Guide to enantioselective dirhodium(II)-catalyzed cyclopropanation with aryldiazoacetates Dedicated to Professor Melanie Sanford in recognition of her receipt of the Tetrahedron Young Investigator Award

ACCEPTED MANUSCRIPT

1

Graphical Abstract

To create your abstract, type over the instructions in the template box below.

Fonts or abstract dimensions should not be changed or altered.

Guide to Enantioselective Dirhodium(II)-

Catalyzed Cyclopropanation with

Aryldiazoacetates

Leave this area blank for abstract info.

a

b

Kathryn M. Chepiga, Changming Qin, Joshua S. Alford, Spandan Chennamadhavuni, Timothy M. Gregg,

a

Jeremy P. Olson, and Huw M. L. Davies *

a

Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA

Department of Chemistry and Biochemistry, Canisius College, Buffalo, NY 14208, USA

b

ACCEPTED MANUSCRIPT

1

Tetrahedron

journal homepage: www.elsevier.com

Guide to Enantioselective Dirhodium(II)-Catalyzed Cyclopropanation with

Aryldiazoacetates

Dedicated to Professor Melanie Sanford in recognition of her receipt of the Tetrahedron Young Investigator Award

a

Kathryn M. Chepiga, Changming Qin, Joshua S. Alford, Spandan Chennamadhavuni, Timothy M.

b

a

a*

Gregg, Jeremy P. Olson, and Huw M. L. Davies

a

Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA

Department of Chemistry and Biochemistry, Canisius College, Buffalo, NY 14208, USA

b

ARTICLE INFO

ABSTRACT

Article history:

Received

Catalytic enantioselective methods for the generation of cyclopropanes has been of long

standing pharmaceutical interest. Chiral dirhodium(II) catalysts prove to be an effective means

Received in revised form

Accepted

Available online

for the generation of diverse cyclopropane libraries. Rh

effective catalyst for asymmetric intermolecular cyclopropanation of methyl aryldiazoacetates

with styrene. Rh (S-PTAD) provides high levels of enantioinduction with ortho-substituted

aryldiazoacetates. The less-established Rh (R-BNP) plays a complementary role to Rh (R-

DOSP) and Rh (S-PTAD) in catalyzing highly enantioselective cyclopropanation of 3-

2 4

(R-DOSP) is generaally the most

2

4

2

4

2

Keywords:

Asymmetric cyclopropanation

Cyclopropanes

Donor/acceptor carbenoids

Dirhodium catalysis

Phenyldiazoacetate

4

2

4

methoxy-substituted aryldiazoacetates. Substitution on the styrene has only moderate influence

on the asymmetric induction of the cyclopropanation.

2

1. Introduction

2 4

substrate scope of Rh (R-DOSP) -catalyzed cyclopropanation is

quite broad in terms of both the trapping agent and the donor

The metal-catalyzed decomposition of diazo compounds in the

3,4,9-18

group on the carbenoid.

influence of the aryl substituent of the aryldiazoacetate on Rh

DOSP) -catalyzed cyclopropanation has not been conducted. The

second catalyst, Rh (S-PTAD) , is the optimal chiral catalyst

when the acceptor group in the donor/acceptor carbenoid is a

However, a detailed study on the

presence of alkenes is a general method for the stereoselective

(R-

1

,2

2

synthesis of cyclopropanes. We have previously shown the

rhodium-catalyzed cyclopropanation of donor/acceptor

carbenoids to be effective for the enantioselective synthesis of

4

2

4

3

-

cyclopropanes with one or more quaternary stereogenic centers.

19

20

21

22

phosphonate, trifluoromethyl, cyano, or keto group. Due to

the perceived superiority of Rh (R-DOSP) in the reactions of

aryldiazoacetates, Rh (S-PTAD) has not been thoroughly

evaluated in the reactions of this class of carbenoid precursor.

The third catalyst, Rh (R-BNP) , is an interesting catalyst of D

symmetry that has been applied to a number of carbenoid

6

As many cyclopropyl amines are known to have significant

7

,8

2

4

CNS activity,

cyclopropanation

diarylcyclopropylamines as potential therapeutic agents (Scheme

). For the methodology to be broadly useful in drug discovery,

we have initiated a program to use our

2

4

methodology to access novel

2

4

-

1

access to a range of diarylcyclopropyl derivatives with high

levels of enantioenrichment is required. Herein, we define the

optimal catalysts for the cyclopropanation with various types of

methyl aryldiazoacetates.

23-27

reactions,

but has not been previously evaluated in the

cyclopropanation of donor/acceptor carbenoids.

Scheme 1. Route to cyclopropyl amines from aryldiazoacetates

Three chiral dirhodium-(II) catalysts were selected for this

2 4

study (Figure 1). The first catalyst, Rh (R-DOSP) , is considered

to be the optimal catalyst for the reactions of donor/acceptor

carbenoids when the acceptor group is a methyl ester. The

1

,4

Figure 1. Dirhodium-(II) catalysts used in this study

ACCEPTED MANUSCRIPT

2

2. Results and Discussion

BNP)₄gave <60% ee in the cyclopropanation reactions of

unsubstituted or 4-substituted aryldiazoacetates with these same

substrates. The one exception, however, is the reaction of 4-

The study began by exploring the effect of aryl substitution

on the enantioselectivity in the cyclopropanation of styrene by

aryldiazoacetates. The results for a series of aryldiazoacetates

methoxyphenyldiazoacetate 1e with Rh

the cyclopropane 3e in exceptionally high enantioselectivity

entry 5, 96% ee). Rh (R-DOSP) also performed well in the

2 4

(S-PTAD) , which gave

(

1a-l) using the three chiral dirhodium catalysts Rh

2 4

(R-DOSP) ,

(

2

4

Rh (S-PTAD) and Rh (R-BNP)₄are summarized in Table 1.

2

4

2

reactions of 2-substituted aryldiazoacetates 1f (entry 6, 92% ee)

and 1g (entry 7, 86% ee), and moderately well with 3,4-

dichlorophenyldiazoacate 1h (entry 8, 82% ee), confirming that

Excellent levels of diastereoselectivity were achieved in all cases

>95:5 dr) and the isolated yields of the cyclopropanes were

(

generally high, ranging from 63-98%. The absolute configuration

of the major isomer of the cyclopropanes is tentatively assigned

Rh

2

(R-DOSP)

4

is the optimal catalyst for

a

range of

aryldiazoacetates. The enantioselection with Rh

2

(S-PTAD) is

4

2

8

as 1S,2R.

Rh

2

(R-DOSP)

4

provided high levels of

extremely variable. However, in certain cases, it provides

exceptional levels of enantioselectivity, as seen in the reaction

with 2-chlorophenyldiazoacetate 1f, which generates the

cyclopropane 3f in 97% ee (entry 6).

enantioinduction when unsubstituted (1a) or 4-substituted (1b-e)

methyl aryldiazoacetates were employed as substrates (Table 1,

2 4 2

entries 1-5, 87-90% ee). In general, Rh (S-PTAD) and Rh (R-

Table 1. Examination of the influence of substitution on aryldiazoacetate

N2

Ph

2

CO2Me

1

mol% Rh(II) catalyst

Ar

CO2Me

a-l

Ph

Ar

1

solvent, rt

3a-l

Rh2(R‐DOSP)4^a

yield (%) ee (%)

Rh (S‐PTAD)

a

Rh2(R‐BNP)4^b

yield (%) ee (%)

2

4

entry

1

Ar

product

yield (%)

ee (%)

3a

85

84

88

87

87^b

77^c

21^b

72

69

42

51

2

3

4

5

3b

3c

3d

3e

46^c

77^c

48^c

96^c

67^c

71^c

93^c

80

89

84

57

F₃C

Cl

93

87

66

88

MeO

90

6

3f

89

92

80^c

97^c

78

51

Cl

7

8

9

3g

92

86

87^c

88^b

70^c

80^c

60^b

94^c

69

82

93

27

63

97

OMe

Cl

88^b

74

82^b

56

3h

MeO

3i

MeO

1

0

1

3j

78^b

79^b

72^b

16^b

82

88

85^b^,^c

28^b^,^c

85^b^,^c

3^b^,^c

69^c

92^c

3k

OMe

MeO

1

2

3l

98^b

34^b

95^b

9^b

63

90

a

b

c

pentane, toluene, 0.5 mol% catalyst loading

ACCEPTED MANUSCRIPT

3

2 4

Interestingly, Rh (R-DOSP) fails to provide high levels of

enantioinduction when the aryldiazoacetate contains a 3-methoxy

substituent (1i-l) (entries 9-12), especially when the ring is

polysubstituted (1i, k-l). In these cases, the cyclopropanes 3i, k-l

styrenes (4a-g) with 1i gave 5a-g with modest levels of

enantioselectivity (48-67% ee).

are produced in 28-56% ee (entries 9, 11-12). Rh

2

(S-PTAD)

4

is

Table 3. Substrate Scope of Styrene with Rh (R-BNP)₄

2

an effective catalyst only in the case of 3,4-

dimethoxyphenyldiazoacetate 1i, generating the cyclopropane 3i

N2

Ar

4a-g

2

CO Me

MeO

OMe

in 94% ee (entry 9). In contrast, Rh

2

(R-BNP)

4

is an extremely

CO2Me

Ar

0

.5mol% Rh2(R‐BNP)4

effective catalyst with all of the 3-methoxy substituted

aryldiazoacates 1i-l, generating the cyclopropanes 3i-l in 88-97%

ee (entries 9-12).

toluene, rt

1i

5a-g

Rh (R‐BNP)

Rh (R‐DOSP)

2 4

2

4

entry

Ar

product

yield (%) ee (%)

One of the most attractive features of Rh

(S-PTAD) as chiral catalysts is that they are capable of

operating at low catalyst loadings. As Rh

to be the optimal catalyst for 3-methoxyaryldiazoacetate

derivatives, we investigated whether it could also operate at low

catalyst loading. Reactions of aryldiazoacetate 1i, with

2 4

(R-DOSP) and

Rh

2

4

2

9

2

(R-BNP)

4

was found

1

2

3

5a

76

90

80

90

88

90

47

50

82

64

67

62

5b

5c

successively lower loadings of Rh

2 4

(R-BNP) are summarized in

Table 2. Rh (R-BNP) was effective at catalyzing highly

2

4

enantioselective cyclopropanation with catalyst loadings of 1.0

and 0.5 mol%, providing 3i with virtually the same level of

enantioselectivity (entry 1 vs. 2, 97% ee vs. 96% ee). When the

catalyst loading was decreased further to 0.1 mol% a more

significant drop in the level of enantioselectivity was observed

MeO

O2N

4

5d

94

80

28

50

(

entry 3, 91% ee). Further decreasing the catalyst loading to 0.01

mol%, however, caused a dramatic decrease in enantioinduction

entry 4, 40% ee). These results suggest that, although Rh (R-

BNP) is capable of moderately high turnover numbers (TONs), it

may not be as robust a catalyst as Rh (R-DOSP) or Rh (S-

PTAD) , which are capable of TONs as high as 850,000 and

,800,000

cyclopropanation.

5

6

5e

5f

90

81

90

19

49

63

67

(

2

F3C

Cl

4

2

4

2

89

4

1

respectively

in

asymmetric

intermolecular

2

9

Cl

7

5g

72

86

79

48

Table 2. Examination of Rh

2

4

(R-BNP) Loading

These studies reveal subtle differences in the ability of the

chiral dirhodium tetracarboxylate catalysts to induce high

enantioselectivity in the cyclopropanation of styrenes, as

summarized in Table 4. The previous expectation that Rh (R-

2

DOSP)

4

would give high asymmetric induction for all

aryldiazoacetates was found not to be true, although it was found

TnQTable7Table 4. A Guide to Chiral Dirhodium-(II) Catalyzed

Cyclopropanation

Ph

N2

2

CO2Me

Ar

0

.5‐1 mol% Rh(II) catalyst

Ar

CO2Me

Ar

Ph

solvent, rt

3a-l

1a-l

6

8

3‐93% yield

0‐97% ee

At the onset of this study, the asymmetric induction of the

cyclopropanation was not expected to be heavily influenced by

the functionality on the aryldiazoacetate. Having observed

considerable variation in enantioselectivity depending on the

nature of the aryl group, we decided to explore the effect of

modifying the substitution on the styrene. These studies were

catalyst

yield (%)

ee (%)

R

Rh2(R-DOSP)4

66‐93

82‐92

R'

R=H, Cl

R'=H, alkyl, Cl, OMe

focused on Rh

2

(R-BNP)

4

-catalyzed cyclopropanation with the

(R-

4

had not been previously evaluated as a catalyst for this

3

,4-dimethoxyphenyldiazoacetate 1i (Table 3), because Rh

2

BNP)

transformation. The levels of enantioselectivity in the

cyclopropanation under Rh (R-BNP) -catalyzed conditions were

found to be moderately influenced by the functionality on the

styrene, as the cyclopropanes 5a-g were obtained with uniformly

high levels of enantioinduction (80-90% ee). Previous studies

Rh2(S‐PTAD)4

Rh2(R‐BNP)4

80‐87

63‐93

80‐97

88‐97

R

2

4

R=Cl, OMe

MeO

R

have shown that Rh

also not especially influenced by the nature of the styrene

the Rh (R-DOSP) -catalyzed cyclopropanation of a range of

2 4

(R-DOSP) -catalyzed cyclopropanation is

3,4,9

and

R

R=H, OMe

2

4

ACCEPTED MANUSCRIPT

4

to be the most effective catalyst for the broadest range of

substituted methyl aryldiazoacetates. In spite of the fact that

Rh (S-PTAD) is the most consistent catalyst when the acceptor

group of the donor/acceptor carbenoid is modified,

of enantioselectivity was found to be highly variable when aryl

substitution of the aryldiazoacetate was modified. In particular,

4.2 General Procedure for the Synthesis of Methyl

31

Phenyldiazoacetates

2

4

1

9-22

The methyl arylacetate (1 equiv.) and p-ABSA (1.3 equiv.)

were dissolved in acetonitrile and cooled to 0 °C using an ice

bath under an argon atmosphere. 1,8-Diazabicycloundec-7-ene

the level

(

DBU, 1.3 equiv.) was then added to the stirring mixture over the

Rh

2

(S-PTAD)

4

was very effective with 2-chlorophenyl

(R-BNP) becomes the best

course of 5 minutes. After the addition of the DBU, the reaction

mixture continued to stir at 0 °C for an additional 15 minutes.

Once this allotted time had passed, the ice bath was removed and

the reaction mixture was stirred for 24 hours at room

temperature. The resulting orange solution was quenched with

aryldiazoacetate derivative. Rh

2

4

catalyst for 3-methoxyphenyl-substituted aryldiazoacetate

derivatives. The cause for these subtle variations, at this stage, is

not well understood. There is no clear steric or electronic trend to

define which catalyst will perform best in a given system, which

suggests the asymmetric induction may involve a combination of

factors including π-stacking interactions. Computational studies

are in progress to develop a rational model to explain these

trends.

saturated NH

ether (3x). The organic layer was then washed with deionized

O to remove any residual salts. The combined organic layers

were dried over MgSO and filtered. The organic layer was then

4

Cl and the aqueous layer was extracted with diethyl

H

2

4

concentrated under reduced pressure. The residue was purified

via flash chromatography on silica gel (10:1 Hexanes:EtOAc).

3. Conclusion

This study provides guidelines for choosing the optimal chiral

4.3 General Procedure for the Synthesis of Methyl

dirhodium-(II) catalyst for cyclopropanation of aryldiazoacetates.

The nature of the aryl group on the aryldiazoacetate strongly

affects the asymmetric induction imparted by the three catalysts

Phenylcyclopropanecarboxylates with Rh

2 4

(R-DOSP)

In a 25-mL round bottom flask (Flask A) equipped with a

magnetic stir bar, styrene (5 equiv.) and Rh (R-DOSP) (0.01

equiv.) were dissolved in dry, degassed pentane (3 mL). The

reaction mixture was then degassed using vacuum/argon cycles

2

4

studied. Depending on the aryl substituent, Rh

2 4

(R-DOSP) ,

Rh (S-PTAD) , or Rh (R-BNP) can be utilized to obtain the

2

4

2

4

desired cyclopropane with a high level of enantioinduction. In

contrast, the functionality on the styrene has only moderate

influence on the level of asymmetric induction in

cyclopropanation reactions. These studies set the chemical

foundation for our ongoing studies to develop therapeutically

useful diarylcyclopropylamines, the results of which will be

reported in due course.

(

x3). In a separate 25-mL round bottom flask (Flask B), the

methyl phenyldiazoacetate (0.5 mmol, 1 equiv.) was dissolved in

dry, degassed pentane (5 mL) and degassed using vacuum/argon

cycles (x3). The contents in Flask B were then added to Flask A

using a syringe pump for the duration of 1 hour. After the

addition, the reaction mixture continued to stir for 1 additional

hour. Once the allotted time had passed, the reaction mixture

was concentrated under reduced pressure and purified using silica

gel column chromatography (increasing gradient starting at 10:1

Hexanes:EtOAc).

4. Experimental Section

4.1 General: All reactions were conducted under anhydrous

conditions in oven-dried glassware under an inert atmosphere of

dry argon, unless otherwise stated. Hexanes, pentane, and

toluene were dried by a solvent purification system (passed

through activated alumina columns). All solvents were degassed

by bubbling argon through the solvent for a minimum of 10

4.4 General Procedure for the Synthesis of Methyl

Phenylcyclopropanecarboxylates with Rh (S-PTAD)₄

2

In a 25-mL round bottom flask (Flask A) equipped with a

magnetic stir bar, styrene (5 equiv.) and Rh (S-PTAD) (0.005

2 4

equiv.) were dissolved in dry, degassed pentane (3 mL). The

reaction mixture was then degassed using vacuum/argon cycles

minutes prior to use. Unless otherwise noted, all other reagents

1

were obtained from commercial sources and used as received.

H

(

x3). In a separate 25-mL round bottom flask (Flask B), the

Nuclear Magnetic Resonance (NMR) spectra were recorded at

00 MHz or 600MHz. Data presented as follows: chemical shift

in ppm on the δ scale relative to δH 7.27 for the residual protons

in CDCl ), coupling constant (J/Hz), integration. Coupling

constants were taken directly from the spectra and are

methyl phenyldiazoacetate (0.5 mmol, 1 equiv.) was dissolved in

dry, degassed pentane (5 mL) and degassed using vacuum/argon

cycles (x3). The contents in Flask B were then added to Flask A

using a syringe pump for the duration of 1 hour. After the

addition, the reaction mixture continued to stir for 1 additional

hour. Once the allotted time had passed, the reaction mixture

was concentrated under reduced pressure and purified using silica

gel column chromatography (increasing gradient starting at 10:1

Hexanes:EtOAc).

4

(

3

1

3

uncorrected. C NMR spectra were recorded at 100 MHz and all

chemical shift values are reported in ppm on the δ scale, with an

internal reference of δC 77.23 for CDCl

3

.

Mass spectral

determinations were carried out by using APCI as ionization

source. Melting points are uncorrected. Infrared spectral data

-

1

are reported in units of cm . Analytical TLC was performed on

silica gel plates using UV light. Flash column chromatography

was performed on silica gel 60Å (230-400 mesh). Optical

rotations were measured on Jasco polarimeters. Analytical

enantioselective chromatographies were measured on Varian

Prostar instrument and used isopropanol:hexane as gradient.

Chiral HPLC conditions were determined by obtaining separation

4

.5 General Procedure for the Synthesis of Methyl

Phenylcyclopropanecarboxylates with Rh (R-BNP)

2

4

In a 25-mL round bottom flask (Flask A) equipped with a

magnetic stir bar, styrene (5 equiv.) and Rh (R-BNP) (0.01

equiv.) were dissolved in dry, degassed toluene (3 mL). The

reaction mixture was then degassed using vacuum/argon cycles

2

4

(

x3). In a separate 25-mL round bottom flask (Flask B), the

2 4

of the racemic product. Rh (R/S-DOSP) was employed as the

methyl phenyldiazoacetate (0.5 mmol, 1 equiv.) was dissolved in

dry, degassed pentane (5 mL) and degassed using vacuum/argon

cycles (x3). The contents in Flask B were then added to Flask A

using a syringe pump for the duration of 1 hour. After the

addition, the reaction mixture continued to stir for 1 additional

hour. Once the allotted time had passed, the reaction mixture

catalyst in the racemic reactions. Styrene (2) and substituted

styrenes (4a-f) were commercially available and purified by

pushing through a silica-filled pipette prior to use. Rh

2

(R-

4 2 4 2 4

DOSP) , Rh (S-PTAD) , Rh (R-BNP) , aryldiazoacetates 1a-

30

3

19

23

2

l, and styrene 4g were all synthesized according published

procedures.

ACCEPTED MANUSCRIPT

5

was concentrated under reduced pressure and purified using silica

gel column chromatography (increasing gradient starting at 10:1

Hexanes:EtOAc).

174.1, 136.1, 133.7, 133.4, 133.2, 128.3, 128.2, 128.1, 126.8,

52.9, 36.9, 33.4, 20.6; IR (film): 3031, 2951, 1717, 1493, 1255;

+

HRMS (APCI) calcd for C17

87.0833.

H

16

O

2

Cl (M+H) 287.0833 found

2

4

.1.1. (1R,2S)-methyl 1,2-diphenylcyclopropanecarboxylate (3a).

Title compound was prepared by general procedure and obtained

as a white solid. 85% yield for Rh (R-DOSP) ; 87% yield for

Rh (S-PTAD) ; 72% yield for Rh (R-BNP) ; HPLC: (Chiralcel

4.1.5.

(1S,2R)-methyl

1-(4-methoxyphenyl)-2-

phenylcyclopropanecarboxylate (3e). Title compound was

prepared by general procedure and obtained as a white solid.

2

4

2

4

2

4

SS-WHELK, 1% i-PrOH in hexane, 1.0 mL/min, 1 mg/mL, 30

min, λ = 254 nm) retention times of 8.62 min (major) and 10.22

66% yield for Rh

2

(R-DOSP)

4 2 4

; 93% yield for Rh (S-PTAD) ; 84%

yield for Rh (R-BNP)

2

4

; HPLC: (Chiralcel OD-H, 0.7% i-PrOH in

min (minor), 88% ee for Rh

PTAD) ; 42% ee for Rh (R-BNP)

acetate 10:1); H NMR (600 MHz, CDCl

2

(R-DOSP)

4

; 21% ee for Rh

= 0.25 (hexane: ethyl

) δ 7.12-7.11 (m, 3H),

.05-7.01 (m, 5H), 6.77-6.75 (m, 2H), 3.70 (s, 3H), 3.11 (dd, J =

.2, 9.3, 1H), 2.13 (dd, J = 4.8, 9.3, 1H), 1.88 (dd, J = 4.8, 7.2,

2

(S-

hexanes, 1.0 mL/min, 1mg/mL, 30 min, λ = 254 nm) retention

times of 11.97 min (major) and 17.71 min (minor), 90% ee for

4

2

4

;

R

f

1

3

Rh

BNP)

chloroform); H NMR (400 MHz; CDCl

2

(R-DOSP)

4

; 96% ee for Rh

2

(S-PTAD)

4

; 57% ee for Rh

2

(R-

= 5.1° (c = 1,

3

) δ 7.10-7.07 (m, 3H),

20

+

7

4

;

R

f

= 0.39 (4:1 Hexanes:EtOAc); [α]

D

1

7

1

13

H); C NMR (100 MHz, CDCl

3

) δ 174.5, 136.5, 134.9, 132.1,

6.95 (d, J = 8.8 Hz, 2H), 6.80-6.77 (m, 2H), 6.68 (d, J = 8.8 Hz,

2H), 3.74 (s, 3H), 3.68 (s, 3H), 3.09 (dd, J = 9.2 and 7.6 Hz, 1H),

2.14 (dd, J = 9.2 and 4.8 Hz, 1H), 1.84 (dd, J = 7.2 and 4.8 Hz,

1

28.2, 127.9, 127.2, 126.5, 52.8, 37.6, 33.3, 20.7; Data are

5

,6

consistent with the literature.

1

3

1

H); C NMR (100 MHz, CDCl

3

) δ 174.9, 158.6, 136.7, 133.1,

4.1.2.

(1S,2R)-methyl

2-phenyl-1-(p-

128.3, 127.9, 127.0, 126.5, 113.4, 55.3, 52.8, 36.9, 33.4, 21.0; IR

tolyl)cyclopropanecarboxylate (3b).

Title compound was

(

film): 3031, 2951, 2836, 1715, 1515, 1245; HRMS (APCI) calcd

+

prepared by general procedure and obtained as a white solid.

4% yield for Rh (R-DOSP) ; 77% yield for Rh (S-PTAD) ; 69%

yield for Rh (R-BNP) ; HPLC: (Chiralcel SS-WHELK, 1% i-

for C18

H

19

O

3

(M+H) 283.1329 found 283.1328.

8

2

4

2

4

2

4

4.1.6.

(1S,2R)-methyl 1-(2-chlorophenyl)-2-

PrOH in hexane, 1.0 mL/min, 1 mg/mL, 30 min, λ = 254 nm)

phenylcyclopropanecarboxylate (3f). Title compound was

retention times of 10.57 min (major) and 14.13 min (minor), 87%

prepared by general procedure and obtained as a transparent oil.

ee for Rh

Rh (R-BNP)

, chloroform); H NMR (400 MHz; CDCl

.98-6.92 (m, 4H), 6.82-6.80 (m, 2H), 3.69 (s, 3H), 3.12 (dd, J =

.2 and 7.2 Hz, 1H), 2.27 (s, 3H), 2.16 (dd, J = 9.6 and 4.8 Hz,

2

(R-DOSP)

4

;

46% ee for Rh

2

(S-PTAD)

4

; 51% ee for

89% yield for Rh

2

(R-DOSP)

4 2 4

; 80% yield for Rh (S-PTAD) ; 78%

2

0

+

2

4

; R = 0.44 (4:1 Hexanes:EtOAc); [α]

f

D

: 17.2° (c.

) δ 7.11-7.07 (m, 3H),

yield for Rh (R-BNP)

2

4

; HPLC: (Chiralcel OJ-H, 0.5% i-PrOH in

1

6

9

1

3

hexanes, 1.0 mL/min, 1mg/mL, 30 min, λ = 254 nm) retention

times of 11.47 min (major) and 15.27 min (major), 92% ee for

Rh (R-

BNP) : 61.8 (c. 1,

3

chloroform); H NMR (300 MHz; CDCl ) δ 7.18-7.02 (m, 7H),

2

(R-DOSP)

4

; 97% ee for Rh

2

(S-PTAD)

4

; 51% ee for Rh

2

1

3

20

H), 1.88 (dd, J = 7.2 and 4.8 Hz, 1H); C NMR (100 MHz,

4

;

R

f

= 0.43 (4:1 Hexanes:EtOAc); [α]

D

1

CDCl

3

) δ 174.8, 136.8, 136.7, 131.9, 131.8, 128.7, 128.3, 127.9,

1

2

26.5, 52.9, 37.3, 33.4, 21.4, 20.9; IR (film): 3028, 2950, 1716,

6.84-6.76 (m, 2H), 3.68 (s, 3H), 3.13 (t, J = 8.7 Hz, 1H), 2.10 (m,

1H), 1.91 (dd, J = 7.2 and 5.1 Hz, 1H); C NMR (100 MHz,

+

13

255; HRMS (APCI) calcd for C18

67.1380

H

19

O

2

(M+H) 267.1380 found

CDCl

3

) δ 173.6, 137.5, 133.5, 129.6, 128.9, 128.2, 127.6, 126.6,

1

26.4, 52.9, 33.5, 29.9, 21.7; IR (film): 3031, 2950, 1718, 1251,

4

.1.3.

(1S,2R)-methyl

2-phenyl-1-(4-

+

16 2

694; HRMS (APCI) calcd for C17H O Cl (M+H) 287.0833

(

trifluoromethyl)phenyl)cyclopropanecarboxylate (3c).

compound was prepared by general procedure and obtained as a

transparent oil. 93% yield for Rh (R-DOSP) ; 67% yield for

Rh (S-PTAD) ; 80% yield for Rh (R-BNP) ; HPLC: (Chiralcel

OD-H, 0.5% i-PrOH in hexanes, 1.0 mL/min, 1mg/mL, 30 min, λ

254 nm) retention times of 8.27 min (minor) and 10.34 min

Title

found 287.0833.

2

4

4.1.7.

(1S,2R)-methyl

1-(2-methoxyphenyl)-2-

2

4

2

4

phenylcyclopropanecarboxylate (3g). Title compound was

prepared by general procedure and obtained as a white solid.

92% yield for Rh

=

2

4 2 4

(R-DOSP) ; 87% yield for Rh (S-PTAD) ; 69%

(

5

1

=

major), 87% ee for Rh

2

(R-DOSP)

; R = 0.44 (4:1 Hexanes:EtOAc); [α]

9.1 (c. 1, chloroform); H NMR (400 MHz; CDCl

8 Hz, 2H), 7.12 (d, J = 8 Hz, 2H), 7.06 (m, 3H), 6.74 (m, 2H),

.66 (s, 3H), 3.14 (dd, J = 9.6 and 7.6 Hz, 1H), 2.17 (dd, J = 9.2

4

; 77% ee for Rh

2

(S-PTAD)

4

;

:

yield for Rh (R-BNP)

in hexanes, 1.0 mL/min, 1mg/mL, 30 min, λ = 254 nm) retention

times of 11.65 min (minor) and 14.00 min (major), 86% ee for

2

4

; HPLC: (SS-WHELK column, 1% i-PrOH

2

0

7% ee for Rh

2

(R-BNP)

4

f

D

1

3

) δ 7.36 (d, J

Rh

BNP)

chloroform); H NMR (400 MHz; CDCl

2

(R-DOSP)

4

; 80% ee for Rh

2

(S-PTAD)

4

; 27% ee for Rh

2

(R-

133.3° (c. 1,

3

) δ 7.19-7.10 (m, 2H),

20

+

3

4

; R = 0.45 (4:1 Hexanes:EtOAc); [α] :

f

D

13

1

and 5.2 Hz, 1H), 1.88 (dd, J = 7.2 and 5.2 Hz, 1H); C NMR

100 MHz, CDCl ) δ 173.9, 139.2, 135.8, 132.4, 128.1, 126.9,

25.0, 124.9, 124.8, 124.7, 53.0, 37.2, 33.5, 20.4; IR (film):

032, 2954, 1719, 1501, 1322, 1257; HRMS (APCI) calcd for

(

1

3

7.04-6.98 (m, 3H), 6.86 (td, J = 7.6, 1.1 Hz, 1H), 6.81-6.74 (m,

2H), 6.53 (d, J = 8 Hz, 1H), 3.65 (s, 3H), 3.36 (s, 3H), 3.24 (dd, J

= 9.6 and 7.6 Hz, 1H), 1.98 (dd, J = 9.2 and 4.8 Hz, 1H), 1.85

+

13

C

18

H

16

O

2

F

3

(M+H) 321.1097 found 321.1097

(dd, J = 7.2 and 4.8 Hz, 1H); C NMR (100 MHz, CDCl

3

) δ

1

2

74.7, 159.2, 137.0, 131.8, 128.9, 127.9, 127.3, 126.1, 124.1,

20.1, 110.5, 55.2, 52.7, 34.3, 32.6, 20.8; IR (film): 3030, 2950,

835, 1716, 1496, 1242; HRMS (APCI) calcd for C18

4

.1.4.

(1S,2R)-methyl 1-(4-chlorophenyl)-2-

phenylcyclopropanecarboxylate (3d). Title compound was

prepared by general procedure and obtained as a transparent oil.

19 3

H O

+

(

M+H) 283.1329 found 283.1329.

87% yield for Rh

2

(R-DOSP)

4 2 4

; 71% yield for Rh (S-PTAD) ; 89%

yield for Rh (R-BNP)

2

4

; HPLC: (Chiralcel OJ-H, 1% i-PrOH in

4.1.8. (1S,2R)-methyl

1-(3,4-dichlorophenyl)-2-

hexanes, 1.0 mL/min, 1mg/mL, 30 min, λ = 254 nm) retention

phenylcyclopropanecarboxylate (3h).

Title compound was

times of 8.62 min (minor) and 12.58 min (major), 88% ee for

prepared by general procedure and obtained as a clear oil; 88%

yield for Rh (R-DOSP) ; 88% yield for Rh (S-PTAD) ; 82%

yield for Rh (R-BNP) ; HPLC: (Chiralcel OD-H, 1% i-PrOH in

hexane, 1 mL/min, 1 mg/mL, 30 min, λ = 254 nm) retention

times of 7.54 min (minor) and 9.78 min (major), 82% ee for

Rh

BNP)

chloroform); H NMR (300 MHz; CDCl

.95 (d, J = 8.7 Hz, 2H), 6.79-6.76 (m, 2H), 3.67 (s, 3H), 3.12

dd, J = 9.3 and 7.5 Hz, 1H), 2.15 (dd, J = 9.3 and 4.8 Hz, 1H),

2

(R-DOSP)

4

; 48% ee for Rh

2

(S-PTAD)

4

; 57% ee for Rh

2

(R-

: 4.8 (c. 1,

) δ 7.12-7.06 (m, 5H),

2

4

2

4

2

0

4

; R = 0.56 (4:1 Hexanes:EtOAc); [α]

f

D

2

4

1

3

6

(

1

Rh

BNP)

2

(R-DOSP)

4 2 4 2

; 60% ee for Rh (S-PTAD) ; 63% ee for Rh (R-

13

20 _ o

.85 (dd, J = 7.2 and 4.8 Hz, 1H); C NMR (100 MHz, CDCl

3

) δ

4

; R = 0.23 (Hexane:EtOAc = 7:1); [α] D: 8.1 (c = 1.60,

f

ACCEPTED MANUSCRIPT

6

1

CHCl

3

); H NMR (400 MHz, CDCl

3

): δ 7.18-7.16 (m, 2H), 7.14-

4.1.12.

(1S,2R)-methyl

2-phenyl-1-(3,4,5-

7

.10 (m, 3H), 6.82-6.79 (m, 3H), 3.68 (s, 3H), 3.14 (dd, J = 9.2,

.6 Hz, 1H), 2.15 (dd, J = 9.2, 4.8 Hz, 1H), 1.84 (dd, J = 7.6, 5.2

trimethoxyphenyl)cyclopropanecarboxylate (3l). Title compound

was prepared by general procedure and obtained as a yellow oil.

1

3

Hz, 1H); C NMR (100 MHz, CDCl

3

) δ 173.3, 135.3, 135.2,

33.7, 131.6, 131.4, 131.2, 129.6, 128.0, 127.9, 126.8, 52.8, 36.3,

3.3, 20.2; IR (film): 2925, 1719, 1257, 1163, 695; HRMS (ESI)

98% yield for Rh

2

4 2 4

(R-DOSP) ; 95% yield for Rh (S-PTAD) ; 63%

1

3

yield for Rh (R-BNP)

2

4

; HPLC: (Chiralcel OD-H, 6% i-PrOH in

hexane, 1 mL/min, 1 mg/mL, 30 min, λ = 254 nm), retention

times of 10.78 min (minor) and 11.79 min (minor), 34% ee for

+

calcd for C17

H

13

O

2

Cl

2

(M-H) 319.0293 found 319.0299.

Rh

BNP)

2

6

2

(R-DOSP)

; R = 0.20 (hexane: ethyl acetate 5:1); [α]

.02, CHCl

.81-6.78 (m, 2H), 6.16 (s, 2H), 3.76 (s, 3H), 3.69 (s, 3H), 3.59

4

; 9% ee for Rh

2

(S-PTAD)

4

; 90% ee for Rh

2

(R-

+17.5° (c =

3 3

); H NMR (400 MHz, CDCl ) δ 7.09-7.07 (m, 3H),

4

.1.9.

(1S,2R)-methyl

1-(3,4-dimethoxyphenyl)-2-

20

4

f

D

phenylcyclopropanecarboxylate (3i). Title compound was

prepared by general procedure and obtained as a white solid. 74%

1

yield for Rh

yield for 1 mol% Rh

BNP) ; 80% yield for 0.1 mol% Rh

.01 mol% Rh (R-BNP) ; HPLC: (Chiralcel OD-H, 6% i-PrOH

2

(R-DOSP)

4

; 70% yield for Rh

; 83% yield for 0.5 mol% Rh

(R-BNP) ; 73% yield for

2

(S-PTAD)

4

; 93%

(

s, 6H), 3.07 (dd, J = 9.2, 7.2 Hz, 1H); 2.14 (dd, J = 9.6, 4.8 Hz,

2

(R-BNP)

4

2

(R-

13

1H), 1.82 (dd, J = 7.6, 5.2 Hz, 1H); C NMR (100 MHz, CDCl

3

)

4

2

4

δ 174.2, 152.3, 136.5, 130.3, 128.0, 127.7, 126.4, 109.4, 60.7,

0

2

4

5

1

5.9, 52.6, 37.4, 33.1 20.8; IR (film): 2925, 1716, 1587, 1413,

258, 1235, 1153, 1124; HRMS (ESI) calcd for C20

in hexane, 1 mL/min, 1 mg/mL, 30 min, λ = 254 nm) retention

times of 13.99 min (minor) and 17.97 min (major), 56% ee for

Rh

23 4

H O

+

(

M+H) 345.1485 found 345.1485.

2

(R-DOSP)

4

; 94% ee for Rh

2

(S-PTAD)

(R-BNP)

; 40% ee for 0.01 mol% Rh

4

; 97% ee for 1 mol%

; 91% ee for

(R-BNP) ; R

+28.4° (c

) δ 7.09-7.07 (m,

2

(R-BNP) ; 96% ee for 0.5 mol% Rh

4

2

4

4.1.13. (1S,2R)-methyl 1-(3,4-dimethoxyphenyl)-2-(m-

0.1 mol% Rh

2

(R-BNP)

4

2

4

f

tolyl)cyclopropanecarboxylate (5a). Prepared by general

procedure with methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate

(118 mg, 0.5 mmol, 1 equiv), 2-methylstyrene (148 mg, 1.25

2

0

=

0.20 (hexane: ethyl acetate 4:1); mp 88-89°C; [α]

1.51, CHCl

D

1

3

); H NMR (400 MHz, CDCl

3

H), 6.81-6.79 (m, 2H), 6.69 (m, 2H), 6.36 (s, 1H), 3.81 (s, 3H),

2 4

mmol, 2.5 equiv), and Rh (R-BNP) (4 mg, 0.0025 mmol, 0.005

.68 (s, 3H), 3.56 (s, 3H), 3.08 (dd, J = 9.2, 7.6 Hz, 1H), 2.14

equiv). The remaining residue was purified on silica gel eluting

with hexanes : ethyl acetate (5:1) to afford a yellow/green oil

1

3

(

dd, J = 9.2, 4.4 Hz, 1H), 1.84 (dd, J = 7.6, 4.8 Hz, 1H);

C

2

0

NMR (100 MHz, CDCl

3

) δ 174.5, 147.8, 136.4, 127.9, 127.7,

(114 mg, 76 % yield). R

f

= 0.12 (hexane: ethyl acetate 5:1); [α]

D

1

127.2, 126.3, 123.9, 115.3, 110.2, 55.5, 52.6, 36.9, 33.1, 20.8; IR

+28.7° (c = 1.23, CHCl ); H NMR (400 MHz, CDCl ) δ 7.11 (d,

3

(

1

3

film): 2924, 1716, 1518, 1455, 1434, 1413, 1341, 1229, 1208,

J = 7.6 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H),

6.63 (m, 2H), 6.42 (d, J = 7.6 Hz, 1H), 6.34 (s, 1H), 3.77 (s, 3H),

3.71 (s, 3H), 3.57 (s. 3H), 3.11 (dd, J = 9.2, 7.6 Hz, 1H), 2.51 (s,

+

177; HRMS (ESI) calcd for C19

13.1433.

H

21

O

4

(M+H) 313.1440 found

3

1

5

1

H), 2.06 (dd, J = 9.2, 5.0 Hz, 1H), 1.99 (dd, J = 7.6, 5.0 Hz,

H); C NMR (100 MHz, CDCl ) δ 174.9, 147.9, 137.8, 134.7,

3

29.7, 127.8, 126.7, 126.0, 125.8, 123.7, 114.7, 110.3, 55.7, 55.6,

2.8, 36.0, 31.2, 20.2, 19.5; IR (film): 2951, 1713, 1516, 1463,

4

.1.10.

(1S,2R)-methyl

1-(3-methoxyphenyl)-2-

Title compound was

13

phenylcyclopropanecarboxylate (3j).

prepared by general procedure and obtained as a yellow oil. 78%

yield for Rh (R-DOSP) ; 72% yield for Rh (S-PTAD) ; 82%

yield for Rh (R-BNP) ; HPLC: (Chiralcel OD-H, 0.7% i-PrOH in

hexane, 1 mL/min, 1 mg/mL, 30 min, λ = 254 nm), retention

times of 9.50 min (major) and 11.38 min (minor), 79% ee for

2

4

2

4

23 4

435, 1251, 1140, 1026, 740; HRMS (APCI) calcd for C20H O

2

4

+

(

M+H) 327.1591 found 327.1591; HPLC: (Chiralcel OD-H, 3%

i-PrOH in hexane, 1 mL/min, 1 mg/mL, 30 min, λ = 254 nm)

retention times of 17.81 min (minor) and 19.31 min (major), 90%

ee for Rh

Rh

BNP)

1

6

2

(R-DOSP)

; R = 0.25 (hexane: ethyl acetate 9:1); [α]

.25, CHCl

.81-6.79 (m, 2H), 6.69-6.63 (m, 2H), 6.53-6.52, (m, 1H), 3.67

4

; 16% ee for Rh

2

(S-PTAD)

4

; 88% ee for Rh

2

(R-

+21.1° (c =

) δ 7.09-7.03 (m, 4H),

20

2

(R-BNP)

4

2 4

, 64% ee for Rh (R-DOSP) .

4

f

D

1

3

); H NMR (400 MHz, CDCl

3

4.1.14.

(1S,2R)-methyl

1-(3,4-dimethoxyphenyl)-2-(p-

tolyl)cyclopropanecarboxylate (5b).

Prepared by general

(

9

s, 3H), 3.59 (s, 3H), 3.12 (dd, J = 9.6, 7.2 Hz, 1H), 2.12 (dd, J =

procedure with methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate

(118 mg, 0.5 mmol, 1 equiv), 4-methylstyrene (148 mg, 1.25

mmol, 2.5 equiv), and Rh (R-BNP) (4 mg, 0.0025 mmol, 0.005

2 4

1

3

.2, 4.8 Hz, 1H), 1.87 (dd, J = 7.6, 5.2 Hz, 1H); C NMR (100

) δ 174.2, 158.8, 136.4, 136.2, 128.5, 127.9, 127.7,

26.3, 124.4, 117.5, 112.9, 55.0, 52.6, 37.3, 33.1, 20.6; IR (film):

925, 1717, 1602, 1454, 1239, 697; HRMS (ESI) calcd for

MHz, CDCl

1

2

3

equiv). The remaining residue was purified on silica gel eluting

with hexanes : ethyl acetate (5:1) to afford a yellow/green oil

+

20

C

18

H

19

O

3

(M+H) 283.1334 found 283.1329.

(147 mg, 90% yield). R

27.7° (c = 1.24, CHCl

J = 8.0 Hz, 2H), 6.69-6.67 (m, 4H), 6.37 (s, 1H), 3.81 (s, 3H),

f

= 0.12 (hexane: ethyl acetate 5:1); [α]

); H NMR (400 MHz, CDCl ) δ 6.88 (d,

3 3

D

1

+

4

.1.11.

(1S,2R)-methyl 1-(3,5-dimethoxyphenyl)-2-

phenylcyclopropanecarboxylate (3k). Title compound was

prepared by general procedure and obtained as a yellow oil. 85%

yield for Rh (R-DOSP) ; 85% yield for Rh (S-PTAD) ; 69%

yield for Rh (R-BNP) ; HPLC: (Chiralcel OD-H, 6% i-PrOH in

hexane, 1 mL/min, 1 mg/mL, 30 min, λ = 254 nm) retention

times of 7.33 min (major) and 9.07 min (minor), 28% ee for

Rh

BNP)

1

6

3

1

3

1

.67 (s, 3H), 3.57 (s, 3H), 3.05 (dd, J = 9.2, 7.6 Hz, 1H), 2.22 (s,

H), 2.11 (dd, J = 9.2, 4.8 Hz, 1H), 1.80 (dd, J = 7.6, 4.8 Hz,

2

4

2

4

13

H); C NMR (100 MHz, CDCl

3

) δ 174.7, 147.9, 136.0, 133.5,

2

4

28.6, 128.0, 127.6, 124.1, 115.5, 110.3, 55.7, 55.6, 52.7, 36.9,

3.1, 21.0, 20.9; IR (film): 2951, 1714, 1589, 1516, 1435, 1413,

341, 1315, 1250, 1228, 1155, 1027; HRMS (APCI) calcd for

2

(R-DOSP)

; R = 0.31 (hexane: ethyl acetate 5:1); [α]

.1, CHCl

.82 (dd, J = 7.2, 2.4 Hz, 2H), 6.24 (t, J=2.4 Hz, 1H), 6.15 (d,

4

; 3% ee for Rh

2

(S-PTAD)

4

; 92% ee for Rh

2

(R-

+33.7° (c =

3 3

); H NMR (400 MHz, CDCl ) δ 7.10-7.08 (m, 3H),

+

2

0

C

20

H

23

O

4

(M+H) 327.1591 found 327.1591; HPLC: (Chiralcel

4

f

D

1

OD-H, 3% i-PrOH in hexane, 1 mL/min, 1 mg/mL, 30 min, λ =

54 nm) retention times of 17.3 min (minor) and 20.1 min

major), 88% ee for Rh (R-BNP) , 67% ee for Rh (R-DOSP)

2

(

2

4

2

4

.

J=2.4 Hz, 2H), 3.68 (s, 3H), 3.56 (s, 6H), 3.08 (dd, J = 9.2, 7.2

Hz, 1H), 2.10 (dd, J = 9.2, 4.8 Hz, 1H), 1.84 (dd, J = 7.2, 4.8 Hz,

1

4.1.15.

(1S,2R)-methyl 1-(3,4-dimethoxyphenyl)-2-(4-

13

H); C NMR (100 MHz, CDCl

3

) δ 174.4, 160.1, 137.2, 136.6,

methoxyphenyl)cyclopropanecarboxylate (5c).

general procedure with methyl

Prepared by

2-diazo-2-(3,4-

1

28.2, 128.0, 126.6, 110.4, 99.8, 55.4, 52.9, 37.7, 33.3, 20.9; IR

(

1

3

film): 2951, 2840, 1715, 1594, 1456, 1425, 1260, 1203, 1151,

dimethoxyphenyl)acetate (118 mg, 0.5 mmol, 1 equiv), 4-

methoxystyrene (168 mg, 1.25 mmol, 2.5 equiv), and Rh (R-

BNP) (4 mg, 0.0025 mmol, 0.005 equiv. The remaining residue

+

046, 715, 692; HRMS (APCI) calcd for C19

13.1434 found 313.1435.

H

21

O

4

(M+H)

2

4

ACCEPTED MANUSCRIPT

7

was purified on silica gel eluting with hexanes : ethyl acetate

f

afford clear oil (123 mg, 89% yield). R = 0.30 (hexane: ethyl

20 1

(

5:1) to afford an off-white solid (137 mg, 80% yield). R

f

= 0.20

+33.1° (c = 1.4,

) δ 6.73-6.61 (m, 6H), 6.41

s, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.67 (s, 3H), 3.60 (s, 3H), 3.03

dd, J = 9.2, 7.6 Hz, 1H), 2.10 (dd, J = 9.2, 4.8 Hz, 1H), 1.76 (dd,

acetate 3:1); [α]

D 3

+13.4° (c = 1.2, CHCl ); H NMR (400 MHz,

CDCl ) δ 7.04 (d, J = 8.4 Hz, 2H), 6.72-6.63 (m, 4H), 6.38 (d, J

= 1.6 Hz, 1H), 3.81 (s, 3H), 3.67 (s. 3H), 3.61 (s, 3H), 3.04 (dd, J

= 9.2, 7.2 Hz, 1H), 2.13 (dd, J = 9.2, 4.8 Hz, 1H), 1.78 (dd, J =

3

7.2, 4.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ 174.4, 148.2,

148.2, 135.4, 132.3, 129.4, 128.0, 127.0, 124.2, 115.4, 110.5,

55.9, 55.8, 52.8, 37.2, 32.6, 21.2; IR (film): 2951, 1715, 1589,

1517, 1496, 1435, 1413, 1371, 1341, 1307, 1228,1177, 1155,

20

hexane: ethyl acetate 3:1); mp 123-125°C; [α]

D

3

1

CHCl

(

3

); H NMR (400 MHz, CDCl

3

1

3

1

3

J = 7.6, 4.8 Hz, 1H); C NMR (100 MHz, CDCl

3

) δ 175.1,

1

5

1

58.6, 148.3, 129.5, 128.9, 127.9, 124.6, 115.9, 113.7, 110.7,

6.1, 55.6, 53.1, 37.1, 33.2, 21.3; IR (film): 2952, 1714, 1611,

+

589, 1515, 1463, 1437, 1413, 1341, 1248, 1228, 1177, 1153;

1139; HRMS (APCI) calcd for C19

H

19ClO

4

(M+H) 346.09664

+

HRMS (APCI) calcd for C20

H

22

O

5

(M+H) 342.14618 found

found 346.09632; HPLC: (Chiralcel OD-H, 5% i-PrOH in

hexane, 1 mL/min, 1 mg/mL, 30 min, λ = 254 nm) retention

times of 14.9 min (minor) and 18.5 min (major), 89% ee for

3

42.14589; HPLC: (Chiralcel OD-H, 5% i-PrOH in hexane, 1

mL/min, 1 mg/mL, 30 min, λ = 254 nm) retention times of 19.2

min (minor) and 22.9 min (major), 90% ee for Rh (R-BNP)

2

4

,

Rh

2

(R-BNP)

4

, 67% ee for Rh

2

(R-DOSP)

4

.

2 4

62% ee for Rh (R-DOSP) .

4.1.19.

(1S,2R)-methyl

2-(3,4-dichlorophenyl)-1-(3,4-

4

.1.16. (1S,2R)-methyl

1-(3,4-dimethoxyphenyl)-2-(4-

dimethoxyphenyl)cyclopropanecarboxylate (5g). Methyl 2-diazo-

2-(3,4-dimethoxyphenyl)acetate (2.7g, 11.6 mmol, 1 equiv) in

153 mL dry and degassed toluene was added by syringe pump

over 2 h to a solution of 1,2-dichloro-4-vinylbenzene (2.4 g, 13.9

nitrophenyl)cyclopropanecarboxylate (5d). Prepared by general

procedure with methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate

(

2

118 mg, 0.5 mmol, 1 equiv), 4-nitrostyrene (186 mg, 1.25 mmol,

.5 equiv), and Rh (R-BNP) (4 mg, 0.0025 mmol, 0.005 equiv).

2

4

2 4

mmol, 1.2 equiv) and Rh (R-BNP) (92.2 mg, 0.06 mmol, 0.005

The remaining residue was purified on silica gel eluting with

hexanes : ethyl acetate (5:1) to afford yellow oil (168 mg, 94%

equiv) in 77 mL toluene. After addition, the solution was

allowed to stir overnight and toluene was removed in vacuo. The

remaining residue was purified on silica gel (hexane:ethyl acetate

2

0

yield). R

f

= 0.28 (hexane: ethyl acetate 3:1); [α]

D

+15.5° (c =

) δ 7.94 (d, J = 8.8 Hz,

H), 6.92 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.2 Hz, 1H), 6.61 (dd,

1

1.07, CHCl

3

); H NMR (400 MHz, CDCl

3

5:1) to afford a clear oil (3.2 g, 72% yield for Rh

[enantiomer shown above]; 2.3g, 52% yield for Rh (S-BNP)

+4.1° (c = 1.03, CHCl

-6.9° (c = 1.05, CHCl ) for Rh (S-BNP)

H NMR (600 MHz, CDCl ) δ 7.10 (d, J = 9.0 Hz, 1H), 7.01 (d, J

2

(R-BNP)

4

2

4

) R

f

20

J = 8.2, 2.0 Hz, 1H), 6.43 (d, J = 2.0 Hz,, 1H), 3.81 (s, 3H), 3.69

= 0.17 (hexane: ethyl acetate 5:1); [α]

D

3

)

20

(

9

s, 3H), 3.62 (s, 3H), 3.16 (dd, J = 9.2, 7.6 Hz, 1H), 2.22 (dd, J =

for Rh

2

(R-BNP)4; [α]

D

3

2

4

;

1

3

1

.2, 5.4 Hz, 1H), 1.91 (dd, J = 7.6, 5.4 Hz, 1H); C NMR (100

) δ 173.9, 148.5, 145.1, 128.7, 126.2, 124.2, 123.0,

15.0, 110.6, 55.9, 55.8, 53.0, 38.4, 32.6, 29.8, 21.8; IR (film):

924, 1717, 1597, 1515, 1463, 1415, 1342, 1229, 1206, 1156,

3

MHz, CDCl

3

= 2.4 Hz, 1H), 6.69 (d, J = 9.0 Hz, 1H), 6.63 (dd, J = 9.0, 2.4 Hz,

1H), 6.51 (dd, J = 9.0, 2.4 Hz, 1H), 6.44 (d, J = 1.8 Hz, 1H), 3.82

1

2

1

(s, 3H), 3.67 (s, 3H), 3.66 (s, 3H), 3.02 (dd, J = 9.0, 7.2 Hz, 1H),

+

13

141; HRMS (APCI) calcd for C19

H

20

O

6

N

1

(M+H) 358.12851

2.13(dd, J = 9.0, 5.1 Hz, 1H), 1.78 (dd, J = 7.2, 5.1 Hz, 1H);

NMR (100 MHz, CDCl

C

found 358.12836; HPLC: (Chiralcel OD-H, 6% i-PrOH in

hexane, 1 mL/min, 1 mg/mL, 60 min, λ = 254 nm) retention

times of 30.4 min (minor) and 41.0 min (major), 80% ee for

3

) δ 174.1, 148.4, 148.3, 137.4, 131.9,

130.5, 130.4, 129.7, 127.0, 126.6, 124.2, 115.2, 110.6, 55.9, 55.8,

52.9, 37.4, 32.1, 21.1; IR (film): 2951, 2836, 1716, 1559, 1516,

Rh

2

(R-BNP)

4

, 50% ee for Rh

2

(R-DOSP)

4

.

1413, 1229, 1178, 1137, 1027, 764; HRMS (APCI) calcd for

+

C

19

H19Cl

2

O

4

(M+H) 381.2498 found 381.2498; HPLC:

4.1.17.

(1S,2R)-methyl

1-(3,4-dimethoxyphenyl)-2-(4-

(

Chiralcel OD-H, 5% i-PrOH in hexane, 1 mL/min, 1 mg/mL, 30

min, λ = 254 nm) retention times of 15.4 min (minor) and 17.9

min (major), 86% ee for Rh (R-BNP) ; retention times of 15.3

min (major) and 19.7 min (minor) 85% ee for Rh (S-BNP)4, 48%

ee for Rh (R-DOSP)

trifluoromethyl)phenyl)cyclopropanecarboxylate (5e). Prepared

by general procedure with methyl 2-diazo-2-(3,4-

dimethoxyphenyl)acetate (118 mg, 0.5 mmol, 1 equiv), styrene

215 mg, 1.25 mmol, 2.5 equiv), and Rh (R-BNP) (4 mg, 0.0025

2

4

2

(

2

4

2

4

.

mmol, 0.005 equiv). The remaining residue was purified on

silica gel eluting with hexanes : ethyl acetate (6:1) to afford a

yellow oil (171 mg, 90% yield); R = 0.24 (hexane: ethyl acetate

Acknowledgments

f

20

1

4:1); [α]

D 3 3

+16.5° (c = 1.6, CHCl ); H NMR (400 MHz, CDCl )

This work was supported by the National Institutes of Health

DA023224).

δ 7.33 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.70-6.65 (m,

(

2

1

H), 6.35 (s, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 3.56 (s, 3H), 3.11 (t,

H), 3.12 (dd, J = 9.2, 7.2 Hz, 1H), 2.18 (dd, J = 9.2, 4.8 Hz,

H), 1.85 (dd, J = 7.2, 4.8 Hz, 1H); C NMR (100 MHz, CDCl )

3

1

3

Supplementary Material

δ 174.5, 148.7, 148.6, 141.5, 128.7, 127.0, 124.8, 124.7, 124.6,

Detailed experimental for the compounds, HPLC traces for all

124.3, 115.6, 110.9, 56.1, 53.2, 38.0, 33.0, 21.7; IR (film): 2954,

1

13

chiral compounds, H NMR and C NMR spectra for all new

compounds are described in Supplementary data. Supplementary

data associated with this article can be found in the online

version.

1

718, 1517, 1465, 1437, 1414, 1324, 1252, 1230, 1210, 1193;

+

HRMS (APCI) calcd for C20

H

19

F

3

O

4

(M+H) 380.12300 found

3

80.12251; HPLC: (Chiralcel OD-H, 6% i-PrOH in hexane, 1

mL/min, 1 mg/mL, 30 min, λ = 254 nm) retention times of 12.6

4

min (minor) and 15.6 min (major), 90% ee for Rh (R-BNP) ,

2

References

6

3% ee for Rh

2

(R-DOSP)

4

.

4

.1.18.

(1S,2R)-methyl

2-(4-chlorophenyl)-1-(3,4-

1. Lebel, H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem.

Rev. 2003, 103, 977.

dimethoxyphenyl)cyclopropanecarboxylate (5f). Prepared by

general procedure with methyl 2-diazo-2-(3,4-

dimethoxyphenyl)acetate (118 mg, 0.5 mmol, 1 equiv), 4-

chlorostyrene (173 mg, 1.25 mmol, 2.5 equiv), and Rh (R-BNP)

4 mg, 0.0025 mmol, 0.005 equiv). The remaining residue was

purified on silica gel eluting with hexanes : ethyl acetate (6:1) to

2

3

.

Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 1, 1-313.

Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall,

M. J. J. Am. Chem. Soc. 1996, 118, 6897.

2

4

.

Davies, H. M. L.; Rusiniak, L. Tet. Lett 1998, 39, 8811.

(

5. Davies, H. M. L.; Panaro, S. A. Tet. Lett 1999, 40, 5287.

6. Davies, H. M. L.; Venkataramani, C. Org. Lett. 2003, 5, 1403.

ACCEPTED MANUSCRIPT

8

7

8

.

Kozikowski, A.; Kurome, T.; Setola, V.; Roth, B. US Patent

03,750, August 13, 2009.

Cho, S. J.; Jensen, N. H.; Kurome, T.; Kadari, S.; Manzano, M. L.;

Malberg, J. E.; Caldarone, B.; Roth, B. L.; Kozikowski, A. P. J.

Med. Chem. 2009, 52, 1885.

2

9

1

.

Davies, H. M. L.; Townsend, R. J. J. Org. Chem. 2001, 66, 6595.

0. Davies, H. M. L.; Nagashima, T.; Klino, J. L., III Org. Lett. 2000,

, 823.

2

1

1. Ventura, D. L.; Li, Z.; Coleman, M. G.; Davies, H. M. L.

Tetrahedron 2009, 65, 3052.

2. Davies, H. M. L.; Coleman, M. G.; Ventura, D. L. Org. Lett. 2007,

9

, 4971.

1

3. Davies, H. M. L.; Boebel, T. A. Tet. Lett. 2000, 41, 8189.

4. Hedley, S. J.; Ventura, D. L.; Dominiak, P. M.; Nygren, C. L.;

Davies, H. M. L. J. Org. Chem. 2006, 71, 5349.

1

5. Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.

6. Bonge, H. T.; Pintea, B.; Hansen, T. Org. Biomol. Chem. 2008, 6,

3

670.

1

7. Bonge, H. T.; Hansen, T. J. Org. Chem. 2010, 75, 2309.

8. Bonge, H. T.; Hansen, T. Tet. Lett. 2010, 51, 5298.

9. Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8,

3

437.

0. Denton, J. R.; Sukumaran, D.; Davies, H. M. L. Org. Lett. 2007, 9,

625.

1. Denton, J. R.; Cheng, K.; Davies, H. M. L. Chem. Commun. 2008,

238.

2

1

2

2. Denton, J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787.

3. Pirrung, M. C.; Zhang, J. Tet. Lett. 1992, 33, 5987.

4. McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.; Murphy,

E.; Doyle, M. P. Tet. Lett. 1992, 33, 5983.

2

5. Liao, M.; Wang, J. Green Chem. 2007, 9, 184.

6. Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Chem. Commun.

1

999, 2185.

2

7. Hodgson, D. M.; Stupple, P. A.; Pierard, F. Y. T. M.; Labande, A.

H.; Johnstone, C. Chem. Eur. J. 2001, 7, 4465.

8. The absolute configuration of the cyclopropanes is tenatively

assigned assuming a similar assymmetric induction as was

observed with styryldiazoacetates (see Davies, H. M. L. H., N. J.

S.; Cantrell, W. R., Jr.; Olive, J. L. J. Am. Chem. Soc. 1993, 115,

9

468.).

9. Pelphrey, P.; Hansen, J.; Davies, H. M. L. Chem. Sci. 2010, 1,

54.

2

3

0. Brooks, L. A. J. Am. Chem. Soc. 1944, 66, 1295.

1. Davies, H. M. L.; Cantrell, W. R., Jr.; Romines, K. R.; Baum, J. S.

Org. Synth. 1992, 70, 93.

ACCEPTED MANUSCRIPT

Supplementary Material

Guide to Highly Enantioselective Chiral Dirhodium(II)-Catalyzed Cyclopropanation

a

Kathryn M. Chepiga, Changming Qin, Joshua S. Alford, Spandan Chennamadhavuni,

b

a

a*

Timothy M. Gregg, Jeremy P. Olson, and Huw M. L. Davies

a

Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States

b

Department of Chemistry and Biochemistry, Canisius College, Buffalo, NY 14208

hmdavie@emory.edu

Table of Contents

General Experimental

Details………………………………………………………………………………………………S-2

General procedure…………………………………………………………………………….S-2 –S4

Characterization of new compounds………………………………………………………..S-4-S-14

References ………………………………………………………………………………………..S-14

1

H, 13C-NMR spectra and HPLC trace……………………………………………………..S15-S75

S-1

ACCEPTED MANUSCRIPT

General: All reactions were conducted under anhydrous conditions in oven-dried glassware

under an inert atmosphere of dry argon, unless otherwise stated. Hexanes, pentane, and toluene

were dried by a solvent purification system (passed through activated alumina columns). All

solvents were degassed by bubbling argon through the solvent for a minimum of 10 minutes

prior to use. Unless otherwise noted, all other reagents were obtained from commercial sources

1

and used as received. H Nuclear Magnetic Resonance (NMR) spectra were recorded at 400

MHz or 600MHz. Data presented as follows: chemical shift (in ppm on the δ scale relative to δH

7

.27 for the residual protons in CDCl ), coupling constant (J/Hz), integration. Coupling

3

13

constants were taken directly from the spectra and are uncorrected.

C NMR spectra were

recorded at 100 MHz and all chemical shift values are reported in ppm on the δ scale, with an

internal reference of δC 77.23 for CDCl . Mass spectral determinations were carried out by

3

using APCI as ionization source. Melting points are uncorrected. Infrared spectral data are

-1

reported in units of cm . Analytical TLC was performed on silica gel plates using UV light.

Flash column chromatography was performed on silica gel 60Å (230-400 mesh). Optical

rotations were measured on Jasco polarimeters. Analytical enantioselective chromatographies

were measured on Varian Prostar instrument and used isopropanol:hexane as gradient. Chiral

HPLC conditions were determined by obtaining separation of the racemic product. Rh (R/S-

2

DOSP) was employed as the catalyst in the racemic reactions. Styrene (2) and substituted

4

styrenes (4a-f) were commercially available and purified by pushing through a silica-filled

1

2

3

4

pipette prior to use. Rh (R-DOSP) , Rh (S-PTAD) , Rh (R-BNP) , aryldiazoacetates 1a-l,

2

4

2

4

2

4

5

and styrene 4g were all synthesized according published procedures.

6

General Procedure for the Synthesis of Methyl Phenyldiazoacetates

The methyl arylacetate (1 equiv.) and p-ABSA (1.3 equiv.) were dissolved in acetonitrile

and cooled to 0 °C using an ice bath under an argon atmosphere. 1,8-Diazabicycloundec-7-ene

(DBU, 1.3 equiv.) was then added to the stirring mixture over the course of 5 minutes. After the

addition of the DBU, the reaction mixture continued to stir at 0 °C for an additional 15 minutes.

Once this allotted time had passed, the ice bath was removed and the reaction mixture was stirred

for 24 hours at room temperature. The resulting orange solution was quenched with saturated

NH Cl and the aqueous layer was extracted with diethyl ether (3x). The organic layer was then

4

washed with deionized H O to remove any residual salts. The combined organic layers were

2

S-2

ACCEPTED MANUSCRIPT

dried over MgSO and filtered. The organic layer was then concentrated under reduced pressure.

4

The residue was purified via flash chromatography on silica gel (10:1 Hexanes:EtOAc).

General Procedure for the Synthesis of Methyl Phenylcyclopropanecarboxylates with

Rh (R-DOSP)₄

2

In a 25-mL round bottom flask (Flask A) equipped with a magnetic stir bar, styrene (5

equiv.) and Rh (R-DOSP) (0.01 equiv.) were dissolved in dry, degassed pentane (3 mL). The

2

4

reaction mixture was then degassed using vacuum/argon cycles (x3). In a separate 25-mL round

bottom flask (Flask B), the methyl phenyldiazoacetate (0.5 mmol, 1 equiv.) was dissolved in dry,

degassed pentane (5 mL) and degassed using vacuum/argon cycles (x3). The contents in Flask B

were then added to Flask A using a syringe pump for the duration of 1 hour. After the addition,

the reaction mixture continued to stir for 1 additional hour. Once the allotted time had passed,

the reaction mixture was concentrated under reduced pressure and purified using silica gel

column chromatography (increasing gradient starting at 10:1 Hexanes:EtOAc).

General Procedure for the Synthesis of Methyl Phenylcyclopropanecarboxylates with

Rh (S-PTAD)₄

2

In a 25-mL round bottom flask (Flask A) equipped with a magnetic stir bar, styrene (5

equiv.) and Rh (S-PTAD) (0.005 equiv.) were dissolved in dry, degassed pentane (3 mL). The