH₂), 23.9 (CH₂), 25.9 (CH₂), 31.4 (CH₂), 31.5

(CH₂), 32.3 (CH₂), 39.4 (CH₂), 43.6 (CH₂), 52.1 (CH₃), 74.9 (CH), 76.5

(CH), 95.6 (C), 106.9 (C), 123.2 (CH), 126.6 (CH), 128.6 (CH), 131.6 (C),

133.7 (CH), 144.1 (C), 189.8 (C), 204.1 (C); MS (EI) m/z 400 (M^þ), 368,

341, 318, 301, 275, 258, 246, 231, 215, 201,187,173,159, 145,129,116,

103, 83, 69, 55, 37, 24; HRMS (EI) calcd for C₂₄H₃₂O₅(M^þ):

400.2248. Found: 400.2242. The enantiomeric excess was de-

termined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/

hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼42.0 min (minor), 55.7 min

(major).

4.4.13. 1-Butanoyl-7-endo-(tert-butyldimethylsilyl)oxy-5-methoxy-

8-oxabenzo[c]bicyclo[3.2.1]-octan-2-one (endo-38). Colorless vis-

25

cous oil; [

a

]

ꢂ40.0 (c 1.00, CHCl₃) (19% ee (endo)); IR (neat) 2951,

D

2893,1948, 1724,1604,1462,1373,1304,1261,1215,1169,1111,1034,

949, 837 cm^ꢂ^{1 1}H NMR (CDCl₃)

;

d

ꢂ0.08 (3H, s), 0.06 (3H, s), 0.58

(9H, s), 0.94 (3H, t, J¼7.3 Hz), 1.68 (2H, m), 1.92 (1H, dd, J¼12.9,

1.5 Hz), 2.55 (1H, ddd, J¼6.3, 8.3, 18.3 Hz), 2.55 (1H, dd, J¼12.9,

8.8 Hz), 2.74 (1H, ddd, J¼6.6, 8.3, 18.3 Hz), 3.49 (3H, s), 4.92 (1H, dd,

J¼1.5, 8.8 Hz), 7.43–7.47 (2H, m), 7.59–7.63 (1H, m), 7.96–7.98 (1H,

4.4.10. 1-(Cylohexylcarbonyl)-7-endo-cyclohexyloxy-5-methoxy-8-

m); ¹³C NMR (CDCl₃)

d

ꢂ5.2 (CH₃), ꢂ5.0 (CH₃),13.8 (CH₃),16.5 (CH₂),

oxabenzo[c]bicyclo[3.2.1]-octan-2-one (endo-34f). Colorless prisms

17.6 (C), 25.3 (CH₃), 41.2 (CH₂), 45.4 (CH₂), 52.1 (CH₃), 71.3 (CH), 95.1

(C),107.1 (C), 123.1 (CH), 126.5 (CH), 128.5 (CH), 131.7 (C),133.6 (CH),

144.0 (C), 189.4 (C), 203.4 (C); MS (EI) m/z 404 (M^þ), 388, 374, 362,

346, 328, 315, 302, 287, 273, 261, 250, 231, 217, 204, 188, 175, 159,

146, 138, 115, 101, 85, 74, 59, 47, 35, 24, 12. Anal. Calcd for

C₂₂H₃₂O₅Si: C, 65.31; H, 7.97%. Found: C, 65.17; H, 8.09%. The en-

antiomeric excess was determined by HPLC analysis (DAICEL Chir-

alpak OD-H, 1:800 i-PrOH/hexane, ﬂow 0.2 mL/min, 35 ^ꢀC)

t_R¼6.7 min (minor), 9.0 min (major).

25

(hexane); mp 95–96 ^ꢀC; [

a

]

þ163.7 (c 1.00, CHCl₃) (96% ee

D

(endo)); IR (KBr) 3021, 2936, 2857, 1728, 1699, 1557, 1539, 1520,

1454, 1300, 1267, 1217, 1167, 1098, 1051, 974 cm^ꢂ1; ¹H NMR (CDCl₃)

d

0.98–1.92 (20H, m), 2.01 (1H, dd, J¼1.7, 12.9 Hz), 2.58 (1H, dd,

J¼9.3, 12.9 Hz), 2.82 (1H, tt, J¼3.2, 11.2 Hz), 3.50 (3H, s), 3.52–3.56

(1H, m), 4.66 (1H, dd, J¼1.7, 9.3 Hz), 7.44–7.48 (2H, m), 7.60–7.64

(1H, m), 7.98–8.00 (1H, m); ¹³C NMR (CDCl₃)

d 23.8 (CH₂), 23.9

(CH₂), 25.7 (CH₂), 25.9 (CH₂), 26.0 (CH₂), 28.5 (CH₂), 28.9 (CH₂), 31.5

(CH₂), 32.4 (CH₂), 43.5 (CH₂), 47.7 (CH), 52.0 (CH₃), 75.5 (CH), 76.4

(CH), 96.0 (C), 106.7 (C), 123.2 (CH), 126.7 (CH), 128.6 (CH), 131.5 (C),

133.6 (CH), 144.0 (C), 189.3 (C), 207.1 (C); MS (EI) m/z 412 (M^þ), 380,

4.4.14. 1-Butanoyl-7-endo-butanoyloxy-5-methoxy-8-oxabenzo[c]-

bicyclo[3.2.1]octan-2-one (endo-39). Colorless viscous oil; IR (neat)

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3085

3028, 2966, 1736, 1601, 1458, 1369, 1304, 1269, 1161, 1095, 1034,

933 cm^ꢂ^{1 1}H NMR (CDCl₃)

(CH₃), 16.6 (CH₂), 33.1 (CH₂), 41.1 (CH₂), 50.9 (CH₃), 52.7 (CH), 90.3

(C), 109.7 (C), 126.0 (CH), 127.0 (CH), 127.1 (CH), 127.7 (CH), 130.1 (C),

133.2 (CH), 135.8 (C), 140.8 (C), 191.4 (C), 203.8 (C); MS (EI) m/z 350

(M^þ), 291, 274, 250, 231, 219, 191, 175, 161, 149, 129, 115, 104, 91, 77,

57, 39, 25, 12. Anal. Calcd for C₂₂H₂₂O₄: C, 75.41; H, 6.33%. Found: C,

75.42; H, 6.32%. The enantiomeric excess of major adduct was

determined by HPLC analysis (DAICEL Chiralpak AD-H, 0.5:99.5

i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼30.5 min (minor),

38.2 min (major).

;

d

0.72 (3H, t, J¼7.3 Hz), 0.95 (3H, t,

J¼7.3 Hz), 1.39 (2H, m), 1.68 (2H, m), 1.96 (1H, dd, J¼13.9, 2.2 Hz),

2.07 (2H, m), 2.55 (1H, ddd, J¼6.6, 8.3,18.3 Hz), 2.72 (1H, ddd, J¼6.6,

8.1, 18.3 Hz), 2.84 (1H, dd, J¼13.9, 9.5 Hz), 3.52 (3H, s), 5.75 (1H, dd,

J¼2.2, 9.5 Hz), 7.49–7.54 (2H, m), 7.65–7.69 (1H, m), 8.05–8.07 (1H,

m); ¹³C NMR (CDCl₃)

d 13.4 (CH₃), 13.7 (CH₃), 16.5 (CH₂), 18.1 (CH₂),

35.9 (CH₂), 41.1 (CH₂), 42.6 (CH₂), 52.2 (CH₃), 71.1 (CH), 92.6 (C),

106.8 (C), 123.2 (CH), 127.0 (CH), 128.9 (CH), 130.5 (C), 134.3 (CH),

144.3 (C), 171.6 (C), 188.5 (C), 202.1 (C); MS (EI) m/z 360 (M^þ), 301,

290, 272, 258, 244, 229, 213, 202, 187, 173, 161, 147, 129, 115, 103, 91,

77, 57, 37, 24,13. Anal. Calcd for C₂₀H₂₄O₆: C, 66.65; H, 6.71%. Found:

C, 66.35; H, 6.44%. The enantiomeric excess was determined by

HPLC analysis (DAICEL Chiralpak AD-H, 1:9 i-PrOH/hexane, ﬂow

0.5 mL/min, 35 ^ꢀC) t_R¼10.5 min (major), 21.3 min (minor).

4.4.18. 6-endo-7-endo-1-Butanoyl-5-methoxy-8-oxabenzo[c]-

tetrahydrofuro[3,2-f]bicyclo[3.2.1]-octan-2-one (endo-43). Colorless

25

solid; mp 59–60.5 ^ꢀC; [

a

]

ꢂ137.9 (c 1.00, CHCl₃) (54% ee (endo)); IR

D

(neat) 3073, 3034, 2957, 2874, 2845, 2361, 2342, 1728, 1699, 1599,

1454, 1404,1379,1368,1333,1304,1287,1256,1221, 1198, 1167, 1119,

1096, 1080, 1051, 1048, 1015 cm^ꢂ^{1 1}H NMR (CDCl₃)

; d 0.96 (3H, t,

4.4.15. 1-Butanoyl-7-endo-butyl-5-methoxy-8-oxabenzo[c]bicyclo-

[3.2.1]octan-2-one (endo-40). Colorless viscous oil; IR (neat) 2951,

2873, 1724, 1597, 1454, 1400, 1373, 1296, 1215, 1165, 1088, 1038, 976,

J¼7.3 Hz), 1.52 (1H, m), 1.65–1.76 (2H, m), 1.97 (1H, m), 2.57 (1H,

ddd, J¼6.6, 8.1, 18.1 Hz), 2.70 (1H, dt, J¼8.1, 8.1 Hz), 2.77 (1H, ddd,

J¼6.6, 8.1, 18.1 Hz), 3.30 (1H, dt, J¼2.2, 9.0 Hz), 3.51 (3H, s), 3.66 (1H,

dt, J¼4.4, 9.0 Hz), 5.12 (1H, d, J¼8.3 Hz), 7.44–7.56 (2H, m), 7.63–

899 cm^ꢂ1

;

¹H NMR (CDCl₃)

d

0.80 (3H, t, J¼7.1 Hz), 0.93 (3H, t,

J¼7.3 Hz), 1.11–1.23 (4H, m), 1.61–1.67 (4H, m), 1.67 (1H, dd, J¼12.6,

4.9 Hz), 2.51 (1H, ddd, J¼6.3, 7.8, 18.1 Hz), 2.57 (1H, dd, J¼12.6,

11.7 Hz), 2.72 (1H, ddd, J¼6.8, 7.8, 18.1 Hz), 2.80 (1H, dddd, J¼3.9,

8.5, 4.9, 11.7 Hz), 3.52 (3H, s), 7.46–7.50 (2H, m), 7.64–7.68 (1H, m),

7.71 (1H, m), 8.04–8.10 (1H, m); ¹³C NMR (CDCl₃)

d 13.7 (CH₃), 16.6

(CH₂), 26.5 (CH₂), 41.1 (CH₂), 52.4 (CH₃), 52.5 (CH), 71.8 (CH₂), 84.9

(CH), 94.4 (C), 108.7 (C), 125.2 (CH), 127.0 (CH), 129.2 (CH), 132.0 (C),

133.3 (CH), 140.8 (C), 188.7 (C), 202.4 (C); MS (EI) m/z 316 (M^þ), 256,

246, 231, 217, 203, 187, 176, 163, 147, 129, 115, 104, 91, 77, 68, 55, 39,

24, 12. Anal. Calcd for C₁₈H₂₀O₅: C, 68.34; H, 6.37%. Found: C, 68.48;

H, 6.49%. The enantiomeric excess of major adduct was determined

by HPLC analysis (DAICEL Chiralpak AD-H, 1:19 i-PrOH/hexane,

ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼28.0 min (major), 31.4 min (minor).

8.02–8.04 (1H, m); ¹³C NMR (CDCl₃)

d 13.8 (CH₃), 14.0 (CH₃), 16.6

(CH₂), 22.5 (CH₂), 31.1 (CH₂), 32.0 (CH₂), 39.7 (CH₂), 40.1 (CH), 41.3

(CH₂), 51.9 (CH₃), 94.6 (C), 106.6 (C), 122.8 (CH), 127.0 (CH), 128.6

(CH), 130.1 (C), 134.3 (CH), 146.2 (C), 191.3 (C), 203.9 (C); MS (EI) m/z

330 (M^þ), 314, 302, 288, 276, 259, 250, 241, 232, 217, 199, 186, 174,

167, 157, 119, 108, 101, 91, 78, 51, 24, 12, 3. Anal. Calcd for C₂₀H₂₆O₄:

C, 72.70; H, 7.93%. Found: C, 72.50; H, 8.11%. The enantiomeric ex-

cess was determined by HPLC analysis (DAICEL Chiralpak AD-H,

1:400 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼17.5 min (mi-

nor), 18.9 min (major).

4.4.19. 1-Butanoyl-5,7-endo-dimethoxy-7-exo-methyl-8-oxabenzo[c]-

25

bicyclo[3.2.1]octan-2-one (endo-44). Colorless viscous oil;

[a]

D

þ43.7 (c 0.50, CHCl₃) (8% ee (endo)); IR (neat) 3021, 2967, 2833,

2401, 1734, 1967, 1601, 1520, 1456, 1301, 1277, 1254, 1219, 1147, 1086,

1003 cm^ꢂ1; ¹H NMR (CDCl₃)

d

0.93 (3H, t, J¼7.3 Hz),1.35 (3H, s),1.64

4.4.16. 1-Butanoyl-7-endo-butoxymethyl-5-methoxy-8-oxabenzo[c]-

(2H, sext, J¼7.3 Hz), 1.92 (1H, d, J¼13.6 Hz), 2.54 (1H, dt, J¼7.3,

18.0 Hz), 2.78 (1H, dt, J¼7.3, 18.0 Hz), 2.77 (1H, d, J¼13.6 Hz), 3.22

bicyclo[3.2.1]octan-2-one (endo-41). Colorless viscous oil; ¹H NMR

(CDCl₃)

d

0.74 (3H, t, J¼7.3 Hz), 0.93 (3H, t, J¼7.3 Hz), 1.02 (2H, sext,

(3H, s), 3.60 (3H, s), 7.41–8.03 (4H, m); ¹³C NMR (CDCl₃)

d 13.8

J¼7.3 Hz), 1.17 (2H, m), 1.61–1.71 (2H, m), 2.10 (1H, dd, J¼5.6,

13.2 Hz), 2.52 (1H, ddd, J¼6.6, 8.1, 18.1 Hz), 2.51 (1H, dd, J¼11.5,

13.2 Hz), 2.71 (1H, ddd, J¼6.6, 7.8, 18.1 Hz), 3.02–3.09 (1H, m), 3.12

(2H, dt, J¼6.3, 1.5 Hz), 3.16 (1H, dd, J¼6.1, 9.5 Hz), 3.50 (1H, dd,

J¼3.7, 9.5 Hz), 3.52 (3H, s), 7.43–7.48 (2H, m), 7.60–7.64 (1H, m),

7.97–7.99 (1H, m). The other spectroscopic data and satisfactory

elemental analysis were not obtained because of a small amount of

the product.

(CH₃), 16.4 (CH₂), 20.8 (CH₃), 42.6 (CH₂), 46.0 (CH₂), 50.6 (CH₃), 52.0

(CH₃), 85.2 (C), 98.2 (C), 105.8 (C), 122.0 (CH), 127.7 (CH), 128.7 (CH),

129.3 (C), 134.3 (CH), 146.6 (C), 188.1 (C), 200.6 (C). Satisfactory

elemental analysis was not obtained. The enantiomeric excess was

determined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/

hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼45.7 min (minor), 53.6 min

(major).

4.4.20. 1-Butanoyl-5,7-exo-dimethoxy-7-endo-methyl-8-oxabenzo-

25

4.4.17. 1-Butanoyl-5-methoxy-7-phenyl-8-oxabenzo[c]bicyclo[3.2.1]-

octan-2-one (42). Mixture of diastereomer, 91:9; Colorless viscous

oil; IR (neat) 3062, 2958, 2904, 1728, 1693, 1597, 1496, 1454, 1373,

1296, 1200, 1161, 1041, 987, 914, 856 cm^ꢂ1; ¹H NMR (CDCl₃) Major:

[c]bicyclo[3.2.1]octan-2-one (exo-44). Colorless viscous oil; [a]

D

þ101.4 (c 0.80, CHCl₃) (34% ee (exo)); IR (neat) 3021, 2967, 2936,

2833, 2401,1734,1697,1601,1520,1454,1301,1298,1277,1147,1086,

1003, 970 cm^ꢂ1

;

¹H NMR (CDCl₃)

d

0.93 (3H, t, J¼7.6 Hz), 1.42 (3H,

d

0.93 (3Hꢁ0.91, t, J¼7.6 Hz), 1.68 (2Hꢁ0.91, m), 2.41 (1Hꢁ0.91, dd,

s), 1.64 (2H, m), 2.37 (2H, s), 2.51 (1H, dt, J¼7.6, 18.0 Hz), 2.70 (1H,

J¼13.2, 4.6 Hz), 2.52 (1Hꢁ0.91, dt, J¼7.1, 18.3 Hz), 2.74 (1Hꢁ0.91, dt,

J¼7.1, 18.3 Hz), 2.89 (1Hꢁ0.91, dd, J¼13.2, 12.2 Hz), 3.58 (3Hꢁ0.91,

s), 4.39 (1Hꢁ0.91, dd, J¼4.6, 12.2 Hz), 6.80–6.82 (2Hꢁ0.91, m), 7.02–

7.11 (3Hꢁ0.91, m), 7.46–7.51 (1Hꢁ0.91, m), 7.60–7.62 (1Hꢁ0.91, m),

dt, J¼7.6, 18.0 Hz), 3.18 (3H, s), 3.54 (3H, s), 7.41–8.07 (4H, m); ¹³C

NMR (CDCl₃)

d 13.7 (CH₃), 16.4 (CH₂), 22.0 (CH₃), 42.2 (CH₂), 50.5

(CH₂), 51.8 (CH₃), 52.0 (CH₃), 84.0 (C), 97.7 (C), 104.7 (C), 122.3 (CH),

127.2 (CH), 128.5 (CH), 130.4 (C), 133.7 (CH), 144.4 (C), 187.2 (C),

202.4 (C). Satisfactory elemental analysis was not obtained. The

enantiomeric excess was determined by HPLC analysis (DAICEL

Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC)

t_R¼20.8 min (major), 27.1 min (minor).

7.70–7.84 (2Hꢁ0.91, m); Minor:

d

0.98 (3Hꢁ0.09, t, J¼7.3 Hz), 1.72

(2Hꢁ0.09, m), 2.20 (1Hꢁ0.09, dd, J¼14.6, 8.3 Hz), 2.61 (1Hꢁ0.09,

ddd, J¼6.3, 8.1, 18.1 Hz), 2.82 (1Hꢁ0.09, ddd, J¼6.3, 8.3, 18.1 Hz),

3.16 (1Hꢁ0.09, dd, J¼14.6, 11.0 Hz), 3.54 (3Hꢁ0.09, s), 3.78

(1Hꢁ0.09, dd, J¼8.3, 11.0 Hz), 6.66–6.71 (3Hꢁ0.09, m), 7.02–7.14

(2Hꢁ0.09, m), 7.29–7.34 (2Hꢁ0.09, m), 7.40–7.44 (1Hꢁ0.09, m),

4.4.21. 1-Butanoyl-7-butoxy-7-(tert-butyldimethylsilyl)oxy-5-

methoxy-8-oxabenzo[c]bicyclo[3.2.1]-octan-2-one (45). Mixture of

diastereomer, 74:26; Yellow viscous oil; IR (neat) 3047, 2958, 2873,

8.07–8.10 (1Hꢁ0.09, m); ¹³C NMR (CDCl₃) Major:

d 13.8 (CH₃), 16.7

(CH₂), 41.3 (CH₂), 41.5 (CH₂), 44.7 (CH), 52.4 (CH₃), 95.5 (C), 107.0

(C), 123.2 (CH), 126.9 (CH), 127.9 (CH), 128.4 (CH), 128.9 (CH), 131.4

(C), 134.5 (CH), 136.3 (C), 144.7 (C) 190.7 (C), 203.4 (C); Minor: 13.8

1944, 1732, 1651, 1604, 1462, 1284, 1180, 1072, 1018 cm^ꢂ^{1 1}H NMR

;

(CDCl₃) Major:

d

ꢂ0.28 (3H, s), 0.11 (3H, s), 0.63 (9H, s), 0.91 (3H, t,

3086

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

J¼7.3 Hz), 1.00 (3H, t, J¼7.3 Hz), 1.30–1.39 (2H, m), 1.47–1.54 (2H,

m), 1.63–1.70 (1H, m), 1.77–1.87 (1H, m), 2.10 (1H, d, J¼13.4 Hz),

2.82 (1H, ddd, J¼5.6, 9.8, 17.8 Hz), 2.95 (1H, d, J¼13.4 Hz), 3.08 (1H,

ddd, J¼5.6, 9.5, 17.8 Hz), 3.40 (1H, dt, J¼6.3, 9.0 Hz), 3.56 (3H, s),

3.52–3.59 (1H, m), 7.40–7.47 (2H, m), 7.58–7.60 (1H, m), 7.97–7.99

(3 mL, puriﬁed by distillation with CaH₂) was transferred to

a Schlenk tube (20 mL). After added MS 4 Å (0.5 g), Rh₂(OAc)₄

(4.4 mg, 0.01 mmol), MeOH (2.0 mL), and CH₂Cl₂(1 mL, puriﬁed by

distillation with CaH₂), successively, a solution of diazo compound

1 (102 mg, 0.50 mmol) and butyl vinyl ether (100 mg, 1.00 mmol),

in CH₂Cl₂(5 mL, without puriﬁcation) was added over a period of

1 h using a syringe pump at 23 ^ꢀC. The syringe was washed with

CH₂Cl₂(1 mL, puriﬁed by distillation with CaH₂). After removal of

MS 4 Å through Celite, the reaction mixture was ﬁltered through

a plug of silica gel (3 cm) with AcOEt/hexane (1:1, 60 mL) as an

eluent. The solvent was removed in vacuo, and the residue was

puriﬁed by column chromatography (94:6 hexane/AcOEt) to pro-

vide 67.7 mg (64%) of endo-53a and exo-53a. Relative stereo-

chemistry (endo/exo) of the products 53a–c, 53e and f, 54a–58a, 59,

and 62 could be determined by ¹H NMR analysis on the basis of

a coupling constant between H-1 and H-7, which reported pre-

viously (exo:0 Hz).¹⁹

(1H, m); Minor:

d

0.14 (3H, s), 0.20 (3H, s), 0.75 (3H, t, J¼7.3 Hz),

0.89 (9H, s), 0.94 (3H, t, J¼7.3 Hz), 1.04–1.10 (2H, m), 1.18–1.25 (2H,

m), 1.60–1.69 (2H, m), 2.44 (1H, d, J¼12.7 Hz), 2.62 (1H, ddd, J¼6.6,

8.5, 18.5 Hz), 2.72 (1H, ddd, J¼6.6, 8.3, 18.5 Hz), 2.74 (1H, d,

J¼12.7 Hz), 3.43 (1H, dt, J¼6.3, 9.5 Hz), 3.55 (3H, s), 3.79 (1H, dt,

J¼6.3, 9.5 Hz), 7.38–7.46 (2H, m), 7.57–7.61 (1H, m), 7.97–7.99 (1H,

m); ¹³C NMR (CDCl₃) Major:

d

ꢂ4.4 (CH₃), ꢂ2.6 (CH₃), 14.0 (CH₃),

14.1 (CH₃), 17.0 (CH₂), 17.8 (C), 19.3 (CH₂), 25.2 (CH₃), 32.0 (CH₂),

43.5 (CH₂), 46.4 (CH₂), 52.2 (CH₃), 64.4 (CH₂), 98.2 (C), 105.2 (C),

107.0 (C), 122.3 (CH), 127.4 (CH), 128.7 (CH), 130.7 (C), 133.8 (CH),

144.3 (C), 187.6 (C), 201.2 (C); MS (EI) m/z 476 (M^þ), 461, 405, 387,

330, 317, 287, 261, 247, 230, 217, 202, 186, 173, 160, 147, 129, 105, 89,

73, 57, 43, 29. Anal. Calcd for C₂₆H₄₀O₆Si: C, 65.51; H, 8.46%. Found:

C, 65.41; H, 8.47%. The enantiomeric excess of major adduct was

determined by HPLC analysis (DAICEL Chiralpak OD-3, 1:200 EtOH/

hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼10.2 min (major), 13.5 min

(minor).

4.5.1. 7-exo-Butoxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-one (exo-

26

53a). Colorless viscous oil;

[

a]

þ21.2 (c 0.20, CHCl₃)

D

(exo:endo¼92:8, 82% ee (exo)), IR (CHCl₃) 4216, 3447, 3020, 2934,

2402, 2350, 1730, 1682, 1633, 1520, 1454, 1217, 1093, 929, 772,

669 cm^ꢂ1

;

¹H NMR (CDCl₃)

d

0.91 (3H, t, J¼7.3 Hz), 1.35 (2H, sext,

4.4.22. 1-Butanoyl-7-butoxy-5-methoxy-7-phenyl-8-oxabenzo[c]-

bicyclo[3.2.1]octan-2-one (46). Mixture of diastereomer, 74:26;

J¼7.3 Hz), 1.51 (2H, m), 1.53 (3H, s), 1.81 (1H, ddd, J¼2.2, 8.0,

13.4 Hz), 1.87 (1H, m), 2.08 (1H, m), 2.25 (1H, ddd, J¼8.3. 9.8,

17.6 Hz), 2.38 (1H, dd, J¼7.6, 13.9 Hz), 2.49 (1H, ddt, J¼7.8, 17.5,

2.0 Hz), 3.35 (1H, dt, J¼6.8, 9.3 Hz), 3.45 (1H, dt, J¼6.8, 9.3 Hz), 3.95

25

Colorless viscous oil; [

a]

þ77.8 (c 1.00, CHCl₃) (74:26 Mixture of

D

diastereomer, 44% ee (major), 44% ee (minor)); IR (neat) 3066,

2958, 2877, 1736,1601, 1454, 1369, 1273,1153, 1072, 1018, 818 cm^ꢂ1

¹H NMR (CDCl₃) Major:

J¼7.3 Hz), 0.79–1.40 (6H, m), 2.16 (1H, ddd, J¼5.6, 9.0, 17.8 Hz), 2.41

(1H, ddd, J¼6.3, 9.0, 17.8 Hz), 2.83 (1H, d, J¼14.4 Hz), 2.90 (1H, d,

J¼14.4 Hz), 2.95 (1H, ddd, J¼6.1, 7.6, 9.5 Hz), 3.48 (1H, ddd, J¼5.6,

6.3, 9.5 Hz), 3.66 (3H, s), 7.22–7.67 (8H, m), 8.05–8.07 (1H, m);

;

(1H, dd, J¼2.7, 7.6 Hz), 4.29 (1H, s); ¹³C NMR (CDCl₃)

d 14.0 (CH₃),

d

0.64 (3H, t, J¼7.3 Hz), 0.67 (3H, t,

19.2 (CH₂), 26.1 (CH₃), 31.7 (CH₂), 34.0 (CH₂), 36.3 (CH₂), 44.0 (CH₂),

69.6 (CH₂), 80.8 (C), 82.8 (CH), 87.4 (CH), 206.2 (C); MS (EI) m/z 212

(M^þ),184,156,140,127,121,112,109, 99, 93, 82, 75, 69, 62, 56, 49, 41,

35, 24, 13. Anal. Calcd for C₁₂H₂₀O₃: C, 67.89; H, 9.50%. Found: C,

67.90, H, 9.47%. The enantiomeric excess was determined by ¹H

NMR analysis (91:9) after conversion to the corresponding acetals

by the reaction with (R,R)-hydrobenzoin.

Minor:

d

0.88 (3H, t, J¼7.3 Hz), 0.96 (3H, t, J¼7.3 Hz), 0.79–1.40 (2H,

m), 1.48–1.54 (2H, m), 1.61–1.72 (2H, m), 2.59 (1H, ddd, J¼6.6, 7.3,

18.1 Hz), 2.82–2.98 (1H, m), 2.84 (1H, m), 2.93 (1H, d, J¼13.7 Hz),

3.10 (2H, m), 3.64 (3H, s), 6.92–7.17 (5H, m), 7.22–7.67 (4H, m); ¹³C

4.5.2. 7-endo-Butoxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-one

(endo-53a). Although endo-53a could not be separated by chroma-

tography from a mixture with major exo-53a, it could characterize

NMR (CDCl₃) Major:

d 13.6 (CH₃), 13.7 (CH₃), 16.3 (CH₂), 19.0 (CH₂),

31.8 (CH₂), 42.7 (CH₂), 48.3 (CH₂), 52.7 (CH₃), 66.0 (CH₂), 88.2 (C),

99.0 (C), 105.8 (C), 122.3 (CH), 126.3 (CH), 127.5 (CH), 128.1 (CH),

128.6 (CH), 131.0 (C), 133.4 (CH), 141.1 (C), 144.3 (C), 186.6 (C); Mi-

nor: 13.9 (CH₃), 14.0 (CH₃), 16.4 (CH₂), 19.5 (CH₂), 31.9 (CH₂), 42.5

(CH₂), 45.4 (CH₂), 52.0 (CH₃), 63.7 (CH₂), 89.8 (C), 97.0 (C), 106.6 (C),

122.6 (CH), 126.3 (CH), 127.6 (CH), 128.1 (CH), 128.9 (CH), 131.1 (C),

134.0 (CH), 136.0 (C), 143.9 (C), 185.6 (C); MS (EI) m/z 422 (M^þ), 390,

363, 348, 333, 317, 289, 263, 246, 231, 218, 203, 189, 175, 161, 147,

129, 117, 105, 91, 71, 57, 41, 27, 15. Anal. Calcd for C₂₆H₃₀O₅: C, 73.91;

H, 7.16%. Found: C, 73.79; H, 7.16%. The enantiomeric excess of major

adduct was determined by HPLC analysis (DAICEL Chiralpak AD-H,

2:98 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼33.3 min (minor),

38.6 min (major). The enantiomeric excess of minor adduct was

determined by HPLC analysis (DAICEL Chiralpak AD-H, 2:98 i-PrOH/

hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼27.5 min (minor), 52.2 min

(major).

by ¹H NMR.¹H NMR (CDCl₃)

d

0.91 (3H, t, J¼7.6 Hz),1.24–1.33 (2H, m),

1.40 (3H, s), 1.43–1.50 (2H, m), 1.95–2.01 (2H, m), 2.10 (1H, m), 2.23

(1H, dd, J¼9.2, 13.4 Hz), 2.44 (1H, ddt, J¼7.2, 17.5, 1.5 Hz), 2.65 (1H,

ddd, J¼8.7, 11.7, 17.0 Hz), 3.35 (2H, dt, J¼6.4, 1.9 Hz), 4.31 (2H, m).

4.5.3. 7-exo-Ethoxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-one (exo-

25

53b). Colorless viscous oil; [

a

]

þ40.8 (c 0.94, CHCl₃) (exo:endo¼

D

>99:1, 71% ee (exo)), IR (CHCl₃) 3735, 3649, 3567, 2962, 2873, 2361,

1725, 1541, 1464, 1362, 1260, 1092, 1051, 901, 773, 760, 749 cm^ꢂ1; ¹H

NMR (CDCl₃)

d

1.21 (3H, t, J¼7.0 Hz), 1.51 (3H, s), 1.81 (1H, ddd,

J¼2.4, 8.4, 13.5 Hz), 1.88 (1H, m), 2.08 (1H, m), 2.25 (1H, ddd, J¼8.4,

9.6, 17.6 Hz), 2.39 (1H, dd, J¼7.4, 13.8 Hz), 2.49 (1H, ddt, J¼7.9, 17.4,

1.8 Hz), 3.42 (1H, dq, J¼7.0, 9.1 Hz), 3.52 (1H, dq, J¼7.0, 9.1 Hz), 4.00

(1H, dd, J¼2.6, 7.4 Hz), 4.30 (1H, s); ¹³C NMR (CDCl₃)

d 15.3 (CH₃),

26.2 (CH₃), 34.1 (CH₂), 36.2 (CH₂), 44.1 (CH₂), 65.1 (CH₂), 80.8 (C),

82.7 (CH), 87.4 (CH), 206.2 (C); MS (EI) m/z 184 (M^þ), 169, 156, 138,

127, 111, 93, 81, 70, 54, 38, 26, 15. Anal. Calcd for C₁₀H₁₆O₃: C, 65.19;

H, 8.75%. Found: C, 64.94, H, 8.92%. The enantiomeric excess was

determined by ¹H NMR analysis (85.7:14.3) after conversion to the

corresponding acetals by the reaction with (R,R)-hydrobenzoin.

4.5. General procedure for the reaction of diazo diketones 47–

52 with oleﬁns was exempliﬁed the reaction of 1-diazo-2,5-

hexandione (47) with butyl vinyl ether (2a) catalyzed by

(4S,5S)-Pybox-Ph₂–Lu(III) Complex

A solution of 2,6-bis[(4S,5S)-4,5-diphenyl-2-oxazolin-2-yl]pyr-

idine ((4S,5S)-Pybox-Ph₂, 26.1 mg, 0.05 mmol) in THF (1.5 mL) was

added to a solution of Lu(OTf)₃(30.0 mg, 0.05 mmol) in THF (1 mL).

After stirring the mixture for 2 h, the solvent was removed under

reduced pressure and resulting solid was dried in vacuo at room

temperature for 5 h. A solution of Lu(III)–Pybox complex in CH₂Cl₂

4.5.4. 7-exo-Benzyloxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-one

25

(exo-53c). Colorless oil; [

a

]

þ36.3 (c 1.00, CHCl₃) (exo:endo¼95:5,

D

60% ee (exo)), IR (CHCl₃) 3031, 1724, 1453, 1096, 791, 774, 759, 748,

738, 713 cm^ꢂ1; ¹H NMR (CDCl₃)

d

1.54 (3H, s), 1.80 (1H, ddd, J¼2.5,

8.4, 13.4 Hz), 1.97 (1H, m), 2.08 (1H, m), 2.23 (1H, ddd, J¼8.4, 9.8,

18.0 Hz), 2.38 (1H, dd, J¼7.4, 13.9 Hz), 2.48 (1H, ddt, J¼7.9, 18.0,

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3087

2.5 Hz), 4.10 (1H, dd, J¼2.6, 7.4 Hz), 4.38 (1H, s), 4.44 (1H, d,

J¼11.9 Hz), 4.57 (1H, d, J¼11.9 Hz), 7.24–7.40 (5H, m); MS (EI) m/z

246 (M^þ), 230, 156, 137, 122, 106, 78, 49, 27. Anal. Calcd for

C₁₅H₁₈O₃: C, 73.15; H, 7.37%. Found: C, 72.96; H, 7.47%. The enan-

tiomeric excess was determined by ¹H NMR analysis (80:20) after

conversion to the corresponding acetals by the reaction with (R,R)-

hydrobenzoin.

17.0 Hz), 3.25 (1H, m), 4.24 (1H, dd, J¼1.5, 6.8 Hz), 4.48 (1H, ddd,

J¼4.1, 6.8, 10.5 Hz).

4.5.10. 7-exo-(tert-Butyldimethylsilyl)oxy-5-methyl-8-oxa-

25

bicyclo[3.2.1]octan-2-one (exo-59). Colorless oil; [

a]

þ28.1 (c 1.00,

D

CHCl₃) (exo:endo¼> 99:1, 82% ee (exo)), IR (CHCl₃) 3735, 3649,

2932, 2361, 1717, 1541, 1457, 1215, 1082, 837, 791, 775, 760, 747, 738,

721 cm^ꢂ1; ¹H NMR (CDCl₃)

d 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s),

4.5.5. 7-endo-Benzyloxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-one

(endo-53c). Although endo-53c could not be separated by chro-

matography from a mixture with major exo-53c, it could charac-

1.53 (3H, s),1.78 (1H, ddd, J¼2.2, 8.3,13.4 Hz),1.82 (1H, m), 2.05 (1H,

m), 2.24 (1H, ddd, J¼8.3, 9.8, 18.8 Hz), 2.40 (1H, dd, J¼7.3, 13.6 Hz),

2.47 (1H, ddt, J¼7.8, 17.6, 2.1 Hz), 4.12 (1H, s), 4.38 (1H, dd, J¼2.4,

terize by ¹H NMR. ¹H NMR (CDCl₃)

d

1.40 (3H, s), 1.95–2.16 (3H, m),

7,3 Hz); ¹³C NMR (CDCl₃)

d

ꢂ4.6 (CH₃), ꢂ4.5 (CH₃), 18.2 (C), 25.9

2.23 (1H, ddd, J¼1.4, 10.4, 13.7 Hz), 2.48 (1H, ddt, J¼7.4, 17.6, 1.4 Hz),

2.70 (1H, ddd, J¼8.7, 11.5, 17.6 Hz), 4.37 (1H, dd, J¼1.2, 7.4 Hz), 4.40

(1H, d, J¼11.4 Hz), 4.45 (1H, ddd, J¼4.0, 7.4, 10.7 Hz), 4.52 (1H, d,

J¼11.9 Hz), 7.22–7.38 (5H, m).

(CH₃), 26.2 (CH₃), 34.1 (CH₂), 36.3 (CH₂), 47.4 (CH₂), 75.9 (CH), 81.3

(C), 91.3 (CH), 206.2 (C); MS (EI) m/z 270 (M^þ), 255, 237, 213, 195,

165, 149, 131, 117, 97, 75, 57, 41, 27. Anal. Calcd for C₁₄H₂₆O₃Si: C,

62.18; H, 9.69%. Found: C, 62.16; H, 9.87%. The enantiomeric excess

was determined by ¹H NMR analysis (91:9) after conversion to the

corresponding esters by the reduction with NaBH₄followed by the

4.5.6. 7-exo-tert-Butoxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-one

25

(exo-53e). Colorless viscous oil;

[a

]

þ50.7 (c 1.00, CHCl₃)

reaction with (R)-a-methoxyphenylacetic acid.

D

(exo:endo¼95:5, 74% ee (exo)), IR (CHCl₃) 3426, 2971, 2333, 1720,

1452, 1421, 1366, 1232, 1191, 1145, 1098, 1066, 1039, 861, 843, 776,

4.5.11. 7-exo-Butoxy-5-ethyl-8-oxabicyclo[3.2.1]octan-2-one (exo-

20

721, 706 cm^ꢂ1; ¹H NMR (CDCl₃)

d

1.19 (9H, s), 1.52 (3H, s), 1.78 (1H,

54a). Colorless viscous oil; [

a]

ꢂ16.6 (c 1.00, CHCl₃) (exo:endo¼

D

ddd, J¼2.5, 8.0, 13.4 Hz), 1.84 (1H, m), 2.05 (1H, m), 2.29 (1H, ddd,

J¼8.5, 9.5,17.8 Hz), 2.40 (1H, dd, J¼8.0,13.4 Hz), 2.46 (1H, ddt, J¼7.8,

17.5, 2.0 Hz), 4.15 (1H, s), 4.17 (1H, dd, J¼3.2, 7.8 Hz); ¹³C NMR (CDCl₃)

>99:1, 79% ee (exo)), IR (CHCl₃) 3735, 3649, 3567, 2962, 2873, 2361,

1725, 1541, 1464, 1362, 1260, 1092, 1051, 901, 773, 760, 749 cm^ꢂ1; ¹H

NMR (CDCl₃)

d

0.91 (3H, t, J¼7.5 Hz), 1.36 (2H, sext, J¼7.5 Hz), 1.55

d

26.1 (CH₃), 28.29 (CH₃), 33.9 (CH₂), 36.1 (CH₂), 46.6 (CH₂), 74.6 (C),

(2H, m), 1.75–1.91 (4H, m), 2.04 (1H, m), 2.23 (1H, dd, J¼7.5,

13.6 Hz), 2.26 (1H, m), 2.51 (1H, ddt, J¼8.1, 17.6, 2.2 Hz), 3.36 (1H,

m), 3.44 (1H, m), 3.98 (1H, dd, J¼2.4, 7.3 Hz), 4.28 (1H, s); ¹³C NMR

75.1 (CH), 80.7 (C), 90.6 (CH), 206.2 (C); MS (EI) m/z 212 (M^þ), 167,

157, 149, 138, 127, 121, 112, 109, 97, 91, 84, 77, 69, 57, 37, 26, 13. Anal.

Calcd for C₁₂H₂₀O₃: C, 67.89; H, 9.50. Found: C, 67.63; H, 9.74. The

enantiomeric excess was determined by ¹H NMR analysis (87:13)

after conversion to the corresponding esters by the reduction with

(CDCl₃)

d 9.0 (CH₃), 14.0 (CH₃), 19.4 (CH₂), 31.7 (CH₂), 32.3 (CH₂),

33.6 (CH₂), 33,9 (CH₂), 41.8 (CH₂), 69.4 (CH₂), 82.3 (CH), 83.5 (C),

87.2 (CH), 206.2 (C); MS (EI) m/z 226 (M^þ), 223, 213, 185, 171, 154,

141, 126, 113, 85, 69, 54, 41, 27. Anal. Calcd for C₁₃H₂₂O₃: C, 68.99; H,

9.80%. Found: C, 68.73; H, 9.73%. The enantiomeric excess was

determined by ¹H NMR analysis (89.5:10.5) after conversion to the

corresponding acetals by the reaction with (R,R)-hydrobenzoin.

NaBH₄followed by the reaction with (R)-a-methoxyphenylacetic

acid.

4.5.7. 7-endo-tert-Butoxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-one

(endo-53e). Although endo-53e could not be separated by chro-

matography from a mixture with major exo-53e, it could charac-

4.5.12. 7-exo-Butoxy-5-isopropyl-8-oxabicyclo[3.2.1]octan-2-one

25

terize by ¹H NMR. ¹H NMR (CDCl₃)

d

1.13 (9H, s), 1.38 (3H, s), 1.91

(exo-55a). Colorless viscous oil;

[

a]

þ5.62 (c 1.00, CHCl₃)

D

(1H, dd, J¼3.9, 13.2 Hz), 1.97 (1H, m), 2.07 (1H, m), 2.22 (1H, ddd,

J¼1.2, 10.4, 13.2 Hz), 2.40 (1H, ddt, J¼7.0, 17.0, 1.7 Hz), 2.68 (1H, ddd,

J¼8.5, 11.7, 17.1 Hz), 4.11 (1H, dd, J¼1.2, 7.1 Hz), 4.48 (1H, ddd, J¼3.9,

7.1, 10.4 Hz).

(exo:endo¼> 99:1, 84% ee (exo)), IR (CHCl₃) 2963, 2875, 1724, 1468,

1370, 1232, 1094, 1055, 904, 789, 759, 752, 741, 717 cm^ꢂ1; ¹H NMR

(CDCl₃)

d

0.91 (3H, t, J¼7.6 Hz), 0.98 (3H, d, J¼7.1 Hz), 1.08 (3H, d,

J¼6.8 Hz), 1.36 (2H, m), 1.54 (2H, m), 1.73 (1H, ddd, J¼3.5, 8.0,

13.2 Hz), 1.87 (1H, m), 2.06 (2H, m), 2.22 (2H, m), 2.51 (1H, dddd,

J¼1.5, 3.5, 8.3, 17.4 Hz), 3.35 (1H, m), 3.43 (1H, m), 3.96 (1H, dd,

4.5.8. 7-exo-Cyclohexyloxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-

25

one (exo-53f). Pale yellow oil;

[

a]

þ28.3 (c 1.00, CHCl₃)

J¼2.4, 7.3 Hz), 4.30 (1H, s); ¹³C NMR (CDCl₃)

d 13.9 (CH₃), 17.7 (CH₃),

D

(exo:endo¼89:11, 73% ee (exo)), IR (CHCl₃) 3424, 3030, 2928, 2362,

1728, 1496, 1453, 1371, 1256, 1200, 1103, 1030, 924, 891, 701 cm^ꢂ1

¹H NMR (CDCl₃)

1.10–1.93 (10H, m), 1.53 (3H, s), 1.80 (1H, ddd,

17.8 (CH₃), 19.3 (CH₂), 30.1 (CH₂), 31.7 (CH₂), 33.9 (CH₂), 36,4 (CH),

40.9 (CH₂), 69.3 (CH₂), 82.1 (CH), 85.7 (C), 87.1 (CH), 207.5 (C); MS

(EI) m/z 240 (M^þ), 227, 213,197,184,171,157,141,125, 113, 96, 82, 67,

53, 40, 26, 13. Anal. Calcd for C₁₄H₂₄O₃: C, 69.96; H, 10.07%. Found:

C, 69.79; H, 10.19%. The enantiomeric excess was determined by ¹H

NMR analysis (92:8) after conversion to the corresponding acetals

by the reaction with (R,R)-hydrobenzoin.

;

d

J¼2.4, 8.3, 13.4 Hz), 1.88 (1H, m), 2.07 (1H, m), 2.25 (1H, ddd, J¼8.3,

9.7, 18.0 Hz), 2.38 (1H, dd, J¼7.6, 13.7 Hz), 2.47 (1H, ddt, J¼7.8, 17.6,

2.2 Hz), 3.26 (1H, m), 4.15 (1H, dd, J¼2.9, 7.5 Hz), 4.25 (1H, s); ¹³C

NMR (CDCl₃)

d 24.1 (CH₂), 24.2 (CH₂), 25.6 (CH₂), 26.0 (CH₃), 32.1

(CH₂), 32.8 (CH₂), 34.0 (CH₂), 36.2 (CH₂), 44.7 (CH₂), 76.9 (CH), 79.8

(CH), 80.6 (C), 88.8 (CH), 206.2 (C); MS (EI) m/z 238 (M^þ), 225, 211,

197, 173, 157, 141, 127, 114, 83, 70, 57, 41, 26, 13. Anal. Calcd for

C₁₄H₂₂O₃: C, 70.56; H, 9.30%. Found: C, 70.55; H, 9.33%. The enan-

tiomeric excess was determined by ¹H NMR analysis (86.6:13.4)

after conversion to the corresponding acetals by the reaction with

(R,R)-hydrobenzoin.

4.5.13. 7-exo-Butoxy-5-tert-butyl-8-oxabicyclo[3.2.1]octan-2-one

20

(exo-56a). Colorless viscous oil;

[

a

]

ꢂ13.6 (c 0.31, CHCl₃)

D

(exo:endo¼> 99:1, 82% ee (exo)), IR (CHCl₃) 2963, 2874, 1726, 1474,

1368, 1119, 790, 775, 760, 746, 722 cm^ꢂ^{1 1}H NMR (CDCl₃)

;

d

0.91

(3H, t, J¼7.6 Hz), 1.03 (9H, s), 1.36 (2H, sext, J¼7.6 Hz), 1.54 (2H, m),

1.69 (1H, m), 2.02 (1H, dd, J¼7.3, 13.9 Hz), 2.14 (1H, dd, J¼2.2,

13.9 Hz), 2.28 (2H, m), 2.51 (1H, m), 3.35 (1H, m), 3.41 (1H, m), 3.93

4.5.9. 7-endo-Cyclohexyloxy-5-methyl-8-oxabicyclo[3.2.1]octan-2-

one (endo-53f). Although endo-53f could not be separated by

chromatography from a mixture with major exo-53f, it could

(1H, dd, J¼2.2, 7.3 Hz), 4.28 (1H, s); ¹³C NMR (CDCl₃)

d 14.0 (CH₃),

19.4 (CH₂), 25.7 (CH₃), 29.7 (CH₂), 31.8 (CH₂), 34.3 (CH₂), 36,0 (C),

38.8 (CH₂), 69.1 (CH₂), 82.0 (CH), 87.2 (CH), 87.6 (C), 208.1 (C); MS

(EI) m/z 254 (M^þ), 239, 221, 197, 183, 169, 152, 141, 137, 123, 109, 97,

83, 71, 55, 37, 24, 12. Anal. Calcd for C₁₅H₂₆O₃: C, 70.83; H, 10.30%.

Found: C, 70.58; H, 10.49%. The enantiomeric excess was

characterize by ¹H NMR. ¹H NMR (CDCl₃)

d 1.09–1.98 (10H, m), 1.38

(3H, s), 1.98 (2H, m), 2.08 (1H, m), 2.23 (1H, ddd, J¼1.5, 13.4,

10.5 Hz), 2.43 (1H, ddt, J¼7.3, 17.0, 1.5 Hz), 2.68 (1H, ddd, J¼8.5, 11.7,

3088

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

determined by ¹H NMR analysis (91:9) after conversion to the

corresponding acetals by the reaction with (R,R)-hydrobenzoin.

80.4 (C), 85.5 (CH), 108.6 (C), 203.7 (C); Minor:

d

ꢂ3.0 (CH₃), ꢂ2.8

(CH₃), 14.1 (CH₃), 18.4 (C), 19.4 (CH₂), 25.8 (CH₃), 26.7 (CH₃), 31.9

(CH₂), 33.6 (CH₂), 37.7 (CH₂), 49.2 (CH₂), 63.7 (CH₂), 80.7 (C), 90.1

(CH), 109.1 (C), 203.9 (C); MS (EI) m/z 342 (M^þ), 287, 269, 243, 213,

184, 154, 131, 113, 93, 74, 46, 27. Anal. Calcd for C₁₈H₃₄O₄Si: C, 63.11;

H, 10.00%. Found: C, 62.91; H, 10.14%.

4.5.14. 7-exo-Butoxy-5-benzyl-8-oxabicyclo[3.2.1]octan-2-one (exo-

20

57a). Colorless viscous oil;

[

a]

ꢂ4.00 (c 0.30, CHCl₃)

D

(exo:endo¼98:2, 75% ee (exo)), IR (CHCl₃) 3424, 3030, 2928, 2362,

1728, 1496, 1453, 1371, 1256, 1200, 1103, 1030, 924, 891, 701 cm^ꢂ1

¹H NMR (CDCl₃)

;

d

0.91 (3H, t, J¼6.8 Hz), 1.33 (2H, m), 1.53 (2H, m),

4.5.18. 5-Methyl-7-exo-phenyl-8-oxabicyclo[3.2.1]octan-2-one (exo-

20

1.70 (1H, ddd, J¼2.2, 8.1, 12.9 Hz), 2.02 (2H, m), 2.18 (1H, ddd, J¼7.9,

9.6, 17.6 Hz), 2.27 (1H, dd, J¼7.6, 13.9 Hz), 2.43 (1H, ddt, J¼2.2, 8.1,

17.6 Hz), 3.10 (1H, d, J¼13.7 Hz), 3.13 (1H, d, J¼13.7 Hz), 3.32 (1H,

m), 3.41 (1H, m), 3.97 (1H, dd, J¼2.7, 7.6 Hz), 4.34 (1H, s), 7.21–7.32

62). Colorless viscous oil; [

a

]

þ29.9 (c 0.23, CHCl₃) (exo:endo¼

D

>99:1, 80% ee (exo)), IR (CHCl₃) 2970, 1724, 1034, 856, 540 cm^ꢂ1; ¹H

NMR (CDCl₃)

d

1.56 (3H, s), 1.97 (1H, dd, J¼4.4, 13.4 Hz), 1.98 (1H,

m), 2.15 (1H, m), 2.48 (1H, ddt, J¼8.1, 17.5, 2.0 Hz), 2.63 (1H, dd,

(5H, m); ¹³C NMR (CDCl₃)

d 14.0 (CH₃), 19.4 (CH₂), 31.8 (CH₂), 33.8

J¼9.8, 13.4 Hz), 3.35 (1H, dd, J¼4.4, 9.8 Hz), 4.23 (1H, s), 7.19–7.32

(CH₂), 33.9 (CH₂), 42.7 (CH₂), 45.7 (CH₂), 69.8 (CH₂), 82.3 (C), 83.2

(CH), 87.4 (CH), 126.6 (CH), 128.1 (CH), 130.0 (CH), 136.7 (C), 206.2

(C); MS (EI) m/z 280 (M^þ) 270, 231, 216, 205, 197, 186, 169, 157, 142,

131, 123, 115, 105, 91, 81, 67, 53, 37, 26, 16. Anal. Calcd for C₁₈H₂₄O₃:

C, 74.97; H, 8.39%. Found: C, 74.80; H, 8.40%. The enantiomeric

excess of the adduct was determined by HPLC analysis (DAICEL

Chiralpak OD-H, 1:99 i-PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC)

t_R¼27.0 min (major), 36.0 min (minor).

(5H, m); ¹³C NMR (CDCl₃)

d 25.9 (CH₃), 32.9 (CH₂), 37.1 (CH₂), 45.7

(CH₂), 48.9 (CH), 81.4 (C), 89.7 (CH), 126.5 (CH), 126.6 (CH), 128.6

(CH), 145.2 (C), 206.3 (C); MS (EI) m/z 216 (M^þ), 188, 167, 149, 131,

104, 79, 65, 42, 27. Anal. Calcd for C₁₄H₁₆O₂: C, 77.75; H, 7.46%.

Found: C, 77.77; H, 7.38%. The enantiomeric excess of the adduct

was determined by HPLC analysis (DAICEL Chiralpak AD-H, 1:99 i-

PrOH/hexane, ﬂow 0.5 mL/min, 35 ^ꢀC) t_R¼80.0 min (minor),

157.0 min (major).

4.5.15. 7-exo-Butoxy-5-phenyl-8-oxabicyclo[3.2.1]octan-2-one (exo-

Acknowledgements

20

58a). Colorless viscous oil; [

a

]

ꢂ9.00 (c 0.52, CHCl₃) (exo:endo¼

D

>99:1, 78% ee (exo)), IR (CHCl₃) 3010, 2960, 2873, 1727, 1496, 1449,

This work was supported in part by a Grant-in-Aid for Scientiﬁc

Research (nos. 17550097, 20550094, and 20200052) from the

Ministry of Education, Science and Culture, Japan.

1361, 1233, 1119, 1090, 1046, 909, 773, 759 cm^ꢂ^{1 1}H NMR (CDCl₃)

;

d

0.89 (3H, t, J¼7.3 Hz), 1.34 (2H, sext, J¼7.3 Hz), 1.52 (2H, m), 2.16–

2.34 (4H, m), 2.41 (1H, ddd, J¼8.5, 9.5, 17.5 Hz), 2.58 (1H, ddt, J¼2.4,

7.3, 17.5 Hz), 2.79 (1H, dd, J¼7.1, 13.7 Hz), 3.36 (1H, m), 3.45 (1H, m),

4.10 (1H, dd, J¼2.4, 7.5 Hz), 4.49 (1H, s); ¹³C NMR (CDCl₃)

d 13.9 (CH₃),

Supplementary data

19.4 (CH₂), 31.6 (CH₂), 34.2 (CH₂), 37.6 (CH₂), 44.7 (CH₂), 69.5 (CH₂),

82.1 (C), 84.0 (CH), 87.5 (CH),124.4 (CH),127.0 (CH),128.2 (CH),144.2

(C), 205.6 (C); MS (EI) m/z 274 (M^þ), 245, 203, 174, 146, 118, 109, 77,

60, 39. Anal. Calcd for C₁₇H₂₂O₃: C, 74.42; H, 8.08%. Found: C, 74.33;

H, 8.15%. The enantiomeric excess of the adduct was determined by

HPLC analysis (DAICEL Chiralpak AD-H, 1:99 i-PrOH/hexane, ﬂow

0.5 mL/min, 35 ^ꢀC) t_R¼96.0 min (minor), 185.0 min (major).

General methods and materials for additional experimental

section, additional experimental procedures, and ¹H and ¹³C NMR

spectra of the products (PDF). Supplementary data associated with

this article can be found in online version, at doi:10.1016/

j.tet.2010.01.095.

References and notes

4.5.16. 5,7-Dimethyl-7-methoxy-8-oxabicyclo[3.2.1]octan-2-one

25

(60). Colorless viscous oil; [

a

]

þ26.7 (c 0.10, CHCl₃) (81:19, mix-

1. For books and reviewes, see: (a) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996,

96, 223; (b) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward

Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley

and Sons: Hoboken, NJ, 2003.

2. Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem. Soc. 1990, 112, 3100.

3. For representative examples, see (a) Hodgson, D. M.; Bailey, J. M.; Villalonga-

Barber, C.; Drew, M. G. B.; Harrison, T. J. Chem. Soc., Perkin Trans. 1 2000, 3432;

(b) Nakamura, S.; Hirata, Y.; Kurosaki, T.; Anada, M.; Kataoka, O.; Kitagaki, S.;

Hashimoto, S. Angew. Chem., Int. Ed. 2003, 42, 5351; (c) Hirata, Y.; Nakamura, S.;

Watanabe, N.; Kataoka, O.; Kurosaki, T.; Anada, M.; Kitagaki, S.; Shiro, M.;

Hashimoto, S. Chem.dEur. J. 2006, 12, 8898.

4. Padwa, A.; Boonsombat, J.; Rashatasakhon, P.; Willis, J. Org. Lett. 2005, 7, 3725.

5. Nakamura, S.; Sugano, Y.; Kikuchi, F.; Hashimoto, S. Angew. Chem., Int. Ed. 2006,

45, 6532.

6. Geng, Z.; Chen, B.; Chiu, P. Angew. Chem., Int. Ed. 2006, 45, 6197.

7. (a) Mejı´a-Oneto, J. M.; Padwa, A. Org. Lett. 2006, 8, 3275; (b) Mejı´a-Oneto, J. M.;

Padwa, A. Helv. Chim. Acta 2008, 91, 285.

D

ture of diastereomer, 22% ee (major)), IR (CHCl₃) 3735, 2976, 1727,

1455, 1380, 1313, 1259, 1233, 1194, 1147, 1072, 858, 772, 758, 748,

722 cm^ꢂ^{1 1}H NMR (CDCl₃) Major:

; d 1.41 (3H, s), 1.48 (3H, s), 1.81

(1H, d, J¼13.1 Hz), 1.94 (1H, dd, J¼8.7, 13.3 Hz), 2.07 (1H, m), 2.27

(1H, d, J¼13.1 Hz), 2.44 (1H, ddt, J¼7.3, 17.3, 2.9 Hz), 2.69 (1H, ddd,

J¼8.5, 11.4, 17.3 Hz), 3.22 (3H, s), 3.87 (1H, s); ¹³C NMR (CDCl₃)

Major:

d 24.8 (CH₃), 26.9 (CH₃), 34.1 (CH₂), 37.6 (CH₂), 47.7 (CH₂),

52.4 (CH₃), 81.0 (C), 85.2 (C), 89.9 (CH), 205.6 (C); MS (EI) m/z 184

(M^þ), 155, 143, 124, 113, 99, 85, 73, 55, 43, 27, 15. Anal. Calcd for

C₁₀H₁₆O₃: C, 65.19; H, 8.75%. Found: C, 65.15; H, 8.73%. The enan-

tiomeric excess was determined by ¹H NMR analysis (61:39) after

conversion to the corresponding acetals by the reaction with (R,R)-

hydrobenzoin.

8. (a) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Tetrahedron Lett. 1997, 38, 6471;

(b) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Chem. Commun. 1999, 2185; (c)

Hodgson, D. M.; Stupple, P. A.; Pierard, F. Y. T. M.; Labande, A. H.; Johnstone, C.

Chem.dEur. J. 2001, 7, 4465; (d) Hodgson, D. M.; Labande, A. H.; Glen, R.;

Redgrave, A. J. Tetrahedron: Asymmetry 2003, 14, 921; (e) Hodgson, D. M.; Glen,

R.; Grant, G. H.; Redgrave, A. J. J. Org. Chem. 2003, 68, 581; (f) Hodgson, D. M.;

4.5.17. 7-Butoxy-7-(tert-butyldimethylsilyl)oxy-5-methyl-8-ox-

25

abicyclo[3.2.1]octan-2-one (61). Colorless viscous oil; [

a

]

þ2.75 (c

D

1.00, CHCl₃) (63:37, mixture of diastereomer), IR (CHCl₃) 2959,

2933, 2860, 1727, 1464, 1412, 1381, 1362, 1308, 1254, 1173, 1135,

´

Labande, A. H.; Pierard, F. Y. T. M.; Castro, M. A. E. J. Org. Chem. 2003, 68, 6153;

(g) Hodgson, D. M.; Bru¨ ckl, T.; Glen, R.; Labande, A. H.; Selden, D. A.; Dossetter,

A. G.; Redgrave, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5450; (h) Hodgson, D.

M.; Glen, R.; Redgrave, A. J. Tetrahedron: Asymmetry 2009, 20, 754.

1045, 790, 749, 728 cm^ꢂ1

;

¹H NMR (CDCl₃)

d

0.14 (3Hꢁ63/100, s,

Major), 0.16 (3Hꢁ63/100, s, Major), 0.18 (3Hꢁ37/100, s, Minor), 0.19

(3Hꢁ37/100, s, Minor), 0.84 (9H, s), 0.92 (3H, t, J¼7.3 Hz), 1.21–1.60

(6H, m), 1.44 (3Hꢁ37/100, s, Minor), 1.45 (3Hꢁ63/100, s, Major),

1.92 (1H, m), 2.09 (1H, m), 2.43 (1H, m), 2.60 (1H, m), 3.48 (2H, m),

4.05 (1Hꢁ37/100, s), 4.19 (1Hꢁ63/100, s); ¹³C NMR (CDCl₃) Major:

9. (a) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.; Watanabe, N.;

Hashimoto, S. J. Am. Chem. Soc. 1999, 121, 1417; (b) Kitagaki, S.; Yasugahira, M.;

Anada, M.; Nakajima, M.; Hashimoto, S. Tetrahedron Lett. 2000, 41, 5931; (c)

Tsutsui, H.; Shimada, N.; Abe, T.; Anada, M.; Nakajima, M.; Nakamura, S.;

Nambu, H.; Hashimoto, S. Adv. Synth. Catal. 2007, 349, 521; (d) Shimada, N.;

Anada, M.; Nakamura, S.; Nambu, H.; Tsutsuki, H.; Hashimoto, S. Org. Lett. 2008,

10, 3603; (e) Nambu, H.; Hikime, M.; Krishnamurthi, J.; Kamiya, M.; Shimada,

N.; Hashimoto, S. Tetrahedron Lett. 2009, 50, 3675.

d

ꢂ3.3 (CH₃), ꢂ3.0 (CH₃), 14.1 (CH₃), 18.1 (C), 19.4 (CH₂), 25.8 (CH₃),

26.5 (CH₃), 32.1 (CH₂), 33.6 (CH₂), 37.3 (CH₂), 49.7 (CH₂), 63.1 (CH₂),

H. Suga et al. / Tetrahedron 66 (2010) 3070–3089

3089

10. (a) Suga, H.; Inoue, K.; Inoue, S.; Kakehi, A. J. Am. Chem. Soc. 2002, 124, 14836;

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exo-cycloadducts are thermodynamically more stable than endo-cycloadducts,

and endo-53a is slightly more stable (0.81 kcal/mol) than the corresponding

exo-adduct.

18. Desimoni, G.; Faita, G.; Filippone, S.; Mella, M.; Zampori, M. G.; Zema, M.

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12. Absolute conﬁguration of the cycloadduct was not determined.

13. The endo-adduct is deﬁned as the product in which the more important sub-

stituent is on the opposite side of the epoxy bridge, whereas the exo-adduct

indicates the product in which the more important substituent is on the same

side as the epoxy bridge.

14. La(OTf)₃: quant yield, 52% ee; Sm(OTf)₃: 86% yield, 55% ee; Gd(OTf)₃: 69% yield,

60% ee; Tb(OTf)₃: 60% yield, 61% ee; Er(OTf)₃: 74% yield, 59% ee; Tm(OTf)₃:

quant yield, 64% ee; Lu(OTf)₃: 88% yield, 55% ee.

15. (4S,5S)-Pybox-Ph₂–Eu(OTf)₃(10 mol %), CH₂Cl₂, reﬂux: 89% yield, 44% ee;

(4S,5S)-Pybox-Ph₂–Yb(OTf)₃(10 mol %), CHCl₃, reﬂux: 71% yield, 45% ee.

16. (a) Suga, H.; Kakehi, A.; Mitsuda, M. Bull. Chem. Soc. Jpn. 2004, 77, 561; (b) Suga,

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Y.; Tsuchida, T.; Kakehi, A.; Baba, T. J. Org. Chem. 2009, 74, 1099.

17. Although the reason for the switch of the diastereoselectivity in this reaction is

not clear at this point, ﬂat structure of the carbonyl ylide for 2-benzopyryrium-

4-olates may inﬂuence the endo/exo selectivity by inhibition of steric hindrance

with vinyl esters. PM3 calculations (heat of formation) of 3f and 28f show that

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27. The reason for the improvement of enantioselectivity by the addition of basic

inorganic salts is not clear at this point. Considering the reactivity of allyl al-

cohol compared with allyl butyl ether in the presence of (4S,5S)-Pybox-Ph₂–

lanthanoid metal complexes, however, the role of the catalyst is probably not

only activation of the carbonyl ylide by coordination but also bring the re-

actants including allyl alcohol close together to achieve the appropriate tran-

sition state. The addition of basic inorganic salts may be attributed to the

favored coordination of allyl alcohol to the catalyst by hydrogen bonding of allyl

alcohol.

Article Doi

Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides catalyzed by chiral Lewis acids-Scope and limitations of diazo and olefinic substrates

DOI: 10.1016/j.tet.2010.01.095

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