Chiral macrocyclic bis(oxazoline) Cu1 complexes - Structure/stereoselectivity relationships in catalytic cyclopropanations

FULL PAPER

DOI: 10.1002/ejoc.200600827

Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes – Structure/Stereoselectivity

Relationships in Catalytic Cyclopropanations

[a]

ˇ

´

Tomislav Portada, Marin Roje, Zlata Raza, Vesna Caplar, Mladen Zinic,* and

[a][‡]

ˇ

Vitomir Sunjic´

Keywords: Bis(oxazolines) / Catalytic cyclopropanation / Copper(I) complexes / Diastereoselectivity / Macrocyclic ligands

The design and synthesis of 18 chiral macrocycles with built

in C₂-symmetric bis(oxazoline) units is described and the

catalytic properties of their copper(I) complexes in cyclopro-

panations of styrene with ethyl diazoacetate are assessed.

The bridging of two homochiral centers in the bis(oxazoline)

unit gives a macrocyclic ligand, which upon binding of Cu^I

is transformed into a macrocyclic catalytic complex contain-

ing a chiral cavity. Such a complex represents a conceptually

new type of supramolecular organometallic catalyst, pos-

sessing a chiral reaction cavity. A clear relationship between

catalyst structures and the stereoselectivity outcome in the

catalytic cyclopropanations has been established and it is

demonstrated that both the enantioselectivity and the dia-

stereoselectivity can be independently modified by variation

of the ligand structural parameters. The Cu^Icomplex of the

ligand 3b gave a trans/cis diastereomeric ratio of 94:6 (de =

88%), representing the highest diastereoselectivity obtained

to date for cyclopropanations catalyzed by the bis(oxazoline)

class of complexes. An explanation of the observed relation-

ship between stereochemical outcome and ligand structure

is proposed.

Germany, 2007)

manner, while ruthenium(II) complexes of bidentate Schiff-

base ligands^[17]have provided excellent levels of diastereo-

and enantioselectivity in catalytic alkene cyclopropanations.

Chiral ruthenium porphyrin complexes have also been

used^[18,19]in asymmetric inter- and intramolecular cyclo-

propanations of alkenes, while chiral iminophosphoranes

possessing stereogenic phosphorus centers have been suc-

cessfully used as ligands in asymmetric copper-catalyzed cy-

clopropanations of olefins with ethyl diazoacetate.^[20]

However, the C₂-symmetric bis(oxazoline) ligands appear

to be of the highest importance, since they are synthetically

readily available and in some cases also afford very high

enantioselectivities.^[5–9]A range of chiral bis(oxazoline)–

metal complexes have also received a great deal of attention

in various other catalytic processes such as Diels–Alder and

hetero-Diels–Alder reactions, 1,3-dipolar cycloadditions, [2

+ 2] photochemical cycloadditions, Mukaiyama aldol reac-

tions and Mukaiyama–Michael addition reactions,^[21–24]

and allylic substitution reactions,^[24,25]while Pd^IIcomplexes

of chiral bis(oxazolines) have been applied in catalytic al-

lylic alkylations.^[25]A comprehensive review of C₂-symmet-

ric chiral bis(oxazoline) ligands in asymmetric catalysis has

appeared recently.^[26]

Introduction

Many naturally occurring and synthetic biologically im-

portant compounds contain chiral substituted cyclopro-

pane ring systems,^[1]and considerably different biological

activities of the stereoisomers are often observed.^[2]The

need for the efficient synthesis of stereochemically pure cy-

clopropanes has prompted extensive investigation of car-

bene additions to alkene double bonds catalyzed by metal

complexes of different chiral ligands.^[3]Ligands with diverse

structures have been tested, and some of them have given

very good enantioselectivity but as a rule only low or me-

dium diastereoselectivity [rarely higher than 60% de (80:20

trans/cis ratio)].^[4–13]Pfaltz et al.^[4,14]introduced C₂-sym-

metric semicorrin and 5-aza-semicorrin^[10]ligands for the

preparation of Cu^Icatalytic complexes used in catalytic cy-

clopropanations, while Evans,^[7,8]Masamune,^[5]and Pfaltz^[9]

later developed synthetically more accessible bis(oxazoline)

ligands while Katsuki^[11]and Kanemasa^[12]introduced new

ligands of the bipyridine and diamine type, respectively. Co-

balt(II) and cobalt(III) complexes of chiral salen and tetra-

dentate Schiff-base ligands^[15,16]have achieved trans- and

cis-selective cyclopropanations in a highly enantioselective

Many investigations have shown that ligand structure has

a strong influence on the stereoselectivity of cyclopropan-

ation. Even very small structural changes often have drastic

and sometimes unpredictable effects on the enantio-

selectivity, but examples in which the trans/cis diastereo-

selectivity is higher than the most commonly observed ra-

[a] Department of Organic Chemistry and Biochemistry, Rudjer

Bosˇkovic´ Institute,

P. O. Box 180, 10002 Zagreb, Croatia

Fax: +385-1-4680195

E-mail: zinic@irb.hr

[‡] Current address: Glaxo, Smith and Kline, Research Institute,

Zagreb, Croatia

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Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes

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tios of 60:40 to 70:30 are exceptionally rare. It should be groups (cis or trans with respect to the plane of the forming

also noted that in the vast majority of studies the diastereo- cyclopropane ring) in the transition state B (Scheme 1).

selectivity outcome was simply neglected and only the

In the search for a catalyst capable of giving higher total

enantioselectivity was considered. It appears that the search (enantio- and dia-) stereoselectivity we considered struc-

for more efficient catalysts for cyclopropanations should be tures containing topologically more constrained catalytic

directed towards those capable of giving both high enantio- cavities than found in the common acyclic C₂-symmetric

selectivity and also high diastereoselectivity (i.e., high total bis(oxazoline)–Cu^Icatalysts, which prompted us to consider

or cumulative stereoselectivity) and that such investigations macrocyclic structures incorporating C₂-symmetric bis(oxa-

might bring about a new generation of superior stereoselec- zoline) units (Figure 1). Conceptually, the bridging of two

tive catalysts for cyclopropanations. In a wider context, the homochiral centers in a planar, C₂-symmetric bis(oxazoline)

results of such studies could also be of importance for other Cu^Icomplex by a bridge of sufficient rigidity should result

types of stereoselective transformations that use C₂chiral in the induction of a certain degree of helicity in the bridge

organometallic catalysts or give stereoisomeric products.

(Figure 2). In this way, the C₂-chirality around the metallic

It is well known that the mechanism of asymmetric cy- center would be extended to a larger space, determined by

clopropanation catalyzed by metal complexes of chiral bis- the size of the macrocycle. Since the catalytic transforma-

(oxazoline) ligands (Scheme 1, a) involves the formation of tion takes place through the transition state B (Scheme 1,

a metal–carbene complex A (Scheme 1, b).^[24]In the subse- b), in a macrocyclic system of sufficient size the process

quent step, styrene reacts with the electrophilic α-carbon of would occur inside the chiral cavity of the catalyst. Hence,

the ester to give the cyclopropane product as the mixture the macrocyclic analogue of the transition state B should

of diastereomers. The stereochemical outcome is deter- be stereochemically more constrained, so many more non-

mined by the repulsive and/or attractive interactions in covalent interactions may be expected to occur than in the

transition state B. As proposed by Pfaltz,^[4]enantio- acyclic transition state B. Consequently, with the macro-

selectivity in catalytic cyclopropanations is determined by cyclic catalysts higher total stereoselectivity may be ob-

the difference in accessibility of the two enantiotopic faces tained through improvement of enantioselectivity and/or

of the metal-carbene bond and is influenced by the presence diastereoselectivity. In addition, such catalysts offer the

of large substituents on adjacent chiral centers in the bis- unique potential for substrate discrimination through varia-

(oxazoline) ligand, so enantioselectivity will depend on the tion of the size of a macrocyclic ring; the latter property

positions and bulkiness of substituents on stereogenic cen- of substrate recognition would resemble one of the basic

ters. On the other hand, diastereoselectivity will be deter- functions of enzymes or synthetic supramolecular cata-

mined by mutual orientation of phenyl and carbethoxy lysts.^[27]

Scheme 1.

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T. Portada, M. Roje, Z. Raza, V. Caplar, M. Zinic´, V. Sunjic´

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Figure 1. Chiral macrocyclic and acyclic bis(oxazoline) ligands derived from (R)-p-hydroxyphenylglycinol (1, 2a–d, 3a–d, and 4, 5) and

(S)-tyrosinol (6, 7a–d, 8a–d, and 9).

as well as two cyclic derivatives 1 and 6, possessing the

smallest rings, were prepared and their Cu^Icatalytic com-

plexes were also tested. It is well known that the best bis-

(oxazoline) ligands prepared to date, such as those of bis-

(tert-butyl) derivatives A^[7]and B^[28](Figure 3), giving

enantioselectivities of up to 99.9% ee, do not exhibit dia-

stereoselectivities higher than 46% for ligand A or 68% de

(84:16 trans/cis ratio) for ligand B. Here we report dia-

stereoselectivities of 86 and 88% de for 2a and 3b, respec-

tively, these being the highest values obtained to date for

bis(oxazoline) ligands.

Figure 2. Structures of macrocyclic bis(oxazoline)s with chiral reac-

tion cavities.

To test this hypothesis, two series of macrocyclic li-

gands – 2/3 and 7/8, derived from -hydroxyphenylglycinol

and -tyrosinol, respectively – and p,pЈ-oligomethylenedi-

phenylmethane bridges were prepared (Figure 1) and the

catalytic properties of their Cu^Icomplexes were tested in

the cyclopropanation of styrene with ethyl diazoacetate. For

copper(I)-catalyzed cyclopropanation of styrene with ethyl diazo-

purposes of comparison the acyclic analogues 4, 5, and 9, acetate.

Figure 3. The two best bis(oxazoline) ligands prepared to date for

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Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes

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Results and Discussion

Synthesis

Here we describe the syntheses of the macrocyclic ligands

1, 2a–d,^[29]3a–d, 6, 7a–d, and 8a–d (Figure 1), containing

macrocyclic cavities of various sizes, as well as that of the

closely related acyclic analogue 5 prepared for purposes of

comparison, while acyclic 4 and 9 had been prepared ear-

lier.^[30]The macrocyclic bis(oxazolines) of the series 2/3 and

7/8 were prepared from -hydroxyphenylglycinol and -ty-

rosinol, respectively, and differ in the absolute configura-

tions at their stereogenic centers. The bis(oxazoline) frag-

ments were prepared by the treatment of the activated ma-

lonic acid derivatives with -tyrosinol or -hydroxyphen-

ylglycinol. Both optically active amino alcohols were pre-

pared by reduction of the corresponding α-amino acids.^[30]

Our earlier findings with acyclic bis(oxazolines) had

Figure 4. Tautomeric equilibrium of methylene-bridged bis(oxa-

zoline) and stable diethylmethylene-bridged bis(oxazoline).

The syntheses of the macrocyclic bis(oxazoline)s were

shown that the acidic hydrogen atoms on the methylene initially approached through the key 1:1 macrocyclization

bridge undergo tautomeric exchange (Figure 4)^[31]and that step between 11 and 12 under high-dilution conditions as

because of such tautomerism the yields of bis(oxazoline)s outlined in Scheme 2 for the preparation of 7c. The diamide

are generally low due to subsequent oxidative transforma- 10, previously prepared from -tyrosinol in our group,^[30]

tions. To enhance the stabilities of the bis(oxazolines) their served as one component of the macrocyclization. Hydro-

derivatives with two ethyl substituents on the bridging car- genolytic cleavage of the benzylic protection groups in 10

bon were prepared (Figure 4).

in the presence of palladium on carbon gave 11 in quantita-

The spacers with variable numbers of methylene groups tive yield. The second component for macrocyclization,

were introduced in the form of α,ω-disubstituted alkanes in compound 12, was prepared by treatment of bisphenol A

order to vary the sizes and flexibilities of the macrocycles with a large excess of 1,4-dibromoethane (yield 42%).

(Figure 1). In addition to the short and flexible polymethyl- Macrocyclization under the high-dilution conditions to give

ene fragments, however, a more rigid unit, based on bis- 13 (yield 23%) was performed by dropwise addition of ace-

phenol A, was also introduced to ensure the induction of a tonitrile solutions of 11 and 12 to a suspension of cesium

certain degree of helicity in the macrocycle. The bis- carbonate at reflux in a large volume of acetonitrile. The

phenol A derivative with four methyl substituents on its dihydroxy compound 13 gave the dichloride 14 (56%) on

phenol rings was used for the preparation of 3a–d and 8a– treatment with triphosgene and triphenylphosphane, and

d, in which the methyl groups might increase the level of this was subsequently transformed into the target macro-

steric discrimination during the catalytic transformation oc- cyclic bis(oxazoline) 7c (76%) under alkaline conditions

curring in the macrocyclic cavity.

(NaOH in boiling methanol).

Scheme 2. Reaction conditions: i) H₂, 10% Pd/C, MeOH, r.t., 18 h. ii) Cs₂CO₃, MeCN, high dilution, reflux, 18 h. iii) Triphosgene, Ph₃P,

CH₂Cl₂, r.t., 1 h. iv) NaOH, MeOH, reflux, 2 h.

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The reaction path outlined in Scheme 3, however, proved product was observed. The same observations also hold for

to be much more efficient, offering a minimal number of the reactions between tyrosinol derivative 11 and α,ω-dibro-

steps and much better overall yields. The alkane spacers moalkanes.

were introduced by treatment of selected α,ω-dibromoal-

For purposes of wider structure/stereochemical outcome

kanes with the diamide 11, and the formed dihydroxy com- studies, extended beyond the ligands 2a–d and 7a–d, we also

pounds 15a–d (yields 29–59%) were subsequently trans- designed the new ligands 1 and 6 (Figure 1), incorporating

formed into dichlorides 16a–c by treatment with triphos- smaller macrocycles. This was initiated by the observation

gene (yields 66–75%) or thionyl chloride (yields 56–76%). that diastereoselectivity was increased in smaller macrocycle

The key and final step was the simultaneous triple ring clo- cavities.^[29]Instead of bisphenol spacers, 1 and 6 each con-

sure (two oxazoline and the macrocycle ring) in a single reac- tain a bis(methylphenyl)methane fragment attached directly

tion step! Treatment of compounds 16a–d with bisphenol A to the oxygens of the hydroxyphenyl units; since no methyl-

in the presence of Cs₂CO₃thus directly afforded the end- ene group is present between the hydroxyphenyl and the

products 7a–d (yields 28–50%).

bis(methylphenyl)methane fragments, ligands 1 and 6 could

Ligands 2a–d were prepared in the same way, starting be regarded as the n = 0 analogues of the 2 and the 7 series

from hydroxyphenylglycinol diamide 17^[30](Scheme 4), with (Figure 1), respectively.

subsequent debenzylation to provide compound 18 (99%)

Treatment of the dihydroxy compound 11 with thionyl

by hydrogenolytic cleavage. Treatment of 18 with α,ω-dibro- chloride gave the dichloride 21 (86%), which yielded ligand

moalkanes gave the dihydroxy compounds 19a–d (yields 6 (46%) in the macrocyclization reaction with bis(4-bro-

20–64%), which were chlorinated to provide compounds momethylphenyl)methane (22)^[32]as shown in Scheme 5.

20a–d (yields 69–88%) and treated in the last step with bis-

The compounds 3a–d and 8a–d, each bearing four methyl

phenol A to give ligands 2a–d (yields 24–48%). It was ob- groups on the phenyl rings of the bridge (the tetramethyl

served that treatment of diamide 18 with 1,2-dibromoeth- analogues of ligands 2a–d and 7a–d), were also synthesized

ane gave a lower yield then obtained in the reactions with (Figure 1). For this purpose the bisphenol 25, a tetramethyl

higher α,ω-dibromoalkanes, while in the reaction between analogue of bisphenol A, was prepared by an acid-catalyzed

18 and 1,3-dibromopropane the presence of an elimination condensation between 2,6-dimethylphenol and acetone in

Scheme 3. Reaction conditions: i) Br(CH₂)_nBr, n = 2–5, K₂CO₃, MeCN, reflux, 18 h. ii) SOCl₂, CH₂Cl₂, r.t., 18 h or triphosgene, Ph₃P,

CH₂Cl₂, r.t., 1 h. iii) Cs₂CO₃, MeCN, high dilution, reflux, 18 h.

Scheme 4. Reaction conditions: i) H₂, 10% Pd/C, MeOH, r.t., 18 h. ii) Br(CH₂)_nBr, n = 2–5, K₂CO₃, MeCN, reflux, 18 h. iii) SOCl₂,

CH₂Cl₂, r.t., 18 h or triphosgene, Ph₃P, CH₂Cl₂, r.t., 1 h. iv) Bisphenol A, Cs₂CO₃, MeCN, high dilution, reflux, 18 h.

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Scheme 5. Reaction conditions: i) H₂, 10% Pd/C, MeOH, r.t., 18 h. ii) SOCl₂, CH₂Cl₂, r.t., 18 h. iii) Cs₂CO₃, MeCN, high dilution, reflux,

18 h. iv) Br(CH₂)_nBr, n = 2–5, K₂CO₃, MeCN, reflux, 18 h.

77% yield. The syntheses of ligands 8a–d (yields 28–50%)

We also tried to prepare ligand 1 analogously to the

were performed by starting from diamide 10 (Scheme 5) preparation of ligand 6 (Scheme 6). Compound 18, the hy-

and those of ligands 3a–d (yields 14–40%) by starting from droxyphenylglycine analogue of compound 11, was there-

diamide 17 (Scheme 6), with the same synthetic steps as de- fore transformed by treatment with thionyl chloride into the

scribed for compounds 7a–d and 2a–d, respectively.

dichloride 23 (90%), an analogue of dichloride 21. Unlike

Scheme 6. Reaction conditions: i) H₂, 10% Pd/C, MeOH, r.t., 18 h. ii) SOCl₂, CH₂Cl₂, r.t., 18 h. iii) 22, Cs₂CO₃, MeCN, high dilution,

reflux, 18 h. iv) Br(CH₂)_nBr, n = 2–5, K₂CO₃, MeCN, reflux, 18 h. v) K₂CO₃, MeCN, reflux, 8 h. vi) 25, Cs₂CO₃, MeCN, high dilution,

reflux, 18 h. vii) PhOH, K₂CO₃, MeCN, reflux, 18 h.

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the 21 + 22 macrocyclization, however, the attempted 23 + Table 1. Catalytic properties of ligands 2a–d,^[29]7a–d, 4, 5, and 9.

22 macrocyclization failed to give the expected product 1.

For this reason we instead started from the macrocyclic di-

alcohol 24, prepared by a 1:1 macrocyclization between 18

and 22. The product 24 was transformed in two reaction

steps (substitution of hydroxy group by treatment with thio-

nyl chloride in dichloromethane and oxazoline ring closure

by treatment with potassium carbonate in acetonitrile) into

the target macrocycle 1, in an overall yield of 27%, without

isolation of the intermediate macrocyclic dichloride. Since

1 can be prepared from the macrocyclic derivative 24 and

cannot be prepared by the 1:1 macrocylization of 23 + 22,

it can be concluded that the double intramolecular cycliza-

tion of 23 into the bis(oxazoline) derivative is faster and

occurs prior to the macrocyclization step. The bis(oxaz-

oline) derivative formed from 23 is rigid, with two p-hy-

droxyphenyls oriented up and down with respect to the best

bis(oxazoline) plane, which makes the macrocyclization en-

tropically unfavorable so that the concurrent linear polyme-

rization prevails. However, the analogous bis(oxazoline)

formed from 21 is much more flexible, due to the presence

of the two methylene groups connecting the p-hy-

droxyphenyl components and the asymmetric carbons, so

that the macrocyclization step is not so disfavored in this

case.

Ligand

cis/trans

ratio (% de)

ee (cis) [%]

configuration

ee (trans) [%]

configuration

Yield [%]^[a]

2a

2b

2c

2d

7a

7b

7c

7d

4

7:93 (86)

16:84 (68)

23:77 (54)

29:71 (42)

46:54 (8)

55:45 (–10)

41:59 (18)

43:57 (14)

34:66 (32)

35:65 (30)

40:60 (20)

59 (1S,2R)

73 (1S,2R)

54 (1S,2R)

62 (1S,2R)

69 (1R,2S)

70 (1R,2S)

57 (1R,2S)

64 (1R,2S)

55 (1S,2R)

57 (1S,2R)

62 (1R,2S)

65 (1S,2S)

81 (1S,2S)

69 (1S,2S)

68 (1S,2S)

67 (1R,2R)

63 (1R,2R)

58 (1R,2R)

61 (1R,2R)

60 (1S,2S)

56 (1R,2R)

55

58

57

63

54

45

76

63

72

93

53

5

9

[a] Yields are not optimized.

values and the direction of these deviations depended on

the ligand structure. The hydroxyphenylglycinol ligands 2a–

d showed enhanced diastereoselectivity in a range from 42

up to 86% de, while the diastereoselectivities in cyclopro-

panations catalyzed by the tyrosinol ligands 7a–d were in a

range from –10 (negative sign denotes excess of the cis

product) to 18% de, thus being significantly lower than

those observed for the acyclic ligands 4, 5, and 9 and the

macrocycles 2a–d. For the ligands 2a–d a clear dependence

of diastereoselectivity on the macrocyclic ring size was ob-

served, with diastereoselectivity increasing almost linearly

with the decreasing number of methylene groups in the

alkyl spacers from 5 to 2.^[28]It seems plausible that in the

catalytic complex of the smallest ring 2a (n = 2), the C₂to

helical chirality transfer is more efficient than in the largest

and more flexible 2d (n = 5; see Figure 1 and Figure 2).

Consequently, the orientation and approach of styrene to

the more helical carbene complex of 2a is more restricted

than in the case of the less helical complex of 2d, which

results in a much higher diastereoselectivity outcome in the

first case.

For purposes of comparison, the corresponding non-

macrocyclic analogues were also prepared. The acyclic

ligands 4 and 9 had previously been prepared from the di-

amides 17 and 10, respectively,^[30]and the synthesis of li-

gand 5 from 20c and two equivalents of phenol is also out-

lined in Scheme 6.

Catalysis

The catalytic properties of the Cu^Icomplexes of the li-

gands 2a–d and 7a–d were examined in the cyclopropan-

ation of styrene with ethyl diazoacetate as a model reaction.

The reaction yields and the stereochemical outcomes (per-

centages ee and de) were determined by gas chromatog-

raphy of the product mixtures on a Chirasil-DEX CB chiral

column.^[33]

The chemical yields of the cyclopropane products and

the resulting enantio- and diastereoselectivities – expressed

as percentages ee and cis/trans ratios and percentages de,

respectively – obtained in the transformations of the macro-

cyclic ligands 2a–d, 7a–d, and the acyclic ligands 4, 5, and 9

with catalysis by the by Cu^Icomplexes are given in Table 1.

The new macrocyclic bis(oxazolines) 2a–d and 7a–d on

average showed slightly better enantioselectivities than their

nonmacrocyclic analogues. The best enantioselectivity with

the cis (73% ee) and the trans product (81% ee) was

achieved with ligand 2b.

The macrocyclic effect on diastereoselectivity can be de-

duced from comparison of de values for the macrocyclic 2c

(n = 4; 54% de, Table 1) and 1 (56% de, Table 2) with those

for the acyclic analogues 5 (n = 4) (30% de, Table 2) and 4

(32% de, Table 1) giving a 24% de increase in the case of

the macrocyclic ligands.

Table 2. Catalytic properties of ligands 1, 3a–d, 6, and 8a–d.

Ligand

cis/trans

ratio (% de)

ee (cis) [%]

configuration

ee (trans) [%] Yield [%]^[a]

configuration

1

22:78 (56)

11:89 (78)

6:94 (88)

21:79 (58)

26:74 (48)

43:57 (14)

51:49 (–2)

46:54 (8)

36 (1R,2S)

20 (1S,2R)

31 (1S,2R)

11 (1S,2R)

37 (1S,2R)

58 (1R,2S)

52 (1R,2S)

67 (1R,2S)

63 (1R,2S)

67 (1R,2S)

64 (1S,2S)

73 (1S,2S)

75 (1S,2S)

65 (1S,2S)

60 (1S,2S)

54 (1R,2R)

59 (1R,2R)

63 (1R,2R)

60 (1R,2R)

61 (1R,2R)

47

62

65

67

78

73

67

52

67

23

3a

3b

3c

3d

6

8a

8b

8c

8d

However, the most intriguing results are those relating to

diastereoselectivity. The majority of ligands described in the

literature, as well as the nonmacrocyclic ligands 4, 5, and 9,

show diastereoselectivities in a rather narrow range of 20 to

45 de% in the case of the trans-cyclopropanes. Our macro-

42:58 (16)

32:68 (36)

cyclic ligands exhibited significant aberration from these [a] Yields are not optimized.

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Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes

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With the tyrosinol ligands 7a–d no linear dependence of rivative 1 the de is considerably higher than that obtained

diastereoselectivity on the macrocycle ring size was ob- with the tyrosinol derivative 6 and those with the acyclic

served. Because of the presence of the phenylmethylene ligands 4, 5, and 9 (Table 1).

groups in the chiral centers, such macrocycles are more flex-

Ligands 3a–d showed, on average, slightly higher dia-

ible, and C₂to helical chirality transfer must be less ef- stereoselectivities than their non-methylated analogues 2a–

ficient. Consequently, the approach of styrene is less restric- d. Moreover, ligand 3b, with three carbon atoms in its alkane

ted, resulting in lower diastereoselectivity. In support of spacers, catalyzed cyclopropanation with the highest dia-

this, we had found earlier that selected ligands with phenyl stereoselectivity, not only among the ligands investigated in

rings at the stereogenic centers (2, 4, and 5) displayed this work, but also among all of the bis(oxazoline) ligands

stronger Cotton effects (CEs) than the ligands with benzyl described in the literature until now!

groups at the stereogenic centers (7 and 9).^[33]Larger CEs

Reduction of the free space in the reaction cavity through

are attributed to stronger exciton coupling of the two aro- the introduction of additional methyl groups, as in the tet-

matic chromophores at the stereogenic centers in 2, 4, and ramethylated ligand 3b (n = 3), resulted in only a slight

5. The differences in the spectra of 7 and 9 with respect to increase in the diastereoselectivity in relation to the non-

those of 2, 4, and 5 were attributed to the difference in methylated 2a (n = 2) (88% and 86%, resp); both macro-

geometry and the greater conformational freedom of the cyclic ligands, however, exhibited peak diasteroselectivities

para-alkoxybenzyl chromophores in the former mole- within the series, showing that their sizes were close to the

cules.^[34]These observations are consistent with the differ- optimal size of the macrocycle for achievement of the high-

ences in helicity of the hydroxyphenylglycinol- and ty- est de. The decrease in diastereoselectivity in the sequence

rosinol-derived Cu⁺macrocyclic complexes, which is in turn 3b to 3a indicates that ring size reduction and subsequent

reflected in their diastereoselectivities.

The macrocyclic effect is absent in the tyrosinol series, as plex resulted in a decrease in stereoselectivity.

is evident from the de values for the macrocyclic ligand 6 The diastereoselectivities obtained for the ligands 8a–d

restriction of conformational freedom of the catalytic com-

(14% de, Table 2) and the acyclic ligand 9 (20% de, Table 1), are within the same range as those of their non-methylated

the latter even showing a slightly higher diastereoselectivity analogues 7a–d, although with 8a–d the relationship be-

than the macrocyclic ligand.

tween diastereoselectivity and the macrocyclic ring size is

The results of the stereochemical outcomes in cyclopro- clearly evident, increasing with the number of methylene

panations catalyzed by Cu^Icomplexes of the smallest ligand groups in the spacers (Figure 5). Surprisingly, this relation-

1 and 6 and the ligands 3a–d and 8a–d with tetramethylated ship contrasts with that observed in the hydroxyphenylgly-

diphenylmethane bridges are collected in Table 2, while the cine series 2a–d and 3a–d, in which diastereoselectivity de-

dependence of diastereoselectivity on the size of the ligand creases with increasing macrocyclic ring size.

expressed as the number of methylene groups in the spacers

is shown in Figure 5.

Finally, on comparison of the dependence of diastereo-

selectivities on ring size for all prepared and examined li-

gands (Figure 5), it can be concluded that the ligands of

both hydroxyphenylglycinol and tyrosinol series show clear

dependence of diastereoselectivity on the macrocyclic ring

size. For both series of ligands the peak diastereoselectivity

is observed for the ligands possessing spacers with 2–3

methylene groups; the configurations of the prevailing dia-

stereomer, however, are opposite, trans for 2a and 3b and

cis for 7b and 8a.

In terms of enantioselectivity, the tyrosinol derivatives 6

and 8a–d did not show significant deviation from the values

obtained for the corresponding macrocyclic non-methylated

(7a–d) and acyclic (9) analogues. In contrast, the hydroxy-

phenylglycinol derivatives 3a–d showed (relative to their

non-methylated analogues 2a–d) a huge drop in the

enantioselectivities of the cis products (40% ee on average),

while at the same time there was no significant variation of

enantioselectivities for the trans products. It is interesting

to note that catalysis with the hydroxyphenylglycine ligand

1, the smallest of all the prepared macrocyclic bis(oxaz-

olines), even resulted in the configurational inversion of

the cis, but not of the trans, product. This unexpected result

might be the consequence of the much smaller size and in-

Figure 5. Comparison of the dependence of diastereoselectivity on

the macrocycle ring size for the ligands 1, 2, 3, 6, 7, and 8.

The ligands 1 and 6, with the smallest macrocyclic rings, creased rigidity of 1 in relation to ligands of the 2 series, so

showed rather low diastereoselectivities of 56% and 14% de, that the intermediate catalytic states could be different in

respectively, but even with the p-hydroxyphenylglycinol de- the two systems.

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FULL PAPER

Significant effects on the diastereoselectivity were also that of A. The cis-(1S,2R) enantiomer is formed by the tran-

observed in the Cu^Icomplex of one out of five axially chiral sition state C being more stable than that of D, due to more

macrocyclic phenanthroline and bipyridine ligands de- severe steric hindrance between styrene and bis(oxazoline)

scribed by Benaglia’s group.^[35]This complex catalyzed cy- phenyls in the latter. The observed high diastereoselectivity

clopropanation with a diastereoselectivity of –82% de (dia- in favor of the trans products can be explained by much less

stereomeric ratio 9:91 in favor of the cis product), while all pronounced steric repulsions between styrene phenyls and

the other ligands exhibited diastereoselectivities of approx. the macrocyclic bridge connecting R groups of the bis(oxaz-

50% de. Furthermore, the diastereoselectivities of Cu^Icom- oline) stereogenic centers in the transition states A and B

plexes of achiral concave phenanthrolines described by than in the transition states C and D. In the former pair,

Lüning’s group^[36]showed that the macrocyclic structure of the styrene phenyl is located below the bridge segment lying

the catalytic complex also had a strong influence on the above the bis(oxazoline) plane while in the latter pair the

diastereoselectivity outcome.

styrene phenyls are located on the same side and close to

The observed relationship between stereochemical out- the same bridge segment so that steric repulsion makes the

come and ligand structure can be explained as follows. As formation of cis diastereomers energetically less favorable.

already mentioned in the Introduction, according to It can be concluded that the extension of local C₂chirality

Pfaltz^[4]the stereochemistry of the predominating trans of the bis(oxazoline) unit into a larger volume and its tran-

product is determined by the more favorable styrene attack scription into helical chirality of the bridge increases the

from direction a; in the formed transition state I, the bulky energetic discrimination between the transition states A and

ethyl ester group faces a “small” hydrogen substituent. In B on the one hand and those of C and D on the other,

contrast, the attack from direction b produces the less stable which results in considerably increased diastereoselectivity.

transition state II, due to steric repulsion between the large Such discrimination is much less pronounced for the acyclic

substituent on the bis(oxazoline) stereogenic center and the bis(oxazoline) catalytic complexes, however, so much lower

ethyl ester group (Figure 6).

diastereoselectivity is usually observed for acyclic catalysts.

The stereochemical outcomes of the reactions catalyzed

In the ligand series 3a–d, with four additional methyl

by macrocyclic bis(oxazoline) complexes 2- and 3-Cu^Icould groups on the phenyls of the 2,2-diphenylpropane bridges,

be interpreted in terms of the transition states A–D shown a clear dependence of diastereoselectivity on the macrocycle

in Figure 7.

ring size was again observed (Table 2). In the case of the

The formation of the predominant trans-(1S,2S) isomer ligand 3b the highest de reported to date for this type of

could be explained by the formation of the transition state cyclopropanation (de 88%) was obtained. While the ee val-

A. The trans-(1R,2R) enantiomer should be formed by the ues for the trans products obtained by use of ligands 2a–d

transition state B, with the styrene phenyl ring positioned and 3a–d are comparable, those for the cis products are

closer to the bis(oxazoline) ligand, which produces steric much lower in the case of the 3a–d ligands, which can be

repulsion and makes the transition state B less stable than explained in terms of the relative stabilities of the C and D

Figure 6. Stereochemical course of cyclopropanation of styrene by ethyl diazoacetate catalyzed by chiral bis(oxazoline)–Cu^Icomplex as

proposed by Pfaltz.^[4]

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Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes

FULL PAPER

Because of their flexibility, the tyrosinol ligands can easily

adopt transition states giving both cis and trans products,

which results in poorer differentiation and hence lower dia-

stereoselectivity.

Conclusions

The new macrocyclic bis(oxazolines) 1, 2a–d, 3a–d, 6, 7a–

d, and 8a–d have been synthesized. Their copper(I) com-

plexes are the first representatives of conceptually new

supramolecular organometallic catalysts containing chiral

reaction spaces. The catalytic properties of such macrocyclic

copper(I) complexes were tested in the cyclopropanation of

styrene with ethyl diazoacetate as the model reaction, and

it was found that the macrocycle structure and its cavity

size have profound effects on the diastereoselectivity out-

comes of the selected transformation. A clear dependence

of diastereoselectivity on the size of the macrocyclic ring

was observed (Figure 5) and explained. The more flexible

tyrosinol derivatives 7a–d and 8a–d catalyzed cyclopropana-

tions with unusually small diastereoselectivities (–10 to 36%

de), while in contrast the more rigid hydroxyphenylglycine

derivatives 2a–d and 3a–d exhibited surprisingly high dia-

stereoselectivities (42–88% de). With the idea of increasing

the steric discrimination by constraining the macrocyclic

ring, four methyl substituents were added on the bisphenol

bridge, giving the ligands 3a–d and 8a–d. A diastereomeric

ratio of 94:6 trans/cis (88% de) was achieved with the ligand

3b. This result represents the highest diastereoselectivity ob-

served to date in the cyclopropanation of styrene with ethyl

diazoacetate catalyzed by the bis(oxazoline) class of Cu^I

catalytic complexes. Apparently, the helicity, size, and rigid-

ity of the macrocyclic reaction space guide the approach

and orientation of the styrene, resulting, in the cases of the

ligands 2a and 3b, in the formation of the trans-(S,S)-cyclo-

propane products with 86 and 88% de values and 65 and

75% ee values, respectively. It was observed that the intro-

duction of methyl substituents into the bisphenolic bridges

of the more rigid hydroxyphenylglycine-derived ligands 2a–

d, to give 3a–d, profoundly reduced the enantioselectivity of

the cis products (40% ee on average) without any significant

influence on the enantioselectivity of the trans products and

diastereoselectivity; however, this effect is absent in the

more flexible tyrosinol-derived ligands 8a–d.

Figure 7. Transition states (A, B, C, D) leading to stereoisomeric

cyclopropane products. The curves on the bis(oxazoline) R substit-

uents indicate the orientation of the connecting bridge above (thick

line) and bellow (dotted line) the bis(oxazoline) plane in the macro-

cyclic ligands.

transition states for the catalytic complexes 2a–d and 3a–d.

The presence of four additional methyl groups in the bridge

in the 3a–d series reduces the size of the macrocycle relative

to the 2a–d ligands and produces additional steric interac-

tions in the corresponding transition states, and because of

these steric interactions the transition states C in the 3a–d

series should be less stable than those in the 2a–d series.

Consequently, less cis-(1S,2R) enantiomer should be

formed in the reactions catalyzed by 3a–d catalytic com-

plexes and hence lower ee values for cis products should be

observed.

These results, especially the exceptionally high diastereo-

selectivities obtained with the catalytic complexes of the ri-

gid hydroxyphenylglycine-derived macrocyclic bis(oxa-

zolines)s 2a and 3d and the clearly observed dependence of

diastereoselectivity on the macrocycle ring size and its helic-

ity, point the way to a new generation of organometallic

catalysts and could be of wide applicability for many other

catalytic transformations using C₂chiral organometallic

catalysts.^[27]

The main difference between the macrocycles of series 2

and 3 and of the tyrosinol series (7 and 8) is the additional

methylene groups, which make the macrocyclic bridges sig-

Experimental Section

General: ¹H and ¹³C NMR spectra were recorded on a Varian

nificantly more flexible in the ligands of the tyrosinol series. Gemini XL 300 spectrometer with tetramethylsilane (TMS) as an

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T. Portada, M. Roje, Z. Raza, V. Caplar, M. Zinic´, V. Sunjic´

FULL PAPER

internal standard at 300 MHz, in CDCl₃unless otherwise stated.

Chemical shifts (δ) are reported in ppm and coupling constants (J)

in Hz. All NMR spectra are assigned as shown in Figure 8.

IR (KBr): ν = 3351, 3041, 2956, 2923, 2862, 1604, 1487, 1297, 1221,

˜

1179, 1112, 991, 884, 867, 771, 732, 581 cm^–1. Elemental analysis

calcd. (%) for C₁₉H₂₄O₂(284.40): calcd. C 80.24, H 8.51, O 11.25;

found: C 80.38, H 8.61.

General Procedure for Preparation of Diamides 11 and 18 from Di-

amides 10 and 17: Pd/C catalyst (10%, 400 mg) was added to a

solution of dibenzyldiamide (4.00 g) in methanol (150 mL). The

reaction mixture was mixed at room temperature in Parr hydro-

genator at 500 kPa overnight and was then filtered off through a

celite pad. Products were obtained in almost quantitative yields by

evaporation of filtrate without any TLC- or NMR-visible impuri-

ties.

2,2-Diethyl-N¹,N³-bis[(S)-1-(hydroxymethyl)-2-(4-hydroxyphenyl)-

ethyl]malonamide (11): This compound was obtained from 10

(4.0 g, 6.28 mmol) in a process that gave product 11 (2.87 g, 99%)

as a white/yellow foam. [α]_D= –34.8 (c = 0.89 in MeOH). ¹H NMR

([D₆]DMSO): δ = 9.12 (s, 2 H, C4ЈOH), 8.18 (d, J = 8.4 Hz, 2 H,

NH), 6.98 (d, J = 8.4 Hz, 4 H, C2ЈH, C6ЈH), 6.63 (d, J = 8.4 Hz,

4 H, C3ЈH, C5ЈH), 4.78 (brs, 2 H, C*H), 3.94 (m, 2 H, CH_aOH),

3.72 (brs, 2 H, CH₂OH), 3.28 (m, 2 H, CH_bOH), 2.72 (dd, J = 5.6

and 13.7 Hz, 2 H, C1Ј-CH_a), 2.53 (m, 2 H, C1Ј-CH_b), 1.68 (m, 4

H, CH₂CH₃), 0.40 (t, J = 7.2 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR

([D₆]DMSO): δ = 172.6 (C=O), 155.7 (C4Ј), 130.1 (C1Ј), 129.4

(C2Ј, C6Ј), 115.1 (C3Ј, C5Ј), 62.7 (CH₂OH), 57.3 (CEt₂), 52.7 (C*),

Figure 8. Atom numbering.

Spin multiplicities are abbreviated as s (singlet), d (doublet), t (trip-

let) pt (pseudotriplet – doublet of doublets), qua (quadruplet), q

(quintet) and m (multiplet). IR spectra were recorded on a FT ABB

Bomem MB 102 IR spectrometer on KBr plates with CsI optics

35.6 (CH C1Ј), 29.1 (CH CH ), 8.9 (CH CH ) ppm. IR (KBr): ν

˜

2

3

2

3

= 3346, 2967, 2939, 2877, 1653, 1614, 1515, 1457, 1361, 1237, 1172,

1108, 1039, 954, 824, 541, 507 cm^–1. C₂₅H₃₄N₂O₆(458.55): calcd.

C 65.48, H 7.47, N 6.11; found: C 65.36, H 7.28, N 6.16. HRMS:

[M]⁺calculated for C₂₅H₃₄N₂O₆: 458.2417; found: 458.2417.

and DTGS detector. Wavenumbers (ν) are reported as reciprocal

˜

centimeters (cm^–1). Melting points (t_m) were determined on an

Electrothermal Melting Point Apparatus and are uncorrected. Op-

tical rotations were measured at a temperature of 25 °C on an Op-

tical Activity AA-10 Automatic Polarimeter in 1 dm cells at a wave-

length of 589 nm. Low-resolution TOF-ESMS were recorded on a

ThermoQuest FT/MS 2001 DD Fourier Transform Mass Spectrom-

eter (Madison), fitted with a 3 T superconducting magnet. HRMS

were measure with Varian MAT 311 and MAT 8200 spectrometers.

Prepared compounds were purified chromatographically by prepar-

ative TLC on Merck HF₂₅₄silica gel. Reagents were purchased

from commercial suppliers (Fluka, Sigma–Aldrich, Kemika) and

were used without further purification. All solvents were purified

and dried by standard laboratory procedures. All reported reaction

yields are average values of all reactions performed. Macrocyclic

compounds have been named according to phane nomencla-

ture.^[37,38]

2,2-Diethyl-N¹,N³-bis[(R)-2-hydroxy-1-(4-hydroxyphenyl)ethyl]-

malonamide (18): This compound was obtained from 17 (4.00 g,

6.55 mmol) in a process that gave product 18 (2.818 g, 99%) as a

pale yellow foam. [α]_D= –82.2 (c = 0.85 in MeOH). ¹H NMR ([D₆]-

DMSO): δ = 9.23 (s, 2 H, C4ЈOH), 8.72 (d, J = 8.7 Hz, 2 H, NH),

7.04 (d, J = 7.6 Hz, 4 H, C2ЈH, C6ЈH), 6.64 (d, J = 7.6 Hz, 4 H,

C3ЈH, C5ЈH), 4.80 (m, 4 H, C*H and CH₂OH), 3.48 (m, 4 H,

CH₂OH), 1.83 (m, 4 H, CH₂CH₃), 0.59 (t, J = 6.8 Hz, 6 H,

CH₂CH₃) ppm. ¹³C NMR ([D₆]DMSO): δ = 172.8 (C=O), 156.5

(C4Ј), 131.7 (C1Ј), 128.1 (C2Ј, C6Ј), 115.0 (C3Ј, C5Ј), 64.8

(CH₂OH), 57.5 (CEt₂), 54.8 (C*), 29.6 (CH₂CH₃), 9.3

(CH CH ) ppm. IR (KBr): ν = 3327, 2969, 2939, 2877, 1655, 1615,

˜

2

3

1515, 1457, 1382, 1235, 1173, 1073, 1035, 832, 584, 543 cm^–1

.

C₂₃H₃₀N₂O₆(430.50): calcd. C 64.15, H 7.03, N 6.51; found: C

64.37, H 7.30, N 6.78.

Synthesis

General Procedure for Preparation of ω-Bromo-Alkylated Com-

pounds 12, 15a–d, and 19a–d from Phenolic Compounds Bis-

phenol A, 11, and 18: The phenolic compound (1.00 mmol) was dis-

solved in acetonitrile (50 mL) and K₂CO₃(553 mg, 4.00 mmol) and

the α,ω-dibromoalkane (20.0 mmol) was added. The reaction mix-

ture was stirred and heated to reflux overnight. After the system

had cooled to room temperature, inorganic salts were filtered off

and the filtrate was evaporated. The oily residue was purified by

preparative TLC in a CH₂Cl₂/MeOH (10:1) solvent system.

The starting dibenzyldiamides 10 and 17 were prepared by the pro-

cedures developed in our research group.^[30]Compound 22 was pre-

pared by the procedure described in the literature.^[32]

Preparation of 2,2-Bis(4-hydroxy-3,5-dimethylphenyl)propane (25):

Conc. H₂SO₄(14.4 g, 147 mmol) was added slowly to a stirred mix-

ture of 2,6-dimethylphenol (10.0 g; 81.9 mmol), acetone (2.38 g;

40.9 mmol) and water (3.30 g; 183 mmol) cooled to 0 °C, and left

overnight at 4 °C. The solid reaction mixture was dissolved in an

acetone/methanol mixture (7:3, 80 mL) and neutralized with aq.

Na₂CO₃(1 ). The pale brown precipitate was filtered off, washed

with water, dried and recrystallized from toluene, in a process that

2,2-Bis[4-(4-bromobutoxy)phenyl]propane (12): This compound was

obtained from bisphenol A (228 mg) and 1,4-dibromobutane

(4.32 g); after preparative TLC chromatography in hexanes, prod-

uct 12 (209 mg, 42%) was obtained as white crystals. t_m= 67 °C.

¹H NMR: δ = 7.13 (d, J = 8.7 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH), 6.78 (d,

gave product 25 (8.96 g, 77%) as a pale brown, crystalline powder.

1

t_m= 166 °C. H NMR: δ = 6.87 (s, 4 H, C3 H, C5 H), 4.15 (brs, J = 9.0 Hz, 4 H, C2ЈЈЈH, C6ЈЈЈH), 3.96 (t, J = 5.9 Hz, 4 H, C4ЈЈH₂),

2 H, C1OH), 2.34 (s, 12 H, C2CH₃, C6CH₃), 1.62 (s, 6 H, 3.48 (t, J = 6.5 Hz, 4 H, CH₂Br), 2.06 (m, 4 H, C2ЈЈH), 1.94 (m, 4

C4CCH₃) ppm. ¹³C NMR: δ = 149.7 (C1), 142.6 (C4), 126.8 (C3, H, C3ЈЈH), 1.63 (s, 6 H, CH₃) ppm. ¹³C NMR: δ = 156.6 (C1ЈЈЈ),

C5), 122.0 (C2, C6), 41.2 (CMe₂), 31.1 (CMe₂), 16.0 (C2CH₃) ppm.

143.1 (C4ЈЈЈ), 127.6 (C3ЈЈЈ, C5ЈЈЈ), 113.6 (C2ЈЈЈ, C6ЈЈЈ), 66.9 (C4ЈЈ),

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Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes

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41.4 (CMe₂), 33.3 (C1ЈЈ), 30.8 (CMe₂), 29.2 (C2ЈЈ), 27.7 C5ЈЈH₂), 2.79 (dd, J = 6.4 and 13.9 Hz, 2 H, C1Ј-CH_a), 2.66 (dd,

(C3ЈЈ) ppm. IR (KBr): ν = 3053, 2946, 2867, 1608, 1513, 1278, J = 8.5 and 13.9 Hz, 2 H, C1Ј-CH_b), 1.92 (m, 4 H, C4ЈЈH₂), 1.76

1249, 1182, 1046, 832, 741, 550 cm^–1. C₂₃H₃₀Br₂O₂(498.32): calcd. (m, 8 H, CH₂CH₃and C2ЈЈH₂), 1.60 (m, 4 H, CH₂CH₃), 0.51 (t, J

˜

C 55.44, H 6.07; found: C 55.20, H 5.97.

= 7.3 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 173.4 (C=O), 157.8

(C4Ј), 130.0 (C2Ј, C6Ј), 129.4 (C1Ј), 114.6 (C3Ј, C5Ј), 67.4 (C1ЈЈ),

64.4 (CH₂OH), 58.1 (CEt₂), 52.7 (C*), 35.9 (CH₂C1Ј), 33.4 (C5ЈЈ),

32.2 (C4ЈЈ), 28.2 (C2ЈЈ), 26.5 (CH₂CH₃), 26.5 (C3ЈЈ), 8.1

N¹,N³-Bis{(S)-2-[4-(2-bromoethoxy)phenyl]-1-(hydroxymethyl)-

ethyl}-2,2-diethylmalonamide (15a): This compound was obtained

from 11 (459 mg) and 1,2-dibromoethane (3.76 g) in a process that

(CH CH ) ppm. IR (KBr): ν = 3402, 3340, 2936, 2873, 1636, 1512,

˜

2

3

gave product 15a (195 mg, 29%) as a pale yellow, thick oil. [α]_D

=

1245, 1177, 1044, 816, 636, 553 cm^–1. C₃₅H₅₂Br₂N₂O₆(756.64):

–22.2 (c = 1.17 in MeOH). ¹H NMR: δ = 7.11 (d, J = 8.0 Hz, 4 H,

C2ЈH, C6ЈH), 6.82 (d, J = 7.7 Hz, 4 H, C3ЈH, C5ЈH), 6.76 (d, J =

calcd. C 55.56, H 6.93, N 3.70; found: C 55.45, H 7.14, N 3.91.

8.2 Hz, 2 H, NH), 4.24 (m, 6 H, C*H and C1ЈЈH₂), 3.72 (m, 2 H, N¹,N³-Bis{(R)-1-[4-(2-bromoethoxy)phenyl]-2-hydroxyethyl}-2,2-di-

CH_aOH), 3.67, (t, J = 6.0 Hz, 4 H, C2ЈЈH₂), 3.47 (dd, J = 6.0 and ethylmalonamide (19a): This compound was obtained from 18

11.3 Hz, 2 H, CH_bOH), 2.80 (dd, J = 6.2 and 13.9 Hz, 2 H, C1Ј-

CH_a), 2.67 (dd, J = 8.6 and 13.9 Hz, 2 H, C1Ј-CH_b), 1.71 (m, 4 H,

(430 mg) and 1,2-dibromoethane (3.76 g) in a process that gave

product 19a (129 mg, 20%) as a pale yellow, thick oil. [α]_D= –66.1

CH₂CH₃), 0.49 (t, J = 7.1 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = (c = 1.05 in MeOH). H NMR: δ = 7.55 (d, J = 7.4 Hz, 2 H, NH),

173.2 (C=O), 156.8 (C4Ј), 130.3 (C1Ј), 130.0 (C2Ј, C6Ј), 114.8 (C3Ј, 7.21 (d, J = 8.8 Hz, 4 H, C2ЈH, C6ЈH), 6.87 (d, J = 8.5 Hz, 4 H,

C5Ј), 67.8 (C1ЈЈ), 64.3 (CH₂OH), 58.1 (CEt₂), 52.8 (C*), 36.0 C3ЈH, C5ЈH), 5.12 (m, 2 H, C*H), 4.27 (t, J = 6.2 Hz, 4 H,

(CH₂C1Ј), 29.0 (C2ЈЈ), 26.5 (CH₂CH₃), 8.2 (CH₂CH₃) ppm. IR C1ЈЈH₂), 3.82 (m, 4 H, CH₂OH), 3.64, (t, J = 6.2 Hz, 4 H, C2ЈЈH₂),

1

(KBr): ν = 3336, 2970, 2930, 2877, 1655, 1511, 1244, 1178, 1018, 3.31 (brs, 2 H, OH), 1.95 (m, 4 H, CH₂CH₃), 0.81 (t, J = 6.5 Hz,

˜

833, 574 cm^–1. C₂₉H₄₀Br₂N₂O₆(672.48): calcd. C 51.80, H 6.00, N

4.17; found: C 51.70, H 6.10, N 4.30.

6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 173.2 (C=O), 157.5 (C4Ј),

131.5 (C1Ј), 127.8 (C2Ј, C6Ј), 114.9 (C3Ј, C5Ј), 67.7 (C1ЈЈ), 66.2

(CH₂OH), 58.2 (CEt₂), 55.0 (C*), 29.0 (C2ЈЈ), 28.2 (CH₂CH₃), 8.8

N¹,N³-Bis{(S)-2-[4-(3-bromopropoxy)phenyl]-1-(hydroxymethyl)-

ethyl}-2,2-diethylmalonamide (15b): This compound was obtained

from 11 (459 mg) and 1,3-dibromopropane (4.04 g) in a process

that gave product 15b (406 mg, 58%) as a pale yellow, thick oil.

[α]_D= –26.3 (c = 2.13 in MeOH). ¹H NMR: δ = 7.10 (d, J = 8.2 Hz,

(CH CH ) ppm. IR (KBr): ν = 3334, 3036, 2967, 2933, 2876, 1654,

˜

2

3

1613, 1511, 1457, 1385, 1244, 1178, 1074, 1031, 877, 829, 573,

542 cm^–1. C₂₇H₃₆Br₂N₂O₆(644.42): calcd. C 50.33, H 5.63, N 4.35;

found: C 50.44, H 5.38, N 4.37.

4 H, C2ЈH, C6ЈH), 6.82 (m, 6 H, C3ЈH, C5ЈH and NH), 4.23 (brs, N¹,N³-Bis{(R)-1-[4-(3-bromopropoxy)phenyl]-2-hydroxyethyl}-2,2-di-

2 H, C*H), 4.04 (t, J = 5.8 Hz, 4 H, C1ЈЈH₂), 3.72 (dd, J = 3.3 and

8.0 Hz, 2 H, CH_aOH), 3.58 (m, 8 H, CH_bOH and C3ЈЈH₂and

CH₂OH), 2.80 (dd, J = 6.0 and 11.3 Hz, 2 H, CH_bOH), 2.68 (m, 2

H, C1Ј-CH_b), 2.28 (q, J = 6.0 Hz, 4 H, C2ЈЈH₂), 1.72 (m, 4 H, (c = 0.51 in MeOH). H NMR: δ = 7.55 (d, J = 7.4 Hz, 2 H, NH),

CH₂CH₃), 0.50 (t, J = 7.1 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 7.20 (d, J = 8.7 Hz, 4 H, C2ЈH, C6ЈH), 6.87 (d, J = 8.5 Hz, 4 H,

173.2 (C=O), 157.3 (C4Ј), 129.9 (C2Ј, C6Ј), 129.7 (C1Ј), 114.5 (C3Ј, C3ЈH, C5ЈH), 5.11 (m, 2 H, C*H), 4.08 (t, J = 5.8 Hz, 4 H,

C5Ј), 65.1 (C1ЈЈ), 64.2 (CH₂OH), 58.1 (CEt₂), 52.8 (C*), 35.9 C1ЈЈH₂), 3.88 (dd, J = 3.8 and 11.3 Hz, 2 H, CH_aOH), 3.78 (dd, J

ethylmalonamide (19b): This compound was obtained from 18

(430 mg) and 1,3-dibromopropane (4.04 g) in a process that gave

product 19b (316 mg, 47%) as a pale yellow, thick oil. [α]_D= –66.9

1

(CH₂C1Ј), 32.1 (C3ЈЈ), 29.9 (C2ЈЈ), 26.4 (CH₂CH₃), 8.1

= 6.9 and 11.3 Hz, 2 H, CH_bOH), 3.60 (t, J = 6.4 Hz, 4 H, C3ЈЈH₂),

2.96 (brs, 2 H, OH), 2.31 (q, J = 6.1 Hz, 4 H, C2ЈЈH₂), 1.95 (q, J

= 7.3 Hz, 4 H, CH₂CH₃), 0.82 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm.

¹³C NMR: δ = 173.2 (C=O), 157.9 (C4Ј), 131.2 (C1Ј), 127.7 (C2Ј,

C6Ј), 114.4 (C3Ј, C5Ј), 65.6 (CH₂OH), 65.0 (C1ЈЈ), 58.1 (CEt₂),

55.0 (C*), 32.1 (C3ЈЈ), 29.9 (C2ЈЈ), 27.0 (CH₂CH₃), 8.4

(CH CH ) ppm. IR (KBr): ν = 3422, 2970, 2934, 2877, 1638, 1509,

˜

2

3

1455, 1244, 1034, 816 cm^–1.

N¹,N³-Bis{(S)-2-[4-(4-bromobutoxy)phenyl]-1-(hydroxymethyl)-

ethyl}-2,2-diethylmalonamide (15c): This compound was obtained

from 11 (459 mg) and 1,4-dibromobutane (4.32 g) in a process that

(CH CH ) ppm. IR (KBr): ν = 3396, 3326, 3062, 2970, 2933, 2877,

˜

2

3

gave product 15c (408 mg, 56%) as a pale yellow, thick oil. [α]_D

=

1654, 1614, 1512, 1454, 1234, 1177, 1072, 1031, 929, 828, 727, 609,

541 cm^–1. C₂₉H₄₀Br₂N₂O₆(672.48): calcd. C 51.80, H 6.00, N 4.17;

found: C 51.92, H 6.20, N 4.28.

–23.9 (c = 6.99 in MeOH). ¹H NMR: δ = 7.08 (d, J = 8.5 Hz, 4 H,

C2ЈH, C6ЈH), 6.77 (m, 6 H, C3ЈH, C5ЈH and NH), 4.21 (brs, 2 H,

C*H), 3.93 (t, J = 5.9 Hz, 4 H, C1ЈЈH₂), 3.70 (m, 2 H, CH_aOH),

3.46 (m, 6 H, CH_bOH and C4ЈЈH₂), 2.78 (dd, J = 6.3 and 14.0 Hz, N¹,N³-Bis{(R)-1-[4-(4-bromobutoxy)phenyl]-2-hydroxyethyl}-2,2-di-

2 H, C1Ј-CH_a), 2.66 (dd, J = 8.4 and 14.0 Hz, 2 H, C1Ј-CH_b), 2.03

(m, 4 H, C3ЈЈH₂), 1.90 (m, 4 H, C2ЈЈH₂), 1.71 (m, 4 H, CH₂CH₃), (430 mg) and 1,4-dibromobutane (4.32 g) in a process that gave

0.50 (t, J = 7.2 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 173.3

product 19c (448 mg, 64%) as a pale yellow, thick oil. [α]_D= –61.1

(C=O), 157.6 (C4Ј), 130.0 (C2Ј, C6Ј), 129.6 (C1Ј), 114.5 (C3Ј, C5Ј), (γ = 85.4 gdm^–3, MeOH). H NMR: δ = 7.64 (d, J = 8.0 Hz, 2 H,

66.7 (C1ЈЈ), 64.2 (CH₂OH), 58.0 (CEt₂), 52.7 (C*), 35.9 (CH₂C1Ј), NH), 7.21 (d, J = 8.2 Hz, 4 H, C2ЈH, C6ЈH), 6.79 (d, J = 8.2 Hz,

33.2 (C4ЈЈ), 29.2 (C3ЈЈ), 27.6 (C2ЈЈ), 26.3 (CH₂CH₃), 8.0 4 H, C3ЈH, C5ЈH), 5.16 (m, 2 H, C*H), 4.43 (brs, 2 H, OH), 3.93

ethylmalonamide (19c): This compound was obtained from 18

1

(CH CH ) ppm. IR (KBr): ν = 3411, 3325, 2958, 2877, 1635, 1508,

(t, J = 5.9 Hz, 4 H, C1ЈЈH₂), 3.83 (brs, 4 H, CH₂OH), 3.47 (t, J =

6.4 Hz, 4 H, C4ЈЈH₂), 2.56–1.86 (m, 12 H, CH₂CH₃and C2ЈЈH₂

and C3ЈЈH₂), 0.74 (t, J = 6.9 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR:

δ = 173.4 (C=O), 158.3 (C4Ј), 131.1 (C1Ј), 127.9 (C2Ј, C6Ј), 114.5

(C3Ј, C5Ј), 66.7 (C1ЈЈ), 65.9 (CH₂OH), 58.2 (CEt₂), 55.1 (C*), 33.3

( C4Ј Ј) , 2 9 . 2 ( C3Ј Ј) , 2 7. 7 ( C2ЈЈ), 26.7 (CH₂CH₃) , 8. 3

˜

2

3

1246, 1176, 1042, 945, 825 cm^–1. HRMS: [M]⁺calculated for

C₃₃H₄₈Br₂N₂O₆: 728.18585; found: 728.18590.

N¹,N³-Bis{(S)-2-[4-(5-bromopentyloxy)phenyl]-1-(hydroxymethyl)-

ethyl}-2,2-diethylmalonamide (15d): This compound was obtained

from 11 (459 mg) and 1,5-dibromopentane (4.60 g) in a process that

(CH CH ) ppm. IR (KBr): ν = 3417, 3337, 2963, 2876, 1655, 1513,

˜

2

3

gave product 15d (446 mg, 59%) as a pale yellow, thick oil. [α]_D

=

1246, 1178, 1038, 830, 555 cm^–1.

–22.1 (c = 3.53 in MeOH). ¹H NMR: δ = 7.09 (d, J = 8.4 Hz, 4 H,

C2ЈH, C6ЈH), 6.80 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH), 6.72 (d, J =

N¹,N³-Bis{(R)-1-[4-(5-bromopentyloxy)phenyl]-2-hydroxyethyl}-2,2-

8.1 Hz, 2 H, NH), 4.21 (m, 2 H, C*H), 3.91 (t, J = 6.3 Hz, 4 H, diethylmalonamide (19d): This compound was obtained from 18

C1ЈЈH₂), 3.72 (m, 4 H, CH_aOH), 3.43 (m, 6 H, CH_bOH and (430 mg) and 1,5-dibromopentane (4.60 g) in a process that gave

Eur. J. Org. Chem. 2007, 838–856

www.eurjoc.org

849

ˇ

T. Portada, M. Roje, Z. Raza, V. Caplar, M. Zinic´, V. Sunjic´

FULL PAPER

product 19d (342 mg, 47%) as a pale yellow, thick oil. [α]_D= –56.8

(CH CH ), 29.0 (C2ЈЈ), 8.8 (CH CH ) ppm. IR (KBr): ν = 3433,

3320, 3035, 2966, 2927, 1637, 1512, 1246, 1017, 1246, 1178, 1017,

˜

2

3

2

3

1

(c = 5.74 in MeOH). H NMR: δ = 7.67 (d, J = 8.0 Hz, 2 H, NH),

7.20 (d, J = 8.5 Hz, 4 H, C2ЈH, C6ЈH), 6.80 (d, J = 8.5 Hz, 4 H, 839, 811 cm^–1.

C3ЈH, C5ЈH), 5.13 (m, 2 H, C*H), 4.48 (brs, 2 H, OH), 3.91 (t, J

N¹,N³-Bis{(S)-2-[4-(3-bromopropoxy)phenyl]-1-(chloromethyl)-

= 6.2 Hz, 4 H, C1ЈЈH₂), 3.81 (m, 4 H, CH₂OH), 3.43 (m, 4 H,

C5ЈЈH₂), 1.92 (m, 8 H, CH₂CH₃and C4ЈЈH₂), 1.78 (m, 4 H,

C2ЈЈH₂), 1.60 (m, 4 H, C3ЈЈH₂), 0.74 (t, J = 7.1 Hz, 6 H,

CH₂CH₃) ppm. ¹³C NMR: δ = 173.4 (C=O), 158.4 (C4Ј), 131.0

(C1Ј), 127.8 (C2Ј, C6Ј), 114.5 (C3Ј, C5Ј), 67.4 (C1ЈЈ), 65.7

(CH₂OH), 58.2 (CEt₂), 55.0 (C*), 33.5 (C5ЈЈ), 32.2 (C4ЈЈ), 28.2

(C2ЈЈ), 26.8 (CH₂CH₃), 24.6 (C3ЈЈ), 8.3 (CH₂CH₃) ppm. IR (KBr):

ethyl}-2,2-diethylmalonamide (16b): This compound was obtained

from 15b (700 mg), by Method a in a process that gave product 16b

(413 mg, 56%) as a white solid. t_m= 112 °C. [α]_D= –20.4 (c = 1.42

1

in CH₂Cl₂). H NMR: δ = 7.42 (d, J = 8.1 Hz, 2 H, NH), 7.16 (d,

J = 8.5 Hz, 4 H, C2ЈH, C6ЈH), 6.85 (d, J = 8.4 Hz, 4 H, C3ЈH,

C5ЈH), 4.53 (m, 2 H, C*H), 4.06 (t, J = 5.7 Hz, 4 H, C1ЈЈH₂), 3.65

(dd, J = 4.1 and 11.3 Hz, 2 H, CH_aCl), 3.59 (t, J = 6.4 Hz, 4 H,

C3ЈЈH₂), 3.52 (dd, J = 3.4 and 11.2 Hz, 2 H, CH_bCl), 2.86 (d, J =

7.4 Hz, 4 H, C1Ј-CH₂), 2.29 (q, J = 6.0 Hz, 4 H, C2ЈЈH₂), 1.78 (m,

4 H, CH₂CH₃), 0.69 (t, J = 7.3 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR:

δ = 172.4 (C=O), 157.5 (C4Ј), 130.2 (C1Ј), 130.1 (C2Ј, C6Ј), 114.6

(C3Ј, C5Ј), 65.2 (C1ЈЈ), 57.9 (CEt₂), 50.9 (C*), 46.5 (CH₂Cl), 36.5

(CH₂C1Ј), 32.2 (C3ЈЈ), 30.4 (CH₂CH₃), 29.9 (C2ЈЈ), 9.1

ν = 3423, 3334, 2943, 2877, 1645, 1508, 1243, 1177, 1037, 829, 727,

˜

541 cm^–1. C₃₃H₃₈Br₂N₂O₆(718.51): calcd. C 55.16, H 5.33, N 3.90;

found: C 55.11, H 5.75, N 4.15.

General Procedures for the Preparation of Dichlorides 14, 16a–d,

20a–d, 21, and 23 from Dihydroxy Compounds 13, 15a–d, 19a–d, 12,

and 18. Method a: Thionyl chloride (1.19 g, 10.0 mmol) was added

to a solution of the dihydroxy compound (1.00 mmol) in dichloro-

methane (20 mL) and the reaction mixture was mixed at room tem-

perature overnight. Solvent was then evaporated and the dry resi-

due was purified by preparative TLC in CH₂Cl₂/MeOH (20:1) to

give the product.

(CH CH ) ppm. IR (KBr): ν = 3300, 2961, 2925, 2877, 1635, 1512,

˜

2

3

1242, 1033, 823, 528 cm^–1.

N¹,N³-Bis{(S)-3-[4-(4-bromobutoxy)phenyl]-1-(chloromethyl)ethyl}-

2,2-diethylmalonamide (16c): This compound was obtained from

15c (729 mg) by both Method a and Method b. Method a yielded

582 mg (76%) and Method b yielded 505 mg (66%) of product 16c

Method b: Triphosgene (252 mg, 0.844 mmol) was added with stir-

ring to a solution of triphenylphosphane (608 mg, 2.32 mmol) in

dichloromethane (15 mL), cooled down to 0 °C. After gas evol-

ution had subsided, a dichloromethane solution of the dihydroxy

compound (1.00 mmol) was added. The reaction mixture was

stirred at room temperature for 1 h, and then treated as in

Method a.

1

as a white solid. t_m= 99 °C. [α]_D= –21.0 (c = 6.15 in CH₂Cl₂). H

NMR: δ = 7.41 (d, J = 8.0 Hz, 2 H, NH), 7.14 (d, J = 8.2 Hz, 4

H, C2ЈH, C6ЈH), 6.81 (d, J = 8.0 Hz, 4 H, C3ЈH, C5ЈH), 4.41 (m,

2 H, C*H), 3.94 (t, J = 5.8 Hz, 4 H, C1ЈЈH₂), 3.64 (dd, J = 4.0 and

11.1 Hz, 2 H, CH_aCl), 3.47 (m, 6 H, CH_bCl and C4ЈЈH₂), 2.84 (d,

J = 7.2 Hz, 4 H, C1Ј-CH₂), 2.04 (m, 4 H, C3ЈЈH₂), 1.90 (m, 4

H, C2ЈЈH₂), 1.77 (m, 4 H, CH₂CH₃), 0.67 (t, J = 7.3 Hz, 6 H,

CH₂CH₃) ppm. ¹³C NMR: δ = 172.6 (C=O), 157.9 (C4Ј), 130.2

(C2Ј, C6Ј), 128.9 (C1Ј), 114.6 (C3Ј, C5Ј), 66.7 (C1ЈЈ), 57.9 (CEt₂),

50.9 (C*), 46.4 (CH₂Cl), 36.4 (CH₂C1Ј), 33.3 (C4ЈЈ), 30.3

(CH₂CH₃), 29.2 (C3ЈЈ), 27.7 (C2ЈЈ), 8.9 (CH₂CH₃) ppm. IR (KBr):

(12S,18S)-12,18-Bis(chloromethyl)-15,15-diethyl-2,2-dimethyl-

4,9,21,26-tetraoxa-13,17-diaza-1,3,10,20(1,4)-tetrabenzenacyclohexa-

cosaphane-14,16-dione (14): This compound was obtained from 13

(795 mg) by Method b in a process that gave product 14 (466 mg,

56%) as a white foam. [α]_D= –8.6 (c = 1.34 in CH₂Cl₂). ¹H NMR:

δ = 7.29 (d, J = 8.0 Hz, 2 H, NH), 7.11 (d, J = 8.5 Hz, 4 H, C2ЈH,

C6ЈH or C3ЈЈЈH, C5ЈЈЈH), 7.10 (d, J = 8.7 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH

or C2ЈH, C6ЈH), 6.80 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH or C2ЈЈЈH,

ν = 3316, 3035, 2962, 2871, 1636, 1583, 1512, 1473, 1442, 1386,

˜

1245, 1177, 1108, 1042, 940, 838, 737, 655, 532 cm^–1.

N¹,N³-Bis{(S)-3-[4-(5-bromopentyloxy)phenyl]-1-(chloromethyl)-

C6ЈЈЈH), 6.74 (d, J = 8.7 Hz, 4 H, C2ЈЈЈH, C6ЈЈЈH, C6ЈЈЈH or C3ЈH, ethyl}-2,2-diethylmalonamide (16d): This compound was obtained

C5ЈH), 4.43 (m, 2 H, C*H), 4.00 (brs, 8 H, C1ЈЈH₂and C4ЈЈH₂), from 15d (757 mg) by both Method a and Method b. Method a

3.64 (dd, J = 4.6 Hz, J = 11.3 Hz, 2 H, CH_aCl), 3.55 (dd, J = 3.6

and 11.0 Hz, 2 H, CH_bCl), 2.84 (m, 4 H, C1Ј-CH₂), 1.93 (brs, 8

H, C2ЈЈH₂and C3ЈЈH₂), 1.72 (m, 4 H, CH₂CH₃), 1.63 (s, 6 H,

C4ЈЈЈCCH₃), 0.57 (t, J = 7.3 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR:

yielded 579 mg (73 %) and Method b yielded 595 mg (75 %) of

product 16d as a white solid. t_m= 92 °C. [α]_D= –18.9 (c = 2.59 in

CH₂Cl₂). H NMR: δ = 7.41 (d, J = 8.0 Hz, 2 H, NH), 7.15 (d, J

1

= 8.5 Hz, 4 H, C2ЈH, C6ЈH), 6.83 (d, J = 8.5 Hz, 4 H, C3ЈH,

δ = 172.5 (C=O), 157.8 (C4Ј), 156.5 (C1ЈЈЈ), 143.1 (C4ЈЈЈ), 130.1 C5ЈH), 4.43 (m, 2 H, C*H), 3.93 (t, J = 6.3 Hz, 4 H, C1ЈЈH₂), 3.65

(C2Ј, C6Ј), 128.6 (C1Ј), 127.6 (C3ЈЈЈ, C5ЈЈЈ), 114.7 (C3Ј, C5Ј), 113.8 (dd, J = 4.1 and 11.3 Hz, 2 H, CH_aCl), 3.52 (dd, J = 3.3 and

(C2ЈЈЈ, C6ЈЈЈ), 67.1 (C1ЈЈ or C4ЈЈ), 67.0 (C4ЈЈ or C1ЈЈ), 57.9 (CEt₂), 11.3 Hz, 2 H, CH_bCl), 3.43 (t, J = 6.7 Hz, 4 H, C5ЈЈH₂), 2.85 (d,

50.7 (C*), 46.6 (CH₂Cl), 41.3 (CMe₂), 36.5 (CH₂C1Ј), 30.6 (CMe₂), J = 7.4 Hz, 4 H, C1Ј-CH₂), 1.93 (m, 4 H, C4ЈЈH₂), 1.79 (m, 8 H,

30.0 (CH₂CH₃), 25.4 (C2ЈЈ or C3ЈЈ), 25.3 (C3ЈЈ and C2ЈЈ), 8.7

CH₂CH₃and C2ЈЈH₂), 1.63 (m, 4 H, C3ЈЈH₂), 0.69 (t, J = 7.3 Hz,

6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 172.4 (C=O), 157.7 (C4Ј),

130.0 (C2Ј, C6Ј), 128.6 (C1Ј), 114.5 (C3Ј, C5Ј), 67.4 (C1ЈЈ), 57.9

(CEt₂), 50.8 (C*), 46.4 (CH₂Cl), 36.4 (CH₂C1Ј), 33.4 (C5ЈЈ), 32.3

( C4Ј Ј) , 3 0 . 3 (CH₂CH₃) , 2 8. 2 ( C2ЈЈ), 24.6 (C3Ј Ј) , 8. 9

(CH CH ) ppm. IR (KBr): ν = 3319, 3036, 2963, 2874, 1638, 1511,

˜

2

3

1248, 1180, 1025, 829, 786, 554 cm^–1.

N¹,N³-Bis{(S)-2-[4-(2-bromoethoxy)phenyl]-1-(chloromethyl)ethyl}-

2,2-diethylmalonamide (16a): This compound was obtained from

15a (672 mg) by Method a in a process that gave product 16a

(539 mg, 76%) as a white solid. t_m= 102 °C. [α]_D= –22.4 (c = 1.07

(CH CH ) ppm. IR (KBr): ν = 3316, 2941, 2866, 1636, 1512, 1471,

˜

2

3

1300, 1246, 1177, 1046, 839, 737, 651, 539 cm^–1.

1

in CH₂Cl₂). H NMR: δ = 7.39 (d, J = 8.0 Hz, 2 H, NH), 7.10 (d,

N¹,N³-Bis{(R)-1-[4-(2-bromoethoxy)phenyl]-2-chloroethyl}-2,2-di-

ethylmalonamide (20a): This compound was obtained from 19a

J = 8.5 Hz, 4 H, C2ЈH, C6ЈH), 6.78 (d, J = 8.5 Hz, 4 H, C3ЈH,

C5ЈH), 4.38 (m, 2 H, C*H), 4.18 (t, J = 6.2 Hz, 4 H, C1ЈЈH₂), 3.55 (644 mg) by Method a in a process that gave product 20a (538 mg,

(m, 8 H, CH₂Cl and C2ЈЈH₂), 2.81 (d, J = 2.5 Hz, 2 H, C1Ј-CH_a), 79 %) as a white solid. t_m= 135 °C. [α]_D= –69.0 (c = 1.46 in

2.78 (d, J = 2.2 Hz, 2 H, C1Ј-CH_b), 1.71 (m, 4 H, CH₂CH₃), 0.60 CHCl₃). H NMR: δ = 7.89 (d, J = 7.7 Hz, 2 H, NH), 7.21 (d, J

(t, J = 7.3 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 173.3 (C=O),

= 8.8 Hz, 4 H, C2ЈH, C6ЈH), 6.87 (d, J = 8.8 Hz, 4 H, C3ЈH,

1

156.7 (C4Ј), 129.9 (C2Ј, C6Ј), 129.4 (C1Ј), 114.6 (C3Ј, C5Ј), 67.6 C5ЈH), 5.31 (q, J = 6.3 Hz, 2 H, C*H), 4.27 (t, J = 6.3 Hz, 4 H,

(C1ЈЈ), 57.7 (CEt₂), 50.7 (C*), 46.3 (CH₂Cl), 36.3 (CH₂C1Ј), 30.3 C1ЈЈH₂), 3.84 (dd, J = 4.9 and 11.5 Hz, 2 H, CH_aCl), 3.77 (dd, J

850

www.eurjoc.org

Eur. J. Org. Chem. 2007, 838–856

Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes

FULL PAPER

= 6.3 and 11.3 Hz, 2 H, CH_bCl), 3.63 (t, J = 6.2 Hz, 4 H, C2ЈЈH₂),

1.95 (q, J = 7.3 Hz, 4 H, CH₂CH₃), 0.84 (t, J = 7.3 Hz, 6 H,

by Method a in a process that gave product 21 (426 mg, 86%) as a

white foam. [α]_D= –29.1 (c = 1.99 in MeOH). H NMR: δ = 7.63

1

CH₂CH₃) ppm. ¹³C NMR: δ = 172.5 (C=O), 157.7 (C4Ј), 131.2 (d, J = 8.0 Hz, 2 H, NH), 7.38 (brs, 2 H, C4ЈOH), 7.03 (d, J =

(C1Ј), 127.7 (C2Ј, C6Ј), 114.8 (C3Ј, C5Ј), 67.7 (C1ЈЈ), 58.1 (CEt₂), 8.3 Hz, 4 H, C2ЈH, C6ЈH), 6.75 (d, J = 8.2 Hz, 4 H, C3ЈH, C5ЈH),

53.4 (C*), 47.5 (CH₂Cl), 30.6 (CH₂CH₃), 28.9 (C2ЈЈ), 9.3 4.46 (m, 2 H, C*H), 3.67 (dd, J = 4.2 and 11.2 Hz, 2 H, CH_aCl),

(CH CH ) ppm. IR (KBr): ν = 3301, 3047, 2967, 2933, 2877, 1635,

3.56 (dd, J = 3.3 and 11.0 Hz, 2 H, CH_bCl), 2.89 (dd, J = 6.2 and

˜

2

3

1512, 1457, 1385, 1292, 1245, 1179, 1075, 1015, 879, 831, 743, 669, 14.0 Hz, 2 H, C1Ј-CH_a), 2.77 (dd, J = 8.6 and 13.8 Hz, 2 H, C1Ј-

572, 541 cm^–1.

CH_b), 1.70 (m, 4 H, CH₂CH₃), 0.49 (t, J = 7.1 Hz, 6 H,

CH₂CH₃) ppm. ¹³C NMR: δ = 173.0 (C=O), 154.9 (C4Ј), 130.1

(C1Ј), 128.2 (C2Ј, C6Ј), 115.5 (C3Ј, C5Ј), 57.9 (CEt₂), 51.1 (C*),

46.9 (CH₂Cl), 36.7 (CH₂C1Ј), 31.0 (CH₂CH₃), 8.9 (CH₂CH₃) ppm.

N¹,N³-Bis{(R)-1-[4-(3-bromopropoxy)phenyl]-2-chloroethyl}-2,2-di-

ethylmalonamide (20b): This compound was obtained from 19b

(672 mg) by Method a in a process that gave product 20b (589 mg,

83 %) as a white solid. t_m= 141 °C. [α]_D= –62.7 (c = 0.93 in

IR (KBr): ν = 3255, 2969, 1655, 1614, 1515, 1444, 1355, 1232, 1172,

˜

1107, 825 cm^–1.

1

CH₂Cl₂). H NMR: δ = 7.85 (d, J = 7.5 Hz, 2 H, NH), 7.21 (d, J

= 8.5 Hz, 4 H, C2ЈH, C6ЈH), 6.87 (d, J = 8.6 Hz, 4 H, C3ЈH,

N¹,N³-Bis[(R)-1-(chloromethyl)-2-(4-hydroxyphenyl)ethyl]-2,2-dieth-

C5ЈH), 5.31 (m, 2 H, C*H), 4.09 (t, J = 5.8 Hz, 4 H, C1ЈЈH₂), 3.85 ylmalonamide (23): This compound was obtained from 18 (430 mg)

(dd, J = 5.1 and 11.3 Hz, 2 H, CH_aCl), 3.78 (dd, J = 6.3 and by Method a in a process that gave product 23 (421 mg, 90%) as a

1

11.3 Hz, 2 H, CH_bCl), 3.60 (t, J = 6.3 Hz, 4 H, C3ЈЈH₂), 2.31 (q, white foam. [α]_D= –82.4 (c = 1.20 in MeOH). H ([D₆]DMSO): δ

J = 6.1 Hz, 4 H, C2ЈЈH₂), 1.94 (q, J = 7.3 Hz, 4 H, CH₂CH₃), 0.85 = 9.43 (brs, 2 H, C4ЈOH), 9.15 (d, J = 8.0 Hz, 2 H, NH), 7.12 (d,

(t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 172.5 (C=O),

J = 7.6 Hz, 4 H, C2ЈH, C6ЈH), 6.68 (d, J = 7.7 Hz, 4 H, C3ЈH,

158.3 (C4Ј), 130.7 (C1Ј), 127.7 (C2Ј, C6Ј), 114.6 (C3Ј, C5Ј), 65.1 C5ЈH), 5.05 (m, 2 H, C*H), 3.80 (m, 4 H, CH₂Cl), 1.86 (m, 4 H,

(C1ЈЈ), 58.2 (CEt₂), 53.4 (C*), 47.5 (CH₂Cl), 32.1 (C3ЈЈ), 30.7 CH₂CH₃), 0.60 (t, J = 6.5 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ =

(CH CH ), 29.8 (C2ЈЈ), 9.3 (CH CH ) ppm. IR (KBr): ν = 3301,

172.6 (C=O), 156.9 (C4Ј), 130.1 (C1Ј), 128.1 (C2Ј, C6Ј), 115.5 (C3Ј,

C5Ј), 57.6 (CEt₂), 54.0 (C*), 47.5 (CH₂Cl), 29.9 (CH₂CH₃), 9.3

˜

2

3

2

3

2967, 2933, 2877, 1635, 1612, 1513, 1246, 1179, 1030, 929, 831,

748 cm^–1. C₂₉H₃₈Br₂Cl₂N₂O₄(709.38): calcd. C 49.10, H 5.40, N

3.95; found: C 49.36, H 5.31, N 4.03.

(CH CH ) ppm. IR (KBr): ν = 3256, 2970, 1655, 1615, 1517, 1457,

˜

2

3

1364, 1230, 1175, 836, 538 cm^–1.

N¹,N³-Bis{(R)-1-[4-(4-bromobutoxy)phenyl]-2-chloroethyl}-2,2-di-

ethylmalonamide (20c): This compound was obtained from 19c

(700 mg) by both Method a and Method b. Method a yielded

509 mg (69%) and Method b yielded 538 mg (73%) of product 20c

as a white solid. t_m= 117 °C. [α]_D= –65.4 (c = 6.87 in CH₂Cl₂/

Preparation of (1⁴S,3⁴S)-2,2-Diethyl-13,13-dimethyl-1⁴,1⁵,3⁴,3⁵-

tetrahydro-6,11,15,20-tetraoxa-1,3(2,4)-bis(1,3-oxazola)-

5,12,14,21(1,4)-tetrabenzenacyclodocosaphane (7c): A solution of

compound 14 (46 mg, 0.061 mmol) in NaOH/MeOH (0.5 , 2 mL)

was heated at reflux for 2 h. After it had cooled to room tempera-

ture, product 7c (32 mg, 76 %) precipitated; it was filtered off,

washed with water and dried. [α]_D= –50.8 (c = 1.093 in CH₂Cl₂).

1

MeOH). H NMR: δ = 7.85 (d, J = 7.7 Hz, 2 H, NH), 7.20 (d, J

= 8.5 Hz, 4 H, C2ЈH, C6ЈH), 6.84 (d, J = 8.7 Hz, 4 H, C3ЈH,

C5ЈH), 5.30 (m, 2 H, C*H), 3.97 (t, J = 5.9 Hz, 4 H, C1ЈЈH₂), 3.80 ¹H NMR: δ = 7.10 (pt, J = 8.8 Hz, 8 H, C2ЈH, C6ЈH and C3ЈЈЈH,

(m, 4 H, CH₂Cl), 3.48 (t, J = 6.4 Hz, 4 H, C4ЈЈH₂), 2.06 (m, 4 H, C5ЈЈЈH), 6.78 (m, 8 H, C3ЈH, C5ЈH and C2ЈЈЈH, C6ЈЈЈH, C6ЈЈЈH),

C3ЈЈH₂), 1.94 (m, 8 H, CH₂CH₃and C2ЈЈH₂), 0.84 (t, J = 7.3 Hz, 4.37 (m, 2 H, C4 H), 4.15 (pt, J = 8.8 Hz, 8 H, C5Ha), 4.01 (m, 8

6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 172.7 (C=O), 158.6 (C4Ј),

H, C1ЈЈH₂and C4ЈЈH₂), 3.93 (pt, J = 7.7 Hz, 2 H, C5Hb), 2.93

130.6 (C1Ј), 127.7 (C2Ј, C6Ј), 114.6 (C3Ј, C5Ј), 66.7 (C1ЈЈ), 58.1 (dd, J = 5.2 Hz, J = 13.7 Hz, 2 H, C1Ј-CH_a), 2.68 (dd, J = 7.3 and

(CEt₂), 53.4 (C*), 47.3 (CH₂Cl), 33.2 (C4ЈЈ), 30.5 (CH₂CH₃), 29.2 13.6 Hz, 2 H, C1Ј-CH_b), 1.94 (m, 12 H, C2ЈЈH₂and C3ЈЈH₂and

(C3ЈЈ), 27.6 (C2ЈЈ), 9.1 (CH CH ) ppm. IR (KBr): ν = 3301, 3035,

CH₂CH₃), 1.64 (s, 6 H, C4ЈЈЈCCH₃), 0.77 (t, J = 7.4 Hz, 6 H,

CH₂CH₃) ppm. ¹³C NMR: δ = 167.9 (C2), 157.5 (C4Ј), 156.6

(C1ЈЈЈ), 143.2 (C4ЈЈЈ), 130.6 (C2Ј, C6Ј), 129.6 (C1Ј), 127.6 (C3ЈЈЈ,

C5ЈЈЈ), 114.5 (C3Ј, C5Ј), 113.6 (C2ЈЈЈ, C6ЈЈЈ), 71.0 (C5), 67.1, 67.0

(C1ЈЈ and C4ЈЈ), 66.8 (C4), 46.6 (CEt₂), 41.4 (CMe₂), 40.1

(C4CH2), 30.7 (CMe₂), 25.4 (C2ЈЈ and C3ЈЈ and CH₂CH₃), 8.1

˜

2

3

2963, 2877, 1635, 1513, 1294, 1249, 1179, 1040, 939, 831, 747,

541 cm^–1. C₃₁H₄₂Br₂Cl₂N₂O₄(737.43): calcd. C 50.42, H 5.74, N

3.80; found: C 50.72, H 5.75, N 3.66.

N¹,N³-Bis{(R)-1-[4-(5-bromopentyloxy)phenyl]-2-chloroethyl}-2,2-di-

ethylmalonamide (20d): This compound was obtained from 19d

(729 mg) by both Method a and Method b. Method a yielded

643 mg (84%) and Method b yielded 673 mg (88%) of product 20d

as a white solid. t_m= 117 °C. [α]_D= –57.1 (c = 0.96 in CH₂Cl₂).

¹H NMR: δ = 7.97 (d, J = 7.8 Hz, 2 H, NH), 7.20 (d, J = 8.5 Hz,

(CH CH ) ppm. IR (KBr): ν = 3417, 3031, 2963, 2933, 2871, 1651,

˜

2

3

1610, 1580, 1510, 1471, 1383, 1300, 1245, 1179, 1113, 980, 926,

832, 573 cm^–1. C₄₈H₅₈N₂O₆(759.00): calcd. C 75.96, H 7.70, N

3.69; found: C 75.72, H 7.58, N 3.85.

4 H, C2ЈH, C6ЈH), 6.84 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH), 5.30 General Procedure for the Preparation of Compounds 13, 2a–d, 3a–

(m, 2 H, C*H), 3.94 (t, J = 6.3 Hz, 4 H, C1ЈЈH₂), 3.80 (m, 4 H, d, 7a–d, 8a–d, 6, and 24 by Macrocyclization: A solution of both

CH₂Cl), 3.43 (t, J = 6.7 Hz, 4 H, C5ЈЈH₂), 1.93 (m, 8 H, CH₂CH₃reactants (0.40 mmol of each) in acetonitrile (150 mL) was added

and C4ЈЈH₂), 1.80 (m, 4 H, C2ЈЈH₂), 1.61 (m, 4 H, C3ЈЈH₂), 0.84

dropwise to a stirred suspension of Cs₂CO₃(977 mg, 3.00 mmol) in

acetonitrile (150 mL) with heating at reflux for 3–4 h. The boiling

(t, J = 7.3 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 172.6 (C=O),

158.5 (C4Ј), 130.3 (C1Ј), 127.6 (C2Ј, C6Ј), 114.5 (C3Ј, C5Ј), 67.4 reaction mixture was stirred overnight, and cooled to room tem-

(C1ЈЈ), 58.1 (CEt₂), 53.5 (C*), 47.4 (CH₂Cl), 33.5 (C5ЈЈ), 32.3 perature. Inorganic salts were removed, the filtrate was concen-

( C4ЈЈ), 3 0 . 7 (CH ₂CH₃) , 2 8. 2 ( C2ЈЈ), 24.6 (C3Ј Ј) , 9 . 3 trated, and the oily residue was purified by preparative TLC in a

(CH CH ) ppm. IR (KBr): ν = 3297, 3035, 2938, 2871, 1634, 1513,

CH₂Cl₂/EtOAc (7:3) solvent system.

˜

2

3

1469, 1386, 1294, 1246, 1179, 1041, 939, 830, 744, 640, 547 cm^–1.

C₃₃H₄₆Br₂Cl₂N₂O₄(765.49): calcd. C 51.78, H 6.06, N 3.66; found:

C 51.71, H 6.01, N 3.63.

(12S,18S)-15,15-Diethyl-2,2-dimethyl-12,18-bis(hydroxymethyl)-

4,9,21,26-tetraoxa-13,17-diaza-1,3,10,20(1,4)-tetrabenzenacyclohexa-

cosaphane-14,16-dione (13): This compound was obtained from 11

(183 mg) and 12 (199 mg) in a process that gave product 13 (73 mg,

23%) as a white foam. [α]_D= 14.4 (c = 0.90 in CH₂Cl₂). ¹H NMR:

N¹,N³-Bis[(S)-1-(chloromethyl)-2-(4-hydroxyphenyl)ethyl]-2,2-dieth-

ylmalonamide (21): This compound was obtained from 11 (459 mg)

Eur. J. Org. Chem. 2007, 838–856

www.eurjoc.org

851

ˇ

T. Portada, M. Roje, Z. Raza, V. Caplar, M. Zinic´, V. Sunjic´

FULL PAPER

δ = 7.07 (pt, J = 8.8 Hz, 8 H, C2ЈH, C6ЈH and C3ЈЈЈH, C5ЈЈЈH),

1

CH₂Cl₂). H NMR: δ = 7.15 (d, J = 8.7 Hz, 4 H, C2ЈH, C6ЈH or

6.75 (m, 8 H, C2ЈЈЈH, C6ЈЈЈH and C3ЈH, C5ЈH), 6.44 (d, J = C3ЈЈЈH, C5ЈЈЈH), 7.07 (d, J = 8.5 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH or C2ЈH,

8.0 Hz, NH), 4.23 (br s, 2 H, C*H), 3.97 (m, 8 H, C1ЈЈH₂and

C4ЈЈH₂), 3.79 (dd, J = 2.8 Hz, J = 11.0 Hz, 2 H, CH_aOH), 3.49

(m, 4 H, CH_bOH and CH₂OH), 2.83 (dd, J = 4.6 and 14.1 Hz, 2

H, C1Ј-CH_a), 2.60 (dd, J = 10.4 and 11.3 Hz, 2 H, C1Ј-CH_b), 1.91

(br s, 8 H, C2ЈЈH₂and C3ЈЈH₂), 1.62 (m, 10 H, CH₂CH₃and

C4ЈЈЈCCH₃), 0.26 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR:

C6ЈH), 6.82 (d, J = 8.7 Hz, 4 H, C3ЈH, C5ЈH or C2ЈЈЈH, C6ЈЈЈH),

6.73 (d, J = 8.7 Hz, 4 H, C2ЈЈЈH, C6ЈЈЈH or C3ЈH, C5ЈH), 5.17

(dd, J = 6.9 and 9.7 Hz, 2 H, C4 H), 4.58 (dd, J = 8.5 and 9.8 Hz,

2 H, C5H_a), 4.06 (pt, J = 8.2 Hz, 2 H, C5H_b), 4.03–3.97 (m, 8 H,

C1ЈЈH₂and C4ЈЈH₂), 2.23 (m, 2 H, CH_aCH₃), 2.06 (m, 2 H,

CH_bCH₃), 1.94 (m, 8 H, C2ЈЈH and C3ЈЈH), 1.61 (s, 6 H,

δ = 173.4 (C=O), 157.6 (C4Ј), 156.6 (C1ЈЈЈ), 143.1 (C4ЈЈЈ), 129.9 C4ЈЈЈCCH₃), 0.96 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR:

(C2Ј, C6Ј), 129.4 (C1Ј), 127.6 (C3ЈЈЈ, C5ЈЈЈ), 114.8 (C3Ј, C5Ј), 113.8 δ = 168.7 (C2), 158.3 (C4Ј), 156.6 (C1ЈЈЈ), 143.2 (C4ЈЈЈ), 134.8

(C2ЈЈЈ, C6ЈЈЈ), 67.0 (C1ЈЈ or C4ЈЈ), 66.9 (C4ЈЈ or C1ЈЈ), 65.4 (C1Ј), 127.7, 127.6 (C2Ј, C6Ј and C3ЈЈЈ, C5ЈЈЈ), 114.7 (C3Ј, C5Ј),

(CH₂OH), 58.0 (CEt₂), 52.7 (C*), 41.4 (CMe₂), 35.7 (CH₂C1Ј), 30.7 113.8 (C2ЈЈЈ, C6ЈЈЈ), 75.1 (C5), 68.8 (C4), 66.9 (C1ЈЈ and C4ЈЈ), 46.7

(CMe₂), 25.9 (CH₂CH₃), 25.4 (C2ЈЈ or C3ЈЈ), 25.3 (C3ЈЈ and C2ЈЈ), (CEt₂), 41.4 (CMe₂), 30.7 (CMe₂), 25.3, 25.2 (C2ЈЈ and C3ЈЈ), 24.6

7.7 (CH CH ) ppm. IR (KBr): ν = 3407, 3328, 2962, 2927, 2877,

(CH CH ), 8.1 (CH CH ) ppm. IR (KBr): ν = 3433, 3035, 2966,

˜

2 3 2 3

˜

2

3

1637, 1611, 1511, 1469, 1247, 1180, 1026, 829, 568 cm^–1.

2877, 1653, 1610, 1511, 1469, 1294, 1246, 1178, 1108, 986, 923,

830, 553 cm^–1. C₄₆H₅₄N₂O₆(730.94): calcd. C 75.59, H 7.45, N

3.83; found: C 75.55, H 7.20, N 3.75.

(1⁴R,15⁴R)-16,16-Diethyl-8,8-dimethyl-1⁴,1⁵,15⁴,15⁵-tetrahydro-

3,6,10,13-tetraoxa-1,15(2,4)-bis(1,3-oxazola)-2,7,9,14(1,4)-tetra-

benzenacyclohexadecaphane (2a): This compound was obtained

from 20a (273 mg) and bisphenol A (91 mg) in a process that gave

product 2a (86 mg, 32%) as a white foam. [α]_D= +141.3 (c = 2.00

(1⁴R,21⁴R)-22,22-Diethyl-11,11-dimethyl-1⁴,1⁵,21⁴,21⁵-tetrahydro-

3,9,13,19-tetraoxa-1,21(2,4)-bis(1,3-oxazola)-2,10,15,20(1,4)-tetra-

benzenacyclodocosaphane (2d): This compound was obtained from

20d (306 mg) and bisphenol A (91 mg) in a process that gave prod-

uct 2d (73 mg, 24%) as a white foam. [α]_D= +139.8 (c = 1.30 in

1

in CH₂Cl₂). H NMR: δ = 7.13 (d, J = 8.5 Hz, 4 H, C2ЈH, C6ЈH

or C3ЈЈЈH, C5ЈЈЈH), 7.10 (d, J = 9.1 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH or

C2ЈH, C6ЈH), 6.85 (d, J = 8.2 Hz, 4 H, C3ЈH, C5ЈH or C2ЈЈЈH,

C6ЈЈЈH), 6.78 (d, J = 8.8 Hz, 4 H, C2ЈЈЈH, C6ЈЈЈH or C3ЈH, C5ЈH),

5.22 (dd, J = 6.9 and 9.3 Hz, 2 H, C4 H), 4.58 (pt, J = 9.2 Hz, 2

1

CH₂Cl₂). H NMR: δ = 7.16 (d, J = 8.5 Hz, 4 H, C2ЈH, C6ЈH or

C3ЈЈЈH, C5ЈЈЈH), 7.07 (d, J = 8.5 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH or C2ЈH,

C6ЈH), 6.81 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH or C2ЈЈЈH, C6ЈЈЈH),

H, C5H_a), 4.31 (m, 8 H, C1ЈЈH₂and C2ЈЈH₂), 4.02 (pt, J = 7.6 Hz, 6.74 (d, J = 8.5 Hz, 4 H, C2ЈЈЈH, C6ЈЈЈH or C3ЈH, C5ЈH), 5.18

2 H, C5H_b), 2.29 (m, 2 H, CH_aCH₃), 2.06 (m, 2 H, CH_bCH₃), 1.65 (dd, J = 7.1 and 9.6 Hz, 2 H, C4 H), 4.58 (pt, J = 7.8 Hz, 2 H,

(s, 6 H, C4ЈЈЈCCH₃), 0.92 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C C5H_a), 4.03 (pt, J = 7.8 Hz, 2 H, C5H_b), 3.95 (m, 8 H, C1ЈЈH₂and

NMR: δ = 168.7 (C2), 157.3 (C4Ј), 155.7 (C1ЈЈЈ), 143.5 (C4ЈЈЈ),

135.2 (C1Ј), 127.4 (C2Ј, C6Ј and C3ЈЈЈ, C5ЈЈЈ), 115.0 (C3Ј, C5Ј),

C5ЈЈH₂), 2.22 (m, 2 H, CH_aCH₃), 2.03 (m, 2 H, CH_bCH₃), 1.80

(m, 8 H, C2ЈЈH and C4ЈЈH), 1.63 (s, 6 H, C4ЈЈЈCCH₃), 0.91 (t, J =

114.3 (C2ЈЈЈ, C6ЈЈЈ), 75.2 (C5), 68.7 (C4), 65.8 (C1ЈЈ or C2ЈЈ), 65.6 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 168.4 (C2), 158.3 (C4Ј),

(C2ЈЈ or C1ЈЈ), 46.9 (CEt₂), 41.2 (CMe₂), 30.2 (CMe₂), 24.6 156.5 (C1ЈЈЈ), 142.9 (C4ЈЈЈ), 134.5 (C1Ј), 127.7, (C2Ј, C6Ј and C3ЈЈЈ,

(CH CH ), 8.2 (CH CH ) ppm. IR (KBr): ν = 3427, 2967, 2927,

C5ЈЈЈ), 114.4 (C3Ј, C5Ј), 113.6 (C2ЈЈЈ, C6ЈЈЈ), 75.0 (C5), 68.8 (C4),

67.5, 67.4 (C1ЈЈ and C5ЈЈ), 46.9 (CEt₂), 41.3 (CMe₂), 30.5 (CMe₂),

˜

2

3

2

3

2877, 1650, 1608, 1509, 1305, 1241, 1222, 1179, 1108, 1058, 923,

830, 553 cm^–1. HRMS: [M]⁺calculated for C₄₂H₄₆N₂O₆: 28.6 (C2ЈЈ and C4ЈЈ), 25.0 (CH₂CH₃), 22.7 (C3ЈЈ), 8.1

674.33557; found: 674.33530.

(CH CH ) ppm. IR (KBr): ν = 3427, 2937, 2871, 1654, 1611, 1511,

˜

2 3

1469, 1305, 1244, 1179, 1108, 985, 923, 829, 547 cm^–1. HRMS:

[M]⁺calculated for C₄₈H₅₈N₂O₆: 758.42950; found: 758.42940.

(1⁴R,17⁴R)-18,18-Diethyl-9,9-dimethyl-1⁴,1⁵,17⁴,17⁵-tetrahydro-

3,7,11,15-tetraoxa-1,17(2,4)-bis(1,3-oxazola)-2,8,11,16(1,4)-tetra-

benzenacyclooctadecaphane (2b): This compound was obtained

from 20b (284 mg) and bisphenol A (91 mg) in a process that gave

product 2b (70 mg, 25%) as a white foam. [α]_D= +166.7 (c = 0.92

(1⁴R,15⁴R)-16,16-Diethyl-7²,7⁶,8,8,9³,9⁵-hexamethyl-1⁴,1⁵,15⁴,15⁵-

tetrahydro-3,6,10,13-tetraoxa-1,15(2,4)-bis(1,3-oxazola)-

2,7,9,14(1,4)-tetrabenzenacyclohexadecaphane (3a): This compound

was obtained from 20a (273 mg) and 25 (114 mg) in a process that

gave product 3a (41 mg, 14%) as a white foam. [α]_D= +107.9 (c =

0.72 in CH₂Cl₂). ¹H NMR: δ = 7.14 (d, J = 8.7 Hz, 4 H, C2ЈH,

C6ЈH), 6.85 (d, J = 8.7 Hz, 4 H, C3ЈH, C5ЈH), 6.75 (s, 4 H, C3ЈЈЈH,

C5ЈЈЈH), 5.21 (dd, J = 6.9 and 9.9 Hz, 2 H, C4 H), 4.57 (dd, J =

8.3 and 9.9 Hz, 2 H, C5H_a), 4.26 (t, J = 4.5 Hz, 4 H, C1ЈЈH₂or

1

in CH₂Cl₂). H NMR: δ = 7.16 (d, J = 8.5 Hz, 4 H, C2ЈH, C6ЈH

or C3ЈЈЈH, C5ЈЈЈH), 7.11 (d, J = 8.5 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH or

C2ЈH, C6ЈH), 6.84 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH or C2ЈЈЈH,

C6ЈЈЈH), 6.78 (d, J = 8.8 Hz, 4 H, C2ЈЈЈH, C6ЈЈЈH or C3ЈH, C5ЈH),

5.24 (dd, J = 6.3 and 9.9 Hz, 2 H, C4 H), 4.60 (pt, J = 9.1 Hz, 2

H, C5H_a), 4.22–4.01 (m, 10 H, C5H_aand C1ЈЈH₂and C3ЈЈH₂),

2.33 (m, 2 H, CH_aCH₃), 2.23 (m, 4 H, C2ЈЈH), 2.12 (m, 2 H, C2ЈЈH₂), 4.13 (m, 4 H, C1ЈЈH₂or C2ЈЈH₂), 4.01 (pt, J = 7.7 Hz, 2

CH_bCH₃), 1.68 (s, 6 H, C4ЈЈЈCCH₃), 0.96 (t, J = 7.4 Hz, 6 H, H, C5H_b), 2.26 (m, 2 H, CH_aCH₃), 2.12 (s, 12 H, C2ЈЈЈCH₃), 2.04

CH₂CH₃) ppm. ¹³C NMR: δ = 168.7 (C2), 158.2 (C4Ј), 156.5 (m, 2 H, CH_bCH₃), 1.57 (s, 6 H, C4ЈЈЈCCH₃), 0.91 (t, J = 7.5 Hz,

(C1ЈЈЈ), 143.0 (C4ЈЈЈ), 134.7 (C1Ј), 127.2 (C2Ј, C6Ј and C3ЈЈЈ,

C5ЈЈЈ), 114.2 (C3Ј, C5Ј), 113.7 (C2ЈЈЈ, C6ЈЈЈ), 75.3 (C5), 68.7 (C4),

6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 168.6 (C2), 157.4 (C4Ј), 152.8

(C1ЈЈЈ), 145.8 (C4ЈЈЈ), 135.0 (C1Ј), 129.6 (C2ЈЈЈ, C6ЈЈЈ), 127.5 (C2Ј,

63.6, 63.4 (C1ЈЈ and C3ЈЈ), 46.8 (CEt₂), 41.1 (CMe₂), 30.1 (CMe₂), C6Ј), 126.9 (C3ЈЈЈ, C5ЈЈЈ), 114.9 (C3Ј, C5Ј), 75.0 (C5), 70.1 (C2ЈЈ),

29.1 (C2ЈЈ), 24.3 (CH CH ), 8.2 (CH CH ) ppm. IR (KBr): ν = 68.6 (C4), 66.4 (C1ЈЈ), 47.0 (CEt₂), 41.3 (CMe₂), 30.5 (CMe₂), 24.9

(CH CH ), 16.5 (C2ЈЈЈCH ), 8.2 (CH CH ) ppm. IR (KBr): ν =

˜

2

3

2

3

3433, 2965, 2933, 2877, 1654, 1610, 1583, 1512, 1469, 1382, 1245,

1180, 1111, 1058, 987, 829, 547 cm^–1. C₄₄H₅₀N₂O₆(702.89): calcd.

C 75.19, H 7.17, N 3.99; found: C 75.39, H 6.88, N 4.04.

˜

2

3

2

3

3438, 2966, 2925, 2877, 1653, 1611, 1511, 1485, 1454, 1363, 1305,

1246, 1219, 1180, 1109, 1051, 987, 922, 830, 543 cm^–1. TOF-ESMS:

731 [M + H]⁺.

(1⁴R,19⁴R)-20,20-Diethyl-10,10-dimethyl-1⁴,1⁵,19⁴,19⁵-tetrahydro-

3,8,12,17-tetraoxa-1,19(2,4)-bis(1,3-oxazola)-2,9,13,18(1,4)-tetra-

benzenacycloicosaphane (2c): This compound was obtained from

20c (295 mg) and bisphenol A (91 mg) in a process that gave prod-

uct 2c (140 mg, 48%) as a white foam. [α]_D= +171.8 (c = 1.00 in

(1⁴R,17⁴R)-18,18-Diethyl-8²,8⁶,9,9,10³,10⁵-hexamethyl-

1⁴,1⁵,17⁴,17⁵-tetrahydro-3,7,11,15-tetraoxa-1,17(2,4)-bis(1,3-

oxazola)-2,8,11,16(1,4)-tetrabenzenacyclooctadecaphane (3b): This

compound was obtained from 20b (284 mg) and 25 (114 mg) in a

852

www.eurjoc.org

Eur. J. Org. Chem. 2007, 838–856

Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes

FULL PAPER

process that gave product 3b (97 mg, 32%) as a white foam. [α]_D

+107.8 (c = 1.08 in CHCl₃). H NMR: δ = 7.13 (d, J = 8.7 Hz, 4

=

C5ЈЈЈH), 6.82 (pt, J = 9.2 Hz, 8 H, C3ЈH, C5ЈH and C2ЈЈЈH,

C6ЈЈЈH), 4.40–4.23 (m, 10 H, C4H and C1ЈЈH₂and C2ЈЈH₂), 4.20

1

H, C2ЈH, C6ЈH), 6.81 (d, J = 8.7 Hz, 4 H, C3ЈH, C5ЈH), 6.74 (s, (pt, J = 8.9 Hz, 2 H, C5Ha), 3.94 (pt, J = 7.7 Hz, 2 H, C5Hb),

4 H, C3ЈЈЈH, C5ЈЈЈH), 5.19 (dd, J = 6.9 and 9.9 Hz, 2 H, C4 H), 2.89 (dd, J = 5.8 and 13.7 Hz, 2 H, C1Ј-CH_a), 2.39 (dd, J = 6.6

4.56 (dd, J = 8.4 and 9.9 Hz, 2 H, C5H_a), 4.17 (m, 4 H, C1ЈЈH₂), and 13.7 Hz, 2 H, C1Ј-CH_b), 1.94 (m, 4 H, CH₂CH₃), 1.68 (s, 6 H,

4.02–3.84 (m, 6 H, C3ЈЈH₂and C5H_b), 2.29–2.16 (m, 6 H, C2ЈЈH₂

C4ЈЈЈCCH₃), 0.79 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR:

and CH_aCH₃), 2.13 (s, 12 H, C2ЈЈЈCH₃), 2.03 (m, 2 H, CH_bCH₃), δ = 167.9 (C2), 156.9 (C4Ј), 156.0 (C1ЈЈЈ), 143.6 (C4ЈЈЈ), 130.6 (C2Ј,

1.58 (s, 6 H, C4ЈЈЈCCH₃), 0.91 (t, J = 7.5 Hz, 6 H, CH₂CH₃) ppm. C6Ј), 130.0 (C1Ј), 127.4 (C3ЈЈЈ, C5ЈЈЈ), 114.6, 114.4 (C3Ј, C5Ј and

¹³C NMR: δ = 168.6 (C2), 158.2 (C4Ј), 153.3 (C1ЈЈЈ), 145.8 (C4ЈЈЈ), C2ЈЈЈ, C6ЈЈЈ), 70.9 (C5), 66.6, 66.3 (C4 and C1ЈЈ and C2ЈЈ), 46.7

134.7 (C1Ј), 129.6 (C2ЈЈЈ, C6ЈЈЈ), 127.4, 127.0 (C2Ј, C6Ј and C3ЈЈЈ,

C5ЈЈЈ), 114.3 (C3Ј, C5Ј), 75.2 (C5), 68.7 (C4), 68.4 (C3ЈЈ), 63.9

(CEt₂), 41.3 (CMe₂), 40.0 (C4CH₂), 30.2 (CMe₂), 25.8 (CH₂CH₃),

8.4 (CH CH ) ppm. IR (KBr): ν = 3422, 2967, 2931, 2877, 1654,

˜

2

3

(C1ЈЈ), 47.0 (CEt₂), 41.4 (CMe₂), 30.6 (CMe₂), 29.8 (C2ЈЈ), 24.9 1610, 1509, 1242, 1180, 1068, 982, 831, 553 cm^–1. TOF-ESMS: 703

(CH CH ), 16.4 (C2ЈЈЈCH ), 8.2 (CH CH ) ppm. IR (KBr): ν =

[M + H]⁺.

˜

2

3

2

3

3427, 2964, 2933, 2877, 1654, 1611, 1512, 1474, 1382, 1305, 1244,

1179, 1111, 1058, 987, 923, 830, 547 cm^–1. TOF-ESMS: 759 [M +

H]⁺.

(1⁴S,3⁴S)-2,2-Diethyl-12,12-dimethyl-1⁴,1⁵,3⁴,3⁵-tetrahydro-

6,10,14,18-tetraoxa-1,3(2,4)-bis(1,3-oxazola)-5,11,13,19(1,4)-tetra-

benzenacycloicosaphane (7b): This compound was obtained from

16b (295 mg) and bisphenol A (91 mg) in a process that gave prod-

uct 7b (114 mg, 39%) as a white foam. [α]_D= –62.8 (c = 1.70 in

CH₂Cl₂). ¹H NMR: δ = 7.11 (m, 8 H, C2ЈH, C6ЈH and C3ЈЈЈH,

C5ЈЈЈH), 6.80 (m, 8 H, C3ЈH, C5ЈH and C2ЈЈЈH, C6ЈЈЈH), 4.38 (m,

2 H, C4 H), 4.23–4.09 (m, 10 H, C5Ha and C1ЈЈH₂and C3ЈЈH₂),

3.97 (pt, J = 7.4 Hz, 2 H, C5Hb), 2.88 (dd, J = 6.0 Hz, J = 13.7 Hz,

2 H, C1Ј-CH_a), 2.74 (dd, J = 6.6 and 14.0 Hz, 2 H, C1Ј-CH_b), 2.22

(m, 4 H, CH₂CH₃), 1.67 (s, 6 H, C4ЈЈЈCCH₃), 0.70 (t, J = 7.4 Hz,

6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 167.7 (C2), 157.4 (C4Ј), 156.4

(C1ЈЈЈ), 141.3 (C4ЈЈЈ), 130.5 (C2Ј, C6ЈЈЈ), 129.6 (C1Ј), 127.4 (C3ЈЈЈ,

C5ЈЈЈ), 114.2 (C3Ј, C5Ј), 113.7 (C2ЈЈЈ, C6ЈЈЈ), 70.9 (C5), 66.8 (C4),

64.0 (C1ЈЈ and C3ЈЈ), 46.8 (CEt₂), 41.3 (CMe₂), 40.2 (C4CH₂), 30.4

(CMe₂), 29.1 (C2ЈЈ), 26.1 (CH₂CH₃), 8.5 (CH₂CH₃) ppm. IR

(1⁴R,19⁴R)-20,20-Diethyl-9²,9⁶,10,10,11³,11⁵-hexamethyl-

1⁴,1⁵,19⁴,19⁵-tetrahydro-3,8,12,17-tetraoxa-1,19(2,4)-bis(1,3-

oxazola)-2,9,13,18(1,4)-tetrabenzenacycloicosaphane (3c): This

compound was obtained from 20c (295 mg) and 25 (114 mg) in a

process that gave product 3c (126 mg, 40%) as a white foam. [α]_D

1

= +147.3 (c = 1.46 in CH₂Cl₂). H NMR: δ = 7.17 (d, J = 8.8 Hz,

4 H, C2ЈH, C6ЈH), 6.87 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH), 6.80 (s,

4 H, C3ЈЈЈH, C5ЈЈЈH), 5.20 (dd, J = 7.4 and 9.6 Hz, 2 H, C4 H),

4.61 (pt, J = 9.2 Hz, 2 H, C5H_a), 4.09 (m, 6 H, C5H_aand C1ЈЈH₂),

3.80 (m, 4 H, C4ЈЈH₂), 2.30–2.07 (m, 16 H, C2ЈЈЈCH₃and

CH₂CH₃), 2.00 (m, 8 H, C2ЈЈH₂and C3ЈЈH₂), 1.60 (s, 6 H,

C4ЈЈЈCCH₃), 0.91 (m, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 168.1

(C2), 158.1 (C4Ј), 153.4 (C1ЈЈЈ), 145.7 (C4ЈЈЈ), 134.6 (C1Ј), 129.5

(C2ЈЈЈ, C6ЈЈЈ), 127.6 (C2Ј, C6Ј), 126.8 (C3ЈЈЈ, C5ЈЈЈ), 114.6 (C3Ј,

C5Ј), 75.1 (C5), 71.1 (C4ЈЈ), 68.8 (C4), 66.9 (C1ЈЈ), 46.6 (CEt₂),

41.3 (CMe₂), 30.6 (CMe₂), 26.1, 25.6 (C2ЈЈ and C3ЈЈ), 24.6

(KBr): ν = 3423, 2964, 2933, 2877, 1653, 1610, 1510, 1472, 1300,

˜

1244, 1180, 1112, 1059, 984, 829, 572 cm^–1. HRMS: [M]⁺calculated

for C₄₆H₅₄N₂O₆: 730.3982; found: 730.3981.

(CH CH ), 16.5 (C2ЈЈЈCH ), 8.1 (CH CH ) ppm. IR (KBr): ν =

(1⁴S,3⁴S)-2,2-Diethyl-13,13-dimethyl-1⁴,1⁵,3⁴,3⁵-tetrahydro-

6,11,15,20-tetraoxa-1,3(2,4)-bis(1,3-oxazola)-5,12,14,21(1,4)-tetra-

benzenacyclodocosaphane (7c): This compound was obtained from

16c (306 mg) and bisphenol A (91 mg) in a process that gave prod-

uct 7c (152 mg, 50%) as a white foam. [α]_D= –52.1 (c = 0.75 in

CH₂Cl₂). All spectroscopic data were same as already described.

˜

2

3

2

3

3448, 2963, 2875, 1654, 1612, 1513, 1475, 1245, 1179, 1111, 987,

923, 830, 547 cm^–1. TOF-ESMS: 787 [M + H]⁺.

(1⁴R,21⁴R)-22,22-Diethyl-10²,10⁶,11,11,12³,12⁵-hexamethyl-

1⁴,1⁵,21⁴,21⁵-tetrahydro-3,9,13,19-tetraoxa-1,21(2,4)-bis(1,3-

oxazola)-2,10,15,20(1,4)-tetrabenzenacyclodocosaphane (3d): This

compound was obtained from 20d (306 mg) and 25 (114 mg) in a

process that gave product 3d (104 mg, 32%) as a white foam. [α]_D

(1⁴S,3⁴S)-2,2-Diethyl-14,14-dimethyl-1⁴,1⁵,3⁴,3⁵-tetrahydro-

6,12,16,22-tetraoxa-1,3(2,4)-bis(1,3-oxazola)-5,13,15,23(1,4)-tetra-

benzenacyclotetracosaphane (7d): This compound was obtained

from 16d (317 mg) and bisphenol A (91 mg) in a process that gave

product 7d (135 mg, 43%) as a white foam. [α]_D= –58.0 (c = 10.0

1

= +128.9 (c = 1.29 in CH₂Cl₂). H NMR: δ = 7.19 (d, J = 8.5 Hz,

4 H, C2ЈH, C6ЈH), 6.85 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH), 6.80 (s,

4 H, C3ЈЈЈH, C5ЈЈЈH), 5.21 (dd, J = 7.3 and 9.8 Hz, 2 H, C4 H),

4.62 (dd, J = 8.7 and 9.8 Hz, 2 H, C5H_a), 4.10 (pt, J = 7.8 Hz, 2

H, C5H_b), 4.00 (m, 4 H, C1H₂), 3.79 (t, J = 6.2 Hz, 4 H, C5ЈЈH₂),

2.30–1.84 (m, 24 H, C2ЈЈЈCH₃and C2ЈЈH₂and C3ЈЈH₂and

CH₂CH₃), 1.72–1.66 (m, 4 H, C3ЈЈH₂), 1.62 (s, 6 H, C4ЈЈЈCCH₃),

0.95 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 168.4 (C2),

158.3 (C4Ј), 153.4 (C1ЈЈЈ), 145.7 (C4ЈЈЈ), 134.4 (C1Ј), 129.5 (C2ЈЈЈ,

C6ЈЈЈ), 127.5 (C2Ј, C6Ј), 126.9 (C3ЈЈЈ, C5ЈЈЈ), 114.4 (C3Ј, C5Ј), 74.9

(C5), 71.7 (C5ЈЈ), 68.8 (C4), 67.5 (C1ЈЈ), 46.9 (CEt₂), 41.4 (CMe₂),

30.5 (CMe₂), 29.6 (C4ЈЈ), 28.7 (C2ЈЈ), 25.2 (CH₂CH₃), 22.6 (C3ЈЈ),

1

in CH₂Cl₂). H NMR: δ = 7.09 (pt, J = 7.4 Hz, 8 H, C2ЈH, C6ЈH

and C3ЈЈЈH, C5ЈЈЈH), 6.78 (m, 8 H, C3ЈH, C5ЈH and C2ЈЈЈH,

C6ЈЈЈH), 4.35 (m, 2 H, C4 H), 4.15 (pt, J = 8.9 Hz, 8 H, C5Ha),

3.94 (m, 10 H, C5Hb and C1ЈЈH₂and C5ЈЈH₂), 2.91 (dd, J =

5.5 Hz, J = 14.0 Hz, 2 H, C1Ј-CH_a), 2.68 (dd, J = 7.1 and 13.8 Hz,

2 H, C1Ј-CH_b), 1.92 (m, 4 H, CH₂CH₃), 1.81 (m, 8 H, C2ЈЈH₂and

C4ЈЈH₂), 1.64 (m, 10 H, C4ЈЈH₂and C4ЈЈЈCCH₃), 0.76 (t, J =

7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 167.7 (C2), 157.6 (C4Ј),

156.6 (C1ЈЈЈ), 143.0 (C4ЈЈЈ), 130.5 (C2Ј, C6Ј), 129.4 (C1Ј), 127.5

(C3ЈЈЈ, C5ЈЈЈ), 114.3 (C3Ј, C5Ј), 113.7 (C2ЈЈЈ, C6ЈЈЈ), 71.0 (C5), 67.7,

67.5 (C1ЈЈ and C5ЈЈ), 66.8 (C4), 46.6 (CEt₂), 41.4 (CMe₂), 40.1

(C4CH2), 30.6 (CMe₂), 28.7 (C2ЈЈ and C4ЈЈ), 25.5 (CH₂CH₃), 22.7

16.5 (C2ЈЈЈCH ), 8.3 (CH CH ) ppm. IR (KBr): ν = 3438, 2938,

˜

3

2

3

2871, 1653, 1611, 1512, 1474, 1384, 1305, 1243, 1178, 1111, 988,

923, 830, 549 cm^–1. HRMS: [M]⁺calculated for C₅₂H₆₆N₂O₆:

814.49207; found: 814.49190.

(C3ЈЈ), 8.1 (CH CH ) ppm. IR (KBr): ν = 3427, 3035, 2937, 2866,

˜

2

3

1653, 1610, 1510, 1472, 1300, 1245, 1179, 982, 829 cm^–1. HRMS:

(1⁴S,3⁴S)-2,2-Diethyl-11,11-dimethyl-1⁴,1⁵,3⁴,3⁵-tetrahydro-

6,9,13,16-tetraoxa-1,3(2,4)-bis(1,3-oxazola)-5,10,12,17(1,4)-tetra-

benzenacyclooctadecaphane (7a): This compound was obtained

from 16a (284 mg) and bisphenol A (91 mg) in a process that gave

product 7a (79 mg, 28%) as a white foam. [α]_D= –45.1 (c = 0.61

[M]⁺calculated for C₅₀H₆₂N₂O₆: 786.46082; found: 786.46090.

(1⁴S,3⁴S)-2,2-Diethyl-10²,10⁶,11,11,12³,12⁵-hexamethyl-1⁴,1⁵,3⁴,3⁵-

tetrahydro-6,9,13,16-tetraoxa-1,3(2,4)-bis(1,3-oxazola)-

5,10,12,17(1,4)-tetrabenzenacyclooctadecaphane (8a): This com-

in CH₂Cl₂). ¹H NMR: δ = 7.12 (m, 8 H, C2ЈH, C6ЈH and C3ЈЈЈH, pound was obtained from 16a (284 mg) and 25 (114 mg) in a pro-

Eur. J. Org. Chem. 2007, 838–856

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853

ˇ

T. Portada, M. Roje, Z. Raza, V. Caplar, M. Zinic´, V. Sunjic´

FULL PAPER

cess that gave product 8a (116 mg, 38%) as a white foam. [α]_D

–32.6 (c = 0.89 in CH₂Cl₂). H NMR: δ = 7.08 (d, J = 8.5 Hz, 4

H, C2ЈH, C6ЈH), 6.83 (s, 4 H, C3ЈЈЈH, C5ЈЈЈH), 6.76 (d, J = 8.5 Hz,

4 H, C3ЈH, C5ЈH), 4.37 (m, 2 H, C4 H), 4.22 (m, 10 H, C1ЈЈH₂

1

=

–49.0 (c = 2.88 in CH₂Cl₂). H NMR: δ = 7.10 (d, J = 8.5 Hz, 4

1

H, C2ЈH, C6ЈH), 6.81 (m, 8 H, C3ЈЈЈH, C5ЈЈЈH and C3ЈH, C5ЈH),

4.37 (m, 2 H, C4 H), 4.17 (pt, J = 8.9 Hz, 2 H, C5H_a), 3.98 (m, 6

H, C5H_band C1ЈЈH₂), 3.79 (t, J = 6.3 Hz, 4 H, C5ЈЈH₂), 2.94 (dd,

and C2ЈЈH₂and C5H_a), 3.92 (pt, J = 7.8 Hz, 2 H, C5H_b), 2.90 (dd, J = 5.5 and 13.7 Hz, 2 H, C1Ј-CH_a), 2.70 (dd, J = 7.4 and 13.7 Hz,

J = 5.8 and 13.7 Hz, 2 H, C1Ј-CH_a), 2.78 (dd, J = 6.6 and 13.7 Hz, 2 H, C1Ј-CH_b), 2.22 (s, 12 H, C2ЈЈЈCH₃), 2.01–1.83 (m, 12 H,

2 H, C1Ј-CH_b), 2.23 (s, 12 H, C2ЈЈЈCH₃), 1.96 (m, 4 H, CH₂CH₃), C2ЈЈH₂and C4ЈЈH₂and CH₂CH₃), 1.73–1.66 (m, 4 H, C3ЈЈH₂),

1.64 (s, 6 H, C4ЈЈЈCCH₃), 0.81 (t, J = 7.2 Hz, 6 H, CH₂CH₃) ppm. 1.61 (s, 6 H, C4ЈЈЈCCH₃), 0.77 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm.

¹³C NMR: δ = 167.6 (C2), 157.0 (C4Ј), 153.2 (C1ЈЈЈ), 145.9 (C4ЈЈЈ), ¹³C NMR: δ = 167.7 (C2), 157.6 (C4Ј), 153.5 (C1ЈЈЈ), 145.8 (C4ЈЈЈ),

130.5 (C2Ј, C6Ј), 130.0 (C1Ј), 129.5 (C2ЈЈЈ, C6ЈЈЈ), 126.9 (C3ЈЈЈ,

130.4 (C2Ј, C6Ј), 130.2 (C1Ј), 129.6 (C2ЈЈЈ, C6ЈЈЈ), 127.0 (C3ЈЈЈ,

C5ЈЈЈ), 114.3 (C3Ј, C5Ј), 70.9 (C5), 70.4 (C2ЈЈ), 67.1, 66.6 (C4 and C5ЈЈЈ), 114.4 (C3Ј, C5Ј), 71.7 (C4ЈЈ), 71.0 (C5), 67.7 (C1ЈЈ), 66.9

C1ЈЈ), 46.5 (CEt₂), 41.4 (CMe₂), 39.8 (C4CH₂), 30.5 (CMe₂), 25.6 (C4), 46.6 (CEt₂), 41.5 (CMe₂), 40.2 (C4CH₂), 30.7 (CMe₂), 29.8

(CH CH ), 16.6 (C2ЈЈЈCH ), 8.3 (CH CH ) ppm. IR (KBr): ν =

(C4ЈЈ), 28.8 (C2ЈЈ), 25.5 (CH₂CH₃), 22.7 (C3ЈЈ), 16.5 (C2ЈЈЈCH₃),

˜

2

3

2

3

3427, 2965, 2927, 1653, 1611, 1510, 1486, 1457, 1303, 1247, 1219,

1180, 1113, 1069, 982, 926, 837, 516 cm^–1. TOF-ESMS: 759 [M +

H]⁺.

8.3 (CH CH ) ppm. IR (KBr): ν = 3433, 2936, 2871, 1653, 1611,

˜

2 3

1511, 1474, 1383, 1302, 1243, 1179, 1112, 984, 923, 831, 532 cm^–1.

HRMS: [M]⁺calculated for C₅₄H₇₀N₂O₆: 842.52338; found:

842.52330.

(1⁴S,3⁴S)-2,2-Diethyl-11²,11⁶,12,12,13³,13⁵-hexamethyl-1⁴,1⁵,3⁴,3⁵-

tetrahydro-6,10,14,18-tetraoxa-1,3(2,4)-bis(1,3-oxazola)- (1⁴S,11⁴S)-2,2-Diethyl-1⁴,1⁵,3⁴,3⁵-tetrahydro-6,12-dioxa-1,3(2,4)-

5,11,13,19(1,4)-tetrabenzenacycloicosaphane (8b): This compound

was obtained from 16b (295 mg) and 25 (114 mg) in a process that

gave product 8b (126 mg, 40%) as a white foam. [α]_D= –56.5 (c =

bis(1,3-oxazola)-5,8,10,13(1,4)-tetrabenzenacyclotetradecaphane (6):

This compound was obtained from 21 (198 mg) and 22 (142 mg)

in a process that gave product 6 (113 mg, 46%) as a white foam.

1

0.92 in CH₂Cl₂). ¹H NMR: δ = 7.08 (d, J = 8.0 Hz, 4 H, C2ЈH, [α]_D= –53.0 (c = 19.8 in ClCH₂CH₂Cl). H NMR: δ = 7.23 (d, J

C6ЈH), 6.80 (m, 8 H, C3ЈЈЈH, C5ЈЈЈH and C3ЈH, C5ЈH), 4.36 (m,

= 7.7 Hz, 4 H, C2ЈЈЈH, C6ЈЈЈH or C3ЈЈЈH, C5ЈЈЈH), 7.14 (d, J =

2 H, C4 H), 4.17 (m, 6 H, C1ЈЈH₂and C5H_a), 3.93 (m, 6 H, C5H_b7.7 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH or C2ЈЈЈH, C6ЈЈЈH), 7.00 (d, J =

and C3ЈЈH₂), 2.88 (dd, J = 5.8 and 13.8 Hz, 2 H, C1Ј-CH_a), 2.75

(dd, J = 6.6 and 14.0 Hz, 2 H, C1Ј-CH_b), 2.17 (s, 12 H, C2ЈЈЈCH₃),

2.00–1.81 (m, 8 H, C2ЈЈH₂and CH₂CH₃), 1.59 (s, 6 H,

C4ЈЈЈCCH₃), 0.74 (t, J = 7.3 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR:

8.2 Hz, 4 H, C2ЈH, C6ЈH), 6.74 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH),

5.20–5.08 (m, 4 H, C1ЈЈH₂), 4.39 (m, 2 H, C4 H), 4.13 (pt, J =

8.9 Hz, 2 H, C5H_a), 3.93–3.86 (m, 4 H, C5H_band C4ЈЈЈCH₂), 2.84–

2.74 (m, 4 H, C1Ј-CH₂), 1.83 (m, 2 H, CH_aCH₃), 1.70 (m, 2 H,

δ = 167.7 (C2), 157.3 (C4Ј), 153.3 (C1ЈЈЈ), 145.8 (C4ЈЈЈ), 130.6 (C2Ј, CH_bCH₃), 0.51 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ =

C6Ј), 130.1 (C1Ј), 129.6 (C2ЈЈЈ, C6ЈЈЈ), 126.9 (C3ЈЈЈ, C5ЈЈЈ), 114.1 167.6 (C2), 156.9 (C4Ј), 140.5 (C4ЈЈЈ), 135.4 (C1ЈЈЈ), 130.9 (C1Ј and

(C3Ј, C5Ј), 70.9 (C5), 68.2 (C3ЈЈ), 66.7 (C4), 64.0 (C1ЈЈ), 46.7

(CEt₂), 41.1 (CMe₂), 40.0 (C4CH₂), 30.6 (CMe₂), 29.8 (C2ЈЈ), 25.8

C2Ј, C6Ј), 128.8, 126.6 (C3ЈЈЈ, C5ЈЈЈ and C2ЈЈЈ, C6ЈЈЈ), 114.9 (C3Ј,

C5Ј), 70.3, 69.5 (C5 and C1ЈЈ), 66.0 (C4), 46.4 (CEt₂), 41.4

(C4ЈЈЈCH₂), 39.1 (C4CH₂), 25.3 (CH₂CH₃), 8.2 (CH₂CH₃) ppm. IR

(CH CH ), 16.4 (C2ЈЈЈCH ), 8.3 (CH CH ) ppm. IR (KBr): ν =

˜

2

3

2

3

3427, 2965, 2927, 2877, 1653, 1611, 1511, 1475, 1299, 1245, 1181,

1112, 1059, 985, 831, 526 cm^–1. HRMS: [M]⁺calculated for

C₅₀H₆₂N₂O₆: 786.4608; found: 786.4609.

(KBr): ν = 3417, 2970, 2918, 1649, 1610, 1509, 1221, 1176, 1113,

˜

984 cm^–1. HRMS: [M]⁺calculated for C₄₀H₄₂N₂O₄: 614.3145;

found: 614.3148.

(1⁴S,3⁴S)-2,2-Diethyl-12²,12⁶,13,13,14³,14⁵-hexamethyl-1⁴,1⁵,3⁴,3⁵-

(7R,13R)-10,10-Diethyl-7,13-bis(hydroxymethyl)-5,15-dioxa-8,12-di-

tetrahydro-6,11,15,20-tetraoxa-1,3(2,4)-bis(1,3-oxazola)- aza-1,3,6,14(1,4)-tetrabenzenacyclohexadecaphane-9,11-dione (24):

5,12,14,21(1,4)-tetrabenzenacyclodocosaphane (8c): This compound

was obtained from 16c (306 mg) and 25 (114 mg) in a process that

gave product 8c (121 mg, 37%) as a white foam. [α]_D= –43.8 (c =

This compound was obtained from 18 (172 mg) and 22 (142 mg)

in a process that gave product 24 (98 mg, 37%) as a white foam.

[α]_D= –98.0 (c = 1.65 in MeOH). ¹H NMR ([D₆]acetone): δ = 8.82

1.62 in CH₂Cl₂). ¹H NMR: δ = 7.11 (d, J = 8.0 Hz, 4 H, C2ЈH, (d, J = 7.7 Hz, 2 H, NH), 7.25 (d, J = 8.3 Hz, 4 H, C2ЈЈЈH, C6ЈЈЈH

C6ЈH), 6.83 (m, 8 H, C3ЈЈЈH, C5ЈЈЈH and C3ЈH, C5ЈH), 4.39 (m,

or C3ЈЈЈH, C5ЈЈЈH), 7.21 (d, J = 8.3 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH or

2 H, C4 H), 4.17 (pt, J = 8.9 Hz, 2 H, C5H_a), 4.09 (m, 4 H, C2ЈЈЈH, C6ЈЈЈH), 7.13 (d, J = 8.7 Hz, 4 H, C2ЈH, C6ЈH), 6.80 (d,

C1ЈЈH₂), 3.95 (m, 2 H, C5H_b), 3.85 (m, 4 H, C4ЈЈH₂), 2.97 (dd, J J = 8.6 Hz, 4 H, C3ЈH, C5ЈH), 5.20 (s, 4 H, C1ЈЈH₂), 4.93 (m, 2

= 5.5 and 14.0 Hz, 2 H, C1Ј-CH_a), 2.75 (dd, J = 7.6 and 13.9 Hz,

2 H, C1Ј-CH_b), 2.23 (s, 12 H, C2ЈЈЈCH₃), 1.98 (m, 12 H, C2ЈЈH₂

H, C*H), 3.86 (s, 2 H, C4ЈЈЈCH₂), 3.67 (d, J = 6.3 Hz, 4 H,

CH₂OH), 2.93 (brs, 2 H, CH₂OH), 1.97–1.87 (m, 4 H, CH₂CH₃),

and C3ЈЈH₂and CH₂CH₃), 1.62 (s, 6 H, C4ЈЈЈCCH₃), 0.79 (t, J = 0.63 (t, J = 7.5 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR ([D₆]acetone):

7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C NMR: δ = 167.7 (C2), 157.3 (C4Ј), δ = 174.2 (C=O), 158.2 (C4Ј), 141.7 (C4ЈЈЈ), 136.7 (C1ЈЈЈ), 133.8

153.4 (C1ЈЈЈ), 145.7 (C4ЈЈЈ), 130.4 (C2Ј, C6Ј), 130.1 (C1Ј), 129.5 (C1Ј); 129.7, 128.9, 127.7 (C2Ј C6Ј, C2ЈЈЈ, C6ЈЈЈ and C3ЈЈЈ, C5ЈЈЈ),

(C2ЈЈЈ, C6ЈЈЈ), 126.9 (C3ЈЈЈ, C5ЈЈЈ), 114.5 (C3Ј, C5Ј), 71.4 (C4ЈЈ), 115.7 (C3Ј, C5Ј), 69.1 (C1ЈЈ), 66.5 (CH₂OH), 58.6 (CEt₂), 56.2 (C*)

71.1 (C5), 67.4 (C1ЈЈ), 66.9 (C4), 46.5 (CEt₂), 41.4 (CMe₂), 40.1

(C4CH₂), 30.7 (CMe₂), 26.5, 25.7, 25.1 (C3ЈЈ, C2ЈЈ and CH₂CH₃),

42.1 (C4ЈЈЈCH₂), 32.6 (CH₂CH₃), 10.1 (CH₂CH₃) ppm. IR (KBr):

ν = 3421, 3057, 2966, 2934, 2877, 1661, 1611, 1511, 1459, 1226,

˜

16.6 (C2ЈЈЈCH ), 8.2 (CH CH ) ppm. IR (KBr): ν = 3427, 2963, 1178, 1038, 829, 545 cm^–1.

˜

3

2

3

2927, 2877, 1653, 1510, 1299, 1244, 1180, 1108, 985, 831, 526 cm^–1.

HRMS: [M]⁺calculated for C₅₂H₆₆N₂O₆: 814.49207; found:

814.49190.

Preparation of (1⁴R,11⁴R)-12,12-Diethyl-1⁴,1⁵,12⁴,12⁵-tetrahydro-

3,9-dioxa-1,11(2,4)-bis(1,3-oxazola)-2,5,7,10(1,4)-tetrabenzenacy-

clododecaphane (1): Thionyl chloride (1.19 g, 10 mmol) was added

to a solution of dihydroxy compound 24 (660 mg, 1.00 mmol) in

(1⁴S,3⁴S)-2,2-Diethyl-13²,13⁶,14,14,15³,15⁵-hexamethyl-1⁴,1⁵,3⁴,3⁵-

tetrahydro-6,12,16,22-tetraoxa-1,3(2,4)-bis(1,3-oxazola)- dichloromethane (20 mL) and the reaction mixture was stirred

5,13,15,23(1,4)-tetrabenzenacyclotetracosaphane (8d): This com-

pound was obtained from 16d (317 mg) and 25 (114 mg) in a pro-

overnight at room temperature. Solvent was evaporated and the

dry residue was dissolved in acetonitrile (50 mL). K₂CO₃(553 mg,

4 mmol) was added to this solution and the reaction mixture was

cess that gave product 8d (138 mg, 41%) as a white foam. [α]_D

=

854

www.eurjoc.org

Eur. J. Org. Chem. 2007, 838–856

Chiral Macrocyclic Bis(oxazoline) Cu^IComplexes

FULL PAPER

heated at reflux for 8 h, and then allowed to cool to room tempera-

ture. Inorganic salts were filtered off, the filtrate was concentrated,

and the oily residue was purified by preparative TLC in CH₂Cl₂/

MeOH (20:1). Product 1 (428 mg, 73%) was obtained as a white

cis-(1R,2S) isomer, 22.5 min for the trans-(1R,2R) isomer and

22.9 min for the trans-(1S,2S) isomer of ethyl 2-phenylcyclopro-

panecarboxylate.

1

foam. [α]_D= +170.7 (c = 1.24 in CH₂Cl₂). H NMR: δ = 7.22 (s,

8 H, C2ЈЈЈH, C6ЈЈЈH and C3ЈЈЈH, C5ЈЈЈH), 7.05 (d, J = 8.5 Hz, 4

H, C2ЈH, C6ЈH), 6.77 (d, J = 8.5 Hz, 4 H, C3ЈH, C5ЈH), 5.25–5.14

(m, 6 H, C1ЈЈH₂and C4H), 4.58 (pt, J = 9.2 Hz, 2 H, C5H_a), 4.00

(pt, J = 8.0 Hz, 2 H, C5H_b), 3.86 (s, 2 H, C4ЈЈЈCH₂), 2.25 (m, 2

H, CH_aCH₃), 2 . 00 ( m , 2 H , C H _bC H₃) , 0 . 9 4 ( m , 6 H ,

CH₂CH₃) ppm. ¹³C NMR: δ = 168.0 (C2), 156.8 (C4Ј), 140.3

(C4ЈЈЈ), 134.8 (C1Ј or C1ЈЈЈ), 134.2 (C1ЈЈЈ or C1Ј), 128.2 (C2ЈЈЈ,

C6ЈЈЈ or C3ЈЈЈ, C5ЈЈЈ), 127.1 (C2Ј, C6Ј), 126.1 (C3ЈЈЈ, C5ЈЈЈ or C2ЈЈЈ,

C6ЈЈЈ), 115.2 (C3Ј, C5Ј), 74.6 (C5), 68.7 (C4 or C1ЈЈ), 68.5 (C1ЈЈ or

C4), 46.8 (CEt₂), 41.5 (C4ЈЈЈCH₂), 25.0 (CH₂CH₃), 8.1

Acknowledgments

Financial support from the Croatian Ministry of Science and Tech-

nology (Projects 0098053 and 0098050) is gratefully acknowledged.

The authors thank Dr. sc. S. Kirin for recording the mass spectra.

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(CH CH ) ppm. IR (KBr): ν = 3433, 2970, 2933, 1652, 1610, 1510,

˜

2

3

1221, 1175, 1107, 987, 828 cm^–1. HRMS: [M]⁺calculated for

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C₃₈H₃₈N₂O₄: 586.28316; found: 586.28310.

Preparation of 3,3-Bis{(4R)-4-[4-(4-phenoxybutoxy)phenyl]-4,5-di-

hydro-1,3-oxazol-2-yl}pentane (5): K₂CO₃(553 mg, 4.00 mmol) was

added to a solution of 20c (737 mg, 1.00 mmol) and phenol (94 mg,

1.00 mmol) in acetonitrile (50 mL). The reaction mixture was

heated at reflux for 8 h and was then allowed to cool to room

temperature. The inorganic precipitate was removed and the filtrate

was concentrated, leaving an oily residue that was purified by pre-

parative TLC in CH₂Cl₂/EtOAc (7:3). Product 5 (323 mg, 55%)

was obtained as a white foam. [α]_D= +95.4 (c = 7.4 in CH₂Cl₂).

¹H NMR: δ = 7.28 (t, J = 7.9 Hz, 4 H, C3ЈЈЈH, C5ЈЈЈH), 7.19 (d,

J = 8.5 Hz, 4 H, C2ЈH, C6ЈH), 6.96–6.84 (m, 10 H, C3ЈH, C5ЈH

and C2ЈЈЈH, C6ЈЈЈH and C4ЈЈЈH), 6.73 (d, J = 8.7 Hz, 4 H, C2ЈЈЈH,

C6ЈЈЈH or C3ЈH, C5ЈH), 5.20 (pt, J = 9.0 Hz, 2 H, C4 H), 4.63 (pt,

J = 9.2 Hz, 2 H.C5H_a), 4.09 (pt, J = 8.1 Hz, 2 H.C5H_b), 4.02 (m,

8 H, C1ЈЈH₂and C4ЈЈH₂), 2.13 (m, 4 H, CH₂CH₃), 1.97 (brs, 6 H,

C2ЈЈH and C3ЈЈH), 0.94 (t, J = 7.4 Hz, 6 H, CH₂CH₃) ppm. ¹³C

NMR: δ = 168.4 (C2), 158.8, 158.3 (C4Ј and C1ЈЈЈ), 134.4 (C1Ј),

129.3 (C3ЈЈЈ, C5ЈЈЈ), 127.7 (C2Ј, C6Ј), 120.5 (C4ЈЈЈ), 114.5, 114.3

(C3Ј, C5Ј and C2ЈЈЈ, C6ЈЈЈ), 74.9 (C5), 68.9 (C4), 67.4, 67.2 (C1ЈЈ

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and C4ЈЈ), 46.8 (CEt₂), 25.9 (C2ЈЈ and C3ЈЈ), 25.4 (CH₂CH₃), 8.4 [15] T. Katsuki, Synlett 2003, 281–297.

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(CH CH ) ppm. IR (KBr): ν = 3417, 3041, 2927, 2877, 1656, 1538,

˜

2

3

1512, 1389, 1303, 1250, 1173, 1059, 977, 921, 831, 759, 693,

542 cm^–1. HRMS: [M]⁺calculated for C₄₃H₅₀N₂O₆: 690.36688;

found: 690.36720.

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Catalytic Cyclopropanation: The tested catalytic ligand (0.03 mmol)

was added to a suspension of styrene (0.57 mL, 52 mg; 5 mmol)

and CuOTf·½MePh (3.9 mg, 0.015 mmol) in 1,2-dichloroethane

(1 mL). The formed solution was stirred under argon for 1 h, and

a solution of ethyl diazoacetate (1.0 mmol) in 1,2-dichloroethane

(1.0 mL, as 1  solution) was then introduced by syringe pump

over 4.5 h. After all the ethyl diazoacetate had been added the reac-

tion mixture was stirred at room temperature under argon over-

night. It was then concentrated and the crude product was purified

on a short silica gel column with EtOAc/petroleum ether (1:10) as

eluent.

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ˇ

[25] D. Sepac, Z. Marinic´, T. Portada, M. Zinic´, V. Sunjic´, Tetrahe-

dron 2003, 59, 1159–1167.

Chemical yields were determined by gas chromatography on an

achiral HP-1 column with biphenyl as standard. Diastereoselectiv-

ity and enantioselectivity of catalytic cyclopropanation were deter-

mined by gas chromatography of the product on a chiral Chirasil-

DEX CB column. The initial temperature was 120 °C, temperature

gradient 1.0 °Cmin^–1, the end temperature 150 °C, nitrogen pres-

sure 70 kPa and split 1/50. Under these conditions the retention

times of ethyl 2-phenylcyclopropanecarboxylates on the column de-

scribed were 20.5 min for the cis-(1S,2R) isomer, 21.4 min for the

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3561–3651.

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T. Portada, M. Roje, Z. Raza, V. Caplar, M. Zinic´, V. Sunjic´

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Received: September 21, 2006

Published Online: December 15, 2006

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Article Doi

Chiral macrocyclic bis(oxazoline) Cu1 complexes - Structure/stereoselectivity relationships in catalytic cyclopropanations

DOI: 10.1002/ejoc.200600827

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