Asymmetric catalysis, 131([≠]) - Naproxen derivatives by enantioselective decarboxylation

FULL PAPER

Asymmetric Catalysis, 131^[°]

Naproxen Derivatives by Enantioselective Decarboxylation

Henri Brunner*^[a]and Peter Schmidt^[a]

Keywords: Naproxen / Asymmetric catalysis / Decarboxylation / Alkaloids / Epicinchonaalkaloid amides

A new catalytic method to synthesize the important anti-in-

flammatory agent naproxen [(S)-1] which has to be used as

could be increased by turning to amides of 9-amino-9-deox-

yepicinchona alkaloids. The most successful 2-ethoxybenz-

the (S) enantiomer, involves the enantioselective decarb- amide 31a of 9-amino-9-deoxyepicinchonine 11 gave up to

oxylation of the 6-methoxynaphth-2-yl derivative 2 of 2-cy-

anopropionic acid. Compound 2 was stirred in THF at 15 °C

with catalytic amounts of chiral bases, which abstracted the

carboxyl proton. After decarboxylation, reprotonation of the

anion of 6 afforded the enantiomerically enriched naproxen

nitrile 6, which may be hydrolyzed to naproxen. A variety of

bases were screened, and cinchona alkaloids were found to

give the best enantioselectivities. Thus, with quinidine 10,

up to 34% ee was obtained for (S)-6. The enantiomeric excess

71.9% ee (S)-6. Cyclic ethers like THF were suitable solvents,

and at a temperature of 15 °C, conversion was quantitative

within 24 h in most cases. For high enantioselectivities, 5−10

mol-% of chiral base was sufficient, and the catalyst could be

fully recycled after decarboxylation. The model compound 2-

cyano-2-phenylpropionic acid (40) was decarboxylated with

base 31a to the (S) enantiomer of the corresponding nitrile

41 with 60% ee.

Introduction

applied. Early production of naproxen involved the syn-

thesis of the racemate, followed by resolution.^[3]The resolv-

ing agent (Ϫ)-cinchonidine was replaced by the more effect-

ive N-alkyl--glucamines.^[3]Because of the increasing inter-

est in optically pure 2-arylpropionic acids, strategies have

been developed to produce the desired enantiomers directly

by asymmetric synthesis.^[4,5]Industrial manufacturing

methods leading to naproxen include the Zambon pro-

cess,^[6]the catalytic asymmetric hydrocyanation of 6-me-

thoxy-2-vinylnaphthalene (Du Pont),^[7,8]and the asymmet-

ric hydrogenation of 2-(6-methoxynaphth-2-yl)propenoic

acid (Monsanto).^[9Ϫ11]In addition, (S)-1 has been prepared

by biochemical techniques, such as enantioselective hydro-

lysis of naproxen derivatives.^[12Ϫ14]Recently, naproxen di-

isopropylamide was synthesized in high optical yield by

catalytic asymmetric protonation of the corresponding

amide enolate.^[15,16]

Naproxen is the international nonproprietary name for

(S)-2-(6-methoxynaphth-2-yl)propionic acid (Figure 1).^[1]It

belongs to the group of nonsteroidal anti-inflammatory

drugs (NSAID). It was first synthesized by Syntex and has

been on the market as a prescription drug since 1972, first

as the free acid and later as the sodium salt.^[2]The produc-

tion of naproxen was estimated in 1992 to be about 1000

tons per year. After the patent had expired in 1988 (1993 in

the USA), a generic market developed in many countries.

Early 1994, the Food and Drug Administration of the

United States approved naproxen sodium in a lower dosage

as a nonprescription pain reliever; this led to an increasing

demand for new production methods for naproxen.

Our approach to the synthesis of 2-aryl-substituted pro-

pionic acids is to decarboxylate suitably substituted malonic

acids and their monoesters as well as cyanoacetic acids

(Scheme 1).

Figure 1. Naproxen, (S)-1

2-Aryl-substituted propionic acids, such as naproxen, ex-

ist in two enantiomeric forms. The (S) enantiomer of 1 is

about 28 times more effective than the (R) enantiomer.^[2]

For that reason, it is exclusively (S)-1 which is sold and

[°]

Part 130: H. Brunner, S. Stefaniak, M. Zabel, Synthesis,

in press.

[a]

Institut für Anorganische Chemie der Universität,

93040 Regensburg, Germany

Fax: (internat.) ϩ 49-(0)941/943-4439

E-mail: henri.brunner@chemie.uni-regensburg.de

Scheme 1. Decarboxylation of malonic acids, their monoesters and

cyanoacetic acids

Eur. J. Org. Chem. 2000, 2119Ϫ2133

WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000

1434Ϫ193X/00/0611Ϫ2119 $ 17.50ϩ.50/0

2119

H. Brunner, P. Schmidt

FULL PAPER

In the presence of optically active auxiliaries, the decarb-

oxylation of these prochiral substrates should be enantiose-

lective. Already in 1904, Marckwald obtained low enantio-

merically enriched 2-methylbutyric acid by heating the

brucine salt of ethyl(methyl)malonic acid.^[17,18]Until the

mid 1980s, few reports had been devoted to enantioselective

decarboxylation, all with unsatisfactory results.^[19,20]In

1986, Toussaint et al. published the decarboxylation of ma-

lonic acids under mild conditions in the presence of Cu₂O.

Monocarboxylic acids were obtained in nearly quantitative

yields and a catalytic cycle involving copper(I) was postu-

lated.^[21]The use of a combination of CuCl and cinchona

alkaloids led to optical inductions in the resulting monocar-

boxylic acids.^[22]The highest enantiomeric excess of 27%

in the decarboxylation of methyl(phenyl)malonic acid was

achieved with a substrate/cinchonine/CuCl molar ratio of

1:1.4:0.7. Later it was shown that the amount of CuCl

could be reduced significantly, and an increase in the alkal-

oid concentration raised the optical induction to 36% ee.^[23]

However, only a marginal enantiomeric excess could be ob-

tained with catalytic amounts of alkaloid.^[23]After the role

of copper(I) in the decarboxylation of malonic acids had

been minimized,^[23,24,25]further investigations proved that

the reaction is not copper(I)-catalyzed, but is induced by

bases.^[26,27]Thus, decarboxylations with CuCl are much

slower than those with Cu₂O, which contains the more ba-

sic oxide anion. Alkaloids as bases without any additives

were able to initiate the decarboxylation. In the decarb-

oxylation of the monoethyl ester of methyl(phenyl)malonic

acid, a catalytic amount of alkaloid was sufficient to obtain

a reasonable enantiomeric excess. With 10 mol-% cinchon-

ine in THF, 33.8Ϫ34.5% ee ethyl (S)-2-phenylpropionate

could be obtained.^[26]Enzymatic decarboxylation of 2-(6-

methoxynaphth-2-yl)-2-methylmalonic acid, to produce na-

proxen, has also been attempted. However, only the un-

desired (R)-1 could be isolated in over 95% ee.^[28,29]In this

paper, we report on our studies concerning the enantioselec-

tive decarboxylation of 2-cyano-2-(6-methoxynaphth-2-yl)-

propionic acid (2).^[30,31]The resulting optically active nitrile

may then be hydrolyzed to naproxen.^[32]

Scheme 2. Preparation of the substrate 2

Aryl halides react with carbon nucleophiles, such as an-

ions of active methylene compounds, to form carbonϪ

carbon bonds.^[35,36]This copper(I)-catalyzed coupling reac-

tion is best carried out with aryl iodides. Frequently, a stoi-

chiometric amount of copper(I) salt is necessary for reason-

able yields.^[37]Miura et al. found that the reaction of aryl

iodides with certain active methylene compounds proceeds

catalytically if DMSO is used as the solvent.^[38]Thus, 4 was

heated in DMSO with ethyl cyanoacetate and K₂CO₃as

base, in the presence of 10 mol-% CuI. After treatment with

methyl iodide, the resulting ethyl 2-cyano-2-(6-methoxy-

naphth-2-yl)propionate (5) could be isolated in 70% yield.^[38]

Under the same reaction conditions, we observed no con-

version with diethyl malonate as coupling reagent. After es-

ter hydrolysis of 5, the substrate 2-cyano-2-(6-methoxy-

naphth-2-yl)propionic acid (2) was obtained in 90% yield.

Compound 2 is very sensitive towards decarboxylation.

Loss of CO₂occurs immediately if the compound is dis-

solved in DMSO or acetone. In pure diethyl ether, THF,

and dichloromethane, 2 is stable at room temperature for at

least 24 hours.

Enantioselective Decarboxylation of 2

Decarboxylation of 2 leads to 2-(6-methoxynaphth-2-yl)-

propionitrile (6) which exists in two enantiomeric forms

(Scheme 3). If 2 is decarboxylated thermally, a racemic mix-

ture of 6 is obtained.

Synthesis of the Substrate

2-Cyano-2-(6-methoxynaphth-2-yl)propionic acid (2) was

chosen as the substrate for decarboxylation, because it may

be prepared more efficiently than the corresponding ma-

lonic acid and its monoethyl ester (Scheme 2). As starting

material, readily available 2-methoxynaphthalene (3) was

used. For the formation of 2, a halogen substituent in the

6-position had to be introduced first. Published procedures

were followed, and 3 was iodinated twice in the 2- and 6-

positions, to give the diiodo compound in situ. The halogen

substituent ortho to the methoxy group was removed by the

addition of hydriodic acid, leading to 2-iodo-6-methoxyn-

aphthalene (4).^[33,34]Disubstitution was necessary because

monohalogenation leads exclusively to substitution in the Scheme 3. Decarboxylation of 2, leading to nitrile 6

2120 Eur. J. Org. Chem. 2000, 2119Ϫ2133

Asymmetric Catalysis, 131

FULL PAPER

Table 1. Enantiomeric excess of 6 obtained with different bases in

the decarboxylation of 2

Entry

Base

ee [%]^[a]of 6

Config.

1

2

3

4

5

6

7

5.0; 6.0

(R)

(S)

(R)

(S)

8

11.5; 12.7

15.8; 16.5

33.1; 34.0

2.2; 2.3

9

10

11

12

13

2.9; 2.9

48.6; 50.9; 51.1

[a]

1

Quantitative conversion according to the H-NMR spectra; en-

antiomeric excess determined by GC on a Restek Rt-β DEX cst

column.

Scheme 4. Protonation of the planar ketenimine anion from the top

face or the bottom face, leading to the different enantiomers of

nitrile 6

Cinchonidine (7) and quinine (8) provided (R)-6 in op-

tical yields up to 12.7% ee (entries 1,2; Table 1). In contrast,

cinchonine (9) gave around 16% ee (entry 3) and quinidine

(10) (entry 4) gave up to 34.0% ee of the desired (S)-6. Thus,

simultaneous inversion at the carbon atoms C8 and C9 led

to a change in the configuration of the decarboxylation

product 6. This is not surprising, as the diastereomers in

pairs 7/9 and 8/10 behave almost like enantiomers.^[39,40]

Compared to 9, 10 has an additional methoxy group at-

tached at the quinoline system. This structural detail re-

sulted in an increase in the optical induction, by about 17%.

Alkaloids not containing the cinchona alkaloid structure,

such as strychnine, brucine and sparteine, were less success-

ful. Even the alkaloid (Ϫ)-N-methylephedrine, containing

the β-amino alcohol structure like that of the cinchona al-

kaloids, gave only marginal optical inductions.^[30,31]There-

fore, derivatives of cinchona alkaloids, such as esters and

tosylates, have been tested, but the enantiomeric excess of

34.0% obtained with quinidine 10 could not be ex-

ceeded.^[30,31]

Published procedures were followed to replace the hy-

droxy group of 9 with an amino function, with simultan-

eous inversion at C9; this led to 9-amino-9-deoxyepicin-

chonine (11) (Scheme 5).^[41,42]We carried out the reaction

with 10 similarly and obtained the corresponding 9-amino-

9-deoxyepiquinidine (12). The key step is a Mitsunobu reac-

tion that leads to the C9-azido compound by an S_N2 mech-

anism. To avoid the isolation of the azide, the reduction was

performed in situ, according to Staudinger’s method, by

adding triphenylphosphane followed by hydrolysis of the in-

termediate aminophosphorane.^[43]

In the decarboxylation of the anion of 2, a prochiral in-

termediate,

a

planar ketenimine anion, is formed

(Scheme 4). An acidic compound [XϪH]^ϩmay protonate

the carbanionic carbon atom, leading to nitrile 6. With op-

tically active species [XϪH]^ϩ, si and re face protonation

should take place at different rates and the enantiomers

should be obtained in different quantities. Alkaloids or

other nitrogen bases promote the decarboxylation of 2 by

abstracting the carboxylic acid proton. In the protonation

of the resulting ketenimine anion, the conjugate acids

[XϪH]^ϩshould act as chiral proton donors.

The enantioselective decarboxylation was carried out by

stirring of 170 mg of 2 and 10 mol-% of an optically active

base in 10 mL of abs. THF at 15 °C under nitrogen. After

24 h, the solvent was evaporated and the residue was dis-

solved in ether. The bases were separated and recycled by

extraction of the ether phase with dilute hydrochloric acid.

The ether was removed and conversion was determined by

¹H-NMR spectroscopy. Then the reaction product 6 was

isolated by column chromatography on silica gel. In most

cases, decarboxylation was complete within 24 h. The en-

antiomeric excess of 6 was determined by gas chromato-

graphy.

Screening of Bases

Previous papers report the use of cinchona alkaloids as

suitable bases for the enantioselective decarb-

oxylation.^[22,23,26]Thus, the commercially available cin-

chona alkaloids cinchonidine (7), quinine (8), cinchonine

(9) and quinidine (10) were applied as catalysts (Figure 2).

Scheme 5. Preparation of the 9-amino-9-deoxyepicinchona alkal-

oids 11 and 12

With the free amines 11 and 12, only low optical induc-

tions were obtained (entries 5, 6; Table 1). Surprisingly,

however, the benzamide of 11, N-(9-deoxyepicinchonine-9-

Figure 2. The cinchona alkaloids 7Ϫ10

Eur. J. Org. Chem. 2000, 2119Ϫ2133

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H. Brunner, P. Schmidt

FULL PAPER

Table 2. Enantiomeric excess of 6 obtained in the decarboxylation

of 2 with amides a of 11 and b of 12

Entry

Base

ee (S) [%]^[a]of 6

8

14a

15a

16a

17a

18a

19a

20a

21a

22a

23a

24a

25a

26a

27a

28a

29a

30a

30b

31a

31b

32a

33a

34a

35a

41.0; 41.4

9

41.8; 42.3

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

43.5; 44.3

8.8; 9.2

Figure 3. N-(9-Deoxyepicinchonine-9-yl)benzamide (13)

22.7; 24.3

50.5; 51.0

31.3; 32.3

yl)benzamide^[43](13) (Figure 3), induced an enantiomeric

excess of up to 51.1% ee (entry 7); this indicates that amide

13 is a new leading structure, which gives better optical

yields in the enantioselective decarboxylation reaction than

the other bases tested before.

53.5; 54.1

41.4; 41.7

41.6; 43.5

53.4; 54.0

45.7; 46.3

42.2; 43.9

49.5; 50.4

42.3; 42.6

48.1; 48.6

Amides of 11 and 12 as Catalysts

61.8; 62.2; 63.1; 64.5

63.1; 64.6

By varying the amide substituents, we tried to increase

the enantiomeric excess in the decarboxylation of 2. For the

synthesis of the amides, two methods were applied. Besides

the well-known condensation of amines with acid chlorides

(method A, Scheme 6), amides were formed by the reaction

of amines with trimethylaluminum and carboxylic acid es-

ters (method B).^[44]Method B proved to be advantageous,

because carboxylic acids too sensitive to give acid chlorides

without decomposition can be used as their methyl/ethyl

esters, and side products were not observed. In contrast,

if the conversion was carried out according to method A,

purification by transforming the base into the hydro-

chloride followed by recrystallization was necessary. The

commercial cinchona alkaloids contain small amounts of

their dihydro derivatives, which are difficult to separate.

However, after the amide formation, it is possible to separ-

ate the dihydro compound by column chromatography. Al-

though this purification step decreased the yields consider-

ably, it was carried out in all cases to obtain the pure bases.

66.9; 67.1; 70.1; 70.4

60.3; 61.6

64.8; 65.5; 70.4; 70.9

34.0; 34.9

34.6; 35.0

23.4; 24.0

[a]

Quantitative conversion according to the ¹H-NMR spectra ex-

cept entry 17 (78 and 80% conversion) and entry 29 (82 and 85%

conversion); enantiomeric excess determined by GC on a Restek

Rt-β DEX cst column.

in Table 2. Compared to the benzamide 13 (entry 7,

Table 1), the cyclohexylamide 14a (entry 8, Table 2) resulted

in an enantiomeric excess decrease of about 10%. The 3-

phenylpropyl derivative 15a (entry 9) performed similarly,

and the diphenylacetamide 16a (entry 10) gave slightly

better results. The base 17a contains the (1S)-(Ϫ)-cam-

phanic acid moiety, which is used for separating racemic

alcohols and amines. However, 17a gave enantiomeric ex-

cesses below 10% (entry 11). The coumarin-3-carboxylic

acid amide 18a induced up to 24.3% ee (entry 12) and the

α-methylcinnamic acid amide 19a gave up to 51% ee (entry

13). Thus, bases with aliphatic or olefinic substituents at-

tached to the amide carbon atom were not able to raise

the enantiomeric excess above the 51.1% obtained with the

benzamide 13.

To vary the aromatic substituents at the amide carbon

atom, the naphthamides of 11 were synthesized first of all.

Slightly better optical inductions than with the benzamide

13 were achieved with the 2-naphthamide 21a (entry 15),

whereas with the 1-naphthamide 20a (entry 14) the enantio-

selectivity dropped significantly. The ferrocenylcarboxylic

acid amide 22a (entry 16) and the 2-indolcarboxylic acid

Scheme 6. Preparation of amides from amines 11 and 12 and either

carboxylic acid chlorides (method A) or trimethylaluminum and

carboxylic acid esters (method B)

Most alkaloid derivatives were synthesized with amine amide 23a (entry 17) gave somewhat more than 40% ee. The

11, because the Mitsunobu reaction gave 11 in higher yields 2-furancarboxamide 24a afforded up to 54.0% ee (entry 18).

than 12 and cinchonine (9) leading to 11 is less expensive For investigating the influence of different functional

than quinidine (10) leading to 12 (Scheme 5). Figure 4 groups on the enantiomeric excess, substituted benzoic acid

shows all synthesized amides 14aϪ22a, 24aϪ26a, 28aϪ31a, derivatives were used as amide components. Compared to

and 31b from the carboxylic acid chlorides c by method A the benzamide 13 (entry 7), the base 25a with additional

and 23a, 27a, 30b, and 32aϪ35a from the carboxylic acid tert-butyl groups in the 3- and 5-positions gave less optical

esters d by method B. The results with all of these bases induction, around 46% (entry 19), similar to the 2-fluoro-

that gave the desired (S) enantiomer of 6 are summarized benzamide 26a with an enantiomeric excess of up to 43.9%

2122

Eur. J. Org. Chem. 2000, 2119Ϫ2133

Asymmetric Catalysis, 131

FULL PAPER

Figure 4. Amides a of 11 and b of 12, synthesized according to method A or B, and the carboxylic acid chlorides c, carboxylic esters d,

and carboxylic acids e

(entry 20). The results obtained with the 3-nitrobenzamide ity decreased to 34.0% ee (entry 29), probably due to the

27a (entry 21) were almost identical to that of the unsubsti- additional hydroxy proton, which may act as an undesired

tuted benzamide 13. To study the effect of the same func- proton source in the reprotonation of the ketenimine anion.

tional group in the ortho, meta, or para position of the In contrast to the 2-alkoxybenzamides, the 2-(methoxyme-

phenyl moiety, the three methoxybenzamides 28aϪ30a were thyl) derivative 34a, in which the oxygen atom is not directly

synthesized. The 3-methoxybenzamide 29a (entry 23) with bonded to the aromatic ring, yielded only about 35% ee

48.6% ee was superior to the 4-methoxybenzamide 28a (entry 30). The 2-(acetamido)benzamide derivative 35a, as

(entry 22) with 42.6% ee. However, the best results were another variant with a functional group in the 2-position,

achieved with the 2-methoxybenzamide 30a, which gave gave only 24% ee (entry 31).

61.8Ϫ64.5% ee (entry 24). As functional groups in the ortho

All amides tested so far were synthesized with the amine

position seemed to be the most successful, the 2-ethoxy- component 9-amino-9-deoxyepicinchonine (11). As pointed

benzamide 31a was synthesized and tested, revealing the out earlier, the enantiomeric excess increased when me-

highest optical inductions of 66.9Ϫ70.4% (entry 26) so far. thoxy-substituted quinidine (10) was used instead of unsub-

The 2-butoxybenzamide 32a with a longer alkoxy chain stituted cinchonine (9). We were interested to find out if the

showed similar, although less reproducible results (entry same effect would show up if amides of 9-amino-9-deoxy-

28). With the 2-hydroxybenzamide 33a, the enantioselectiv- epiquinidine (12) were used as catalysts instead of 9-amino-

Eur. J. Org. Chem. 2000, 2119Ϫ2133

2123

H. Brunner, P. Schmidt

FULL PAPER

9-deoxyepicinchonine (11). We therefore synthesized the 2- Table 3. Enantiomeric excess of 6 obtained in the decarboxylation

of 2 with the bases 36Ϫ39

methoxybenzamide 30b and 2-ethoxybenzamide 31b from

the quinidine derivative 12. With the 2-methoxybenzamides

Entry

Base

ee [%]^[a]of 6

Config.

30a and 30b analogous results were achieved (entries, 24,

25), whereas the enantiomeric excess obtained with 31b as

the base (entry 27) was about 10% lower than with the cor-

responding 2-ethoxybenzamide 31a (entry 26). Thus, in the

amide series, an additional methoxy group at the quinoline

system did not lead to higher enantioselectivity.

32

33

34

35

36

37

38

39

69.4; 70.3

67.8; 70.5

2.4; 2.7

(S)

(R)

(S)

5.7; 5.8

[a]

1

Quantitative conversion according to the H-NMR spectra; en-

antiomeric excess determined by GC on a Restek Rt-β DEX cst

column.

Compound 39 was used as a base, because the asymmet-

ric protonation of the lithium salt of naproxen diisopropyl-

amide with 39 had given 97% ee.^[15,16]However, in the en-

antioselective decarboxylation of 2, 39 induced less than 6%

ee (entry 35).

Testing of Additional Bases

Figure 5 shows additional bases which were tested in the

enantioselective decarboxylation reaction. The dihydro al-

kaloid 36 (entry 32; Table 3), synthesized by hydrogenation

of the vinyl derivative 31a, gave optical inductions compar-

able to that of the parent compound 31a; this shows that

the double bond is not significant for high enantioselectiv-

ity. The cinchona alkaloids and the derivatives discussed in

this paper contain two basic nitrogen atoms, the quinoline

and the quinuclidine nitrogen atom. As the quinuclidine ni-

trogen atom is the much more basic one, it should act as

proton acceptor and donor exclusively. To find out about

the influence of the quinoline nitrogen atom, the mono-

(arene) N-oxide 37 was prepared and tested. The optical

inductions obtained with the nonoxidized and oxidized

compounds 36 and 37 were basically identical (entries 32,

33). Thus, it can be ruled out that the quinoline nitrogen

atom has a significant influence on enantioselective decarb-

oxylation. In contrast to benzamide 13 of 11, the corres-

ponding phthalimide 38 supplied a nearly racemic decarb-

oxylation product 6, with a slight excess of the (R) enantio-

mer (entry 34).

Variation of the Reaction Conditions and Kinetic

Investigations

To increase the enantiomeric excess of around 70% ob-

tained under standard reaction conditions with the 2-

alkoxybenzamides of 9-amino-9-deoxyepicinchonine (11)

and their derivatives 36 and 37, the reaction conditions

were varied, starting with the temperature (Table 4). Thus,

the benzamide 13 was stirred with 2 at 5 °C instead of at

15 °C in the standard reaction. As only poor conversions

were observed (TLC monitoring) after 15 h, the reaction

was continued for 144 h to give complete conversion. De-

crease of the temperature to 5 °C resulted in a slightly

higher optical induction, of 53.5% (entry 36), than at 15

°C (48.6Ϫ51.1% ee, entry 7). Analogous tests with the 2-

methoxybenzamide 30a revealed no significant change in

the optical induction (entries 24, 37), whereas the enanti-

omeric excess decreased to 64% with the corresponding 2-

ethoxybenzamide 31a (entries 26, 38). At 10 °C, the enantio-

selectivities induced by base 31a were comparable to the

results obtained under standard conditions (entries 26, 39);

at 20 °C they were a little lower (entries 26, 40). Altogether,

the experiments confirm an optimum reaction temperature

of 15 °C.

Table 4. Variation of the reaction temperature in the decarb-

oxylation of 2

Entry^[a]

Base

T [°C]

ee (S) [%]^[b]of 6

t [h]

36

37

38

39

40

13

5

53.5

144

95.5

117

24

30a

31a

5

63.5; 65.0

63.9; 64.2

66.9; 68.2

65.2; 65.3

5

10

20

24

[a]

Apart from different reaction temperatures and reaction times,

the catalyses were carried out according to the standard procedure.

Ϫ

after the indicated reaction time; enantiomeric excess determined

by GC on a Restek Rt-β DEX cst column.

Quantitative conversion according to the ¹H-NMR spectra

[b]

Figure 5. Additional bases tested in the decarboxylation of 2

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Asymmetric Catalysis, 131

FULL PAPER

Subsequently, the standard procedure was modified by omeric excess compared to in pure THF (entries 26, 56).

changing the base concentration (Table 5). Almost the same Thus, besides THF, other cyclic ethers such as dioxane and

optical inductions were obtained with 5 instead of 10 mol- tetrahydropyran are suitable solvents for the enantioselec-

% of 31a; this indicates that the reaction proceeds with the tive decarboxylation reaction. However, optical inductions

same enantioselectivity with lower amounts of catalyst (ent- could not be increased significantly above 70% ee.

ries 26, 41). On the other hand, an equimolar ratio of sub-

Table 6. Variation of solvent quantity and solvent type in the de-

strate 2 and base 31a did not raise the enantiomeric excess

(entries 26, 42). Thus, catalytic amounts of base are suffi-

cient for highly enantioselective decarboxylation.

carboxylation of 2

Entry^[a]Base Solvent

ee (S) [%]^[b]of 6 t [h]

Table 5. Variation of the base concentration in the decarboxylation

43

44

45

31a 5 mL THF

64.8; 67.3

68.5; 71.9

58.9; 60.7

24

of 2

31a 20 mL THF

30a 10 mL THF ϩ

0.025 mL H₂O

Entry^[a]

Base

Base concentration

[mol-%]^[b]

ee (S) [%]^[c]of 6

46

47

31a THF under argon

31a THF p.a., distilled,

not N₂-saturated

67.4; 70.7

66.7; 70.7

24

41

42

31a

5

100

66.0; 69.2

68.7; 70.5

48

49

50

51

52

53

54

55

56

13

Et₂O

25.6

40

20

40

49

70

24

CH₃CN

CH₂Cl₂

1,4-dioxane

15.2

Ϫ

^[a]Apart from different base concentrations, the catalyses were car-

55.9

[b]

ried out according to the standard procedure. Ϫ The base con-

30a 1,4-dioxane

31a 1,4-dioxane

31a tetrahydropyran

31a 1,3-dioxolane

65.2; 67.4

65.8; 67.2

67.0; 70.9

57.2; 57.3

centration is specified in mol-% base in relation to substrate 2. Ϫ

[c]

1

Quantitative conversion according to the H-NMR spectra after

24 h; enantiomeric excess determined by GC on a Restek Rt-β

DEX cst column.

31a 5 mL THF ϩ 5 mL furan 63.5; 67.3

[a]

For a further optimization of the enantioselective decarb-

oxylation reaction, the quantity and nature of the solvent

were changed (Table 6). When 2 was stirred with 31a in

5 mL instead of in 10 mL (standard) of THF, somewhat

lower optical inductions were obtained (entries 26, 43),

whereas the results with 20 mL of THF resembled those

obtained under standard conditions (entries 26, 44). The

addition of one drop of water to the standard 10 mL of

Apart from different solvents and solvent quantities, the cata-

lyses were carried out according to the standard procedure except

entry 51, where the temperature was raised during the reaction (see

text). Ϫ ^[b]Quantitative conversion according to the ¹H-NMR spec-

tra after the indicated reaction time except entry 48 (23% conver-

sion), entry 50 (no conversion), entry 51 (91% conversion) and

entry 56 (87 and 89% conversion); enantiomeric excess determined

by GC on a Restek Rt-β DEX cst column.

Not only the decarboxylation product 6, but also the sub-

THF containing 30a as a base decreased the enantiomeric strate 2 contains an asymmetric carbon atom. It seemed to

excess to 60% (entry 45). The use of argon or air instead of be interesting to find out if the decarboxylation of enanti-

nitrogen as the protective gas proved not to be relevant for omerically enriched 2 would affect the optical induction in

the enantioselectivity (entries 26, 46, 47). However, to en- the product 6. In earlier studies, the ammonium salt of (Ϫ)-

sure anhydrous conditions, the catalyses were carried out 2-cyanobutyric acid was decarboxylated thermally in vari-

under nitrogen. In diethyl ether as solvent, base 13 was only ous solvents.^[45]The configuration of the product and the

partially soluble and after 40 h an optical induction of enantiomeric excess was dependent on the solvent; this was

25.6% at 23% conversion was obtained (entry 48). Although explained with diastereomeric transition states formed by

complete conversion occurred within 20 h in the solvent asymmetric solvation or an intimate ion pair.^[45]Due to the

CH₃CN (clear solution), the enantiomeric excess was only sensitivity of the cyanopropionic acid 2 towards decarb-

15.2% ee (entry 49). Both 2 and 13 were readily soluble in oxylation, resolution of 2 was not attempted. However, it

CH₂Cl₂, but even after 40 h reaction time, no decarb- was possible to separate ester 5 into its enantiomers by

oxylation was observed (entry 50). Due to the low conver- HPLC. Fractions of 95% ee (ϩ)-5 (first fraction) and 91%

sion after 15 h in the reaction of 2 and 13 in dioxane, the ee (Ϫ)-5 (second fraction) were obtained.^[46]The absolute

temperature was raised to 25 °C. After 49 h, the enantiom- configurations are unknown. The enantiomerically enriched

eric excess of 55.9% at 91% conversion was 5% ee higher esters were hydrolyzed to the corresponding acids and the

than in THF (entries 7, 51). Two of the most successful raw materials (without recrystallization) were decarb-

bases, 30a and 31a, were tested in dioxane as well. After oxylated with base 31a under standard conditions. The

complete conversion, almost identical optical inductions of 67.2% ee (first fraction) and 64.3% ee (second fraction) of

around 66% ee were found. Compared to the results ob- (S)-6 were slightly lower than with the racemic substrate 2.

tained in THF, that stands for a higher enantiomeric excess However, after decarboxylation of the recrystallized acids

with 30a (entries 24, 52) and a somewhat lower optical in- 2, the enantioselectivities of 66.9% ee (first fraction) and

duction with 31a (entries 26, 53). In tetrahydropyran, the 69.9% ee (second fraction) did not differ from that of the

enantioselectivity of 31a was similar to (entry 54) and in catalyses carried out with racemic 2.

1,3-dioxolane (entry 55) it was lower than in THF (entry

A kinetic study was carried out to investigate whether or

26) or dioxane (entry 51). Because base 31a was insoluble not the enantioselectivity remains constant during decarb-

in furan, the decarboxylation was carried out in a 1:1 mix- oxylation (Figure 6). Aliquots from a twelvefold standard

ture of furan and THF; this gave a slight decrease in enanti- reaction with base 31a were analyzed after every hour. The

Eur. J. Org. Chem. 2000, 2119Ϫ2133

2125

H. Brunner, P. Schmidt

FULL PAPER

from Saccharomyces cerevisiae was undertaken. The cyano-

propionic acid 2 proved to be stable for two days in phos-

phate or citrate buffer (pH ϭ 6.0). The rate of the decarb-

oxylation of pyruvate decreased exponentially with increas-

ing concentration of 2, which can be defined as a classical

reversible inhibitor, because the inhibitory effect is not time-

dependent. A plot of pyruvate concentration vs. pyruvate

decarboxylation indicates a strong rate decrease with in-

creasing inhibitor concentration. Therefore, 2 acts as a non-

competitive inhibitor of pyruvate decarboxylase. Thus, py-

ruvate decarboxylase does not accept the cyanopropionic

acid 2 as a substrate for decarboxylation.

Figure 6. Kinetics of the decarboxylation of 2 with base 31a

enantioselectivity did not change with time, although the

optical induction after one hour seemed a little lower than

what it was later.

Conclusion

The plot conversion vs. time was linear for a reaction

time of 6 h; this indicates zero-order behavior of acid 2,

with a rate constant of 11.80 s^Ϫ1. Then, the rate decreased.

Conversion was complete after a reaction time of 12 h.

A new method for synthesizing naproxen derivatives by

enantioselective decarboxylation with catalytic amounts of

bases, with chiral bases giving optical induction, was estab-

lished. Thus, 2-cyano-2-(6-methoxynaphth-2-yl)propionic

acid (2) was decarboxylated with 10 mol-% of cinchona al-

kaloids as bases, of which quinidine (10) afforded the high-

est enantiomeric excess, of up to 34%. Amides of 9-amino-

9-deoxyepicinchonine (11) gave improved optical induc-

tions. The best enantioselectivity was obtained with 31a, the

2-ethoxybenzamide of 11, which gave up to 71.9% ee of (S)-

6. A decrease to 5 mol-% of 31a did not lower the enantio-

selectivity considerably, demonstrating the catalytic nature

of the reaction. A kinetic study proved that the enantio-

meric excess remained constant during the reaction period.

As the same enantioselectivity was obtained with enantio-

merically enriched 2 and with racemic 2, the enantioselectiv-

ity-determining step must be the protonation of the anion

formed in the decarboxylation. The decarboxylation of the

model compound 2-cyano-2-phenylpropionic acid (40) with

the 2-alkoxybenzamide derivatives of 11 gave 60% ee in the

product 41. Thus, the enantioselective decarboxylation re-

action of substituted 2-cyanopropionic acids is a simple and

straightforward reaction. Catalytic amounts of an optically

active base are sufficient for obtaining good enantioselectiv-

ities; in addition, the catalyst may be fully recycled by ex-

traction.

Enantioselective Decarboxylation of 40

The model compound of 2, 2-cyano-2-phenylpropionic

acid (40),^[38]was decarboxylated, giving 2-phenylpropio-

nitrile (41) (Scheme 7). The reaction was carried out with

148 mg of 40, according to the standard decarboxylation

procedure of 2.

Scheme 7. Decarboxylation of 40 leading to nitrile 41

Cinchonine (9) led to slightly lower optical inductions in

41 (entry 57; Table 7) than in the naproxen derivative 6

(entry 3; Table 1). Similarly, the 2-alkoxybenzamides 31a,

32a and 30b all gave around 60% ee of (S)-41 (entries

58Ϫ60).

Table 7. Enantiomeric excess of 41 obtained in the decarboxylation

of 40 with 9 and amides a of 11 and b of 12

ee [%]^[a]of 41

Config.

Experimental Section

Entry

Base

57

58

59

60

9

12.9; 13.0; 13.2

60.0; 60.2

(S)

General Remarks: NMR spectra: Bruker AC 250 and Bruker ARX

400 (internal TMS). Ϫ EI mass spectra: Finnigan MAT 311 A; CI

mass spectra: Finnigan MAT 95. Ϫ GC: HewlettϪPackard HP

5890 series II equipped with a column Rt-β DEX cst (30 m length,

0.32 mm inner diameter, from Restek); GC integration: Spectra

Physics SP 4270 integrator. Ϫ Infrared spectra: Beckman IR 4240

31a

32a

30b

59.5; 59.6

59.6; 61.1

[a]

1

Quantitative conversion according to the H-NMR spectra; en-

antiomeric excess determined by GC on a Restek Rt-β DEX cst

column.

and PerkinϪElmer Paragon 1000PC.

Ϫ Optical rotations:

PerkinϪElmer polarimeter 241 (1-dm cell). Ϫ Melting points:

Büchi SMP 20 (uncorrected values). Ϫ For numbering of the alkal-

oid derivatives see Figure 3.

Attempted Decarboxylation of 2 with Pyruvate

Decarboxylase

The carboxylic acid chlorides 14cϪ16c, 19cϪ21c, 25c, and

29cϪ31c were obtained by reflux of the corresponding acids e with

An approach to investigate the enantioselective decarb-

oxylation of 2 induced by pyruvate decarboxylase isolated distilled SOCl₂for 2 h, followed by distillation in vacuo. For 18c

2126 Eur. J. Org. Chem. 2000, 2119Ϫ2133

Asymmetric Catalysis, 131

FULL PAPER

and methyl 2-chlorocarbonylbenzoate, the crude acid chloride was

for another 4 h. The solvents were removed and the residue was

used after removal of SOCl₂. Compounds 7, 9, 14e, 16e, 17c, 20e, dissolved in CH₂Cl₂and 2  HCl (1:1, 500 mL). After the mixture

24c, 28c, 30e, 33d, NaN₃, monomethyl phthalate, PdCl₂, and diiso-

propyl azodicarboxylate were purchased from Merck; 8, 10, 29e,

and trimethylaluminum (c ഠ 2  in toluene or hexane) were ob-

tained from Fluka; 15e, 18e, 19e, 21e, 23d, 25e, 26c, 27d, 30d, and 3-

chloroperoxybenzoic acid were supplied by Aldrich and were used

without purification.

was vigorously shaken, the aqueous phase was separated and

washed with CH₂Cl₂(2 ϫ 100 mL). The water was removed under

reduced pressure and the hydrochloride was recrystallized from

methanol. The free base was obtained after the salt was dissolved

in water, which was neutralized with Na₂CO₃and extracted with

CH₂Cl₂. Evaporation of the dried (Na₂CO₃) organic solvent

yielded a yellow residue which was purified by distillation (240 °C,

0.01 Torr) to give a slightly yellow oil (11.5 g, 46%). Ϫ [α]²_D²ϭ 69

(c ϭ 2.51, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3370, 3290 cm^Ϫ1(NϪH). Ϫ

Compounds 4,^[33]5,^[38]11,^[41,42]22c,^[47,48]32d,^[49]34e,^[50,51]35d^[52]

and the ethyl ester of 40^[38]were prepared as described in the literat-

ure. Ester 34d was synthesized from the silver salt of acid 34e by

esterification with MeI. Diamine 39 was obtained from 1-[5-chloro-

3

¹H NMR (CDCl₃): δ ϭ 8.75 (d, J ϭ 4.5 Hz, 1 H, H2Ј), 8.03 (d,

³J ϭ 9.2 Hz, 1 H, H8Ј), 7.61 (br. s, 1 H, H5Ј), 7.53 (d, ³J ϭ 4.5 Hz,

1 H, H3Ј), 7.38 (dd, ³J ϭ 9.2 Hz, ⁴J ϭ 2.7 Hz, 1 H, H7Ј), 5.96Ϫ5.82

(m, ³J ϭ 17.1 Hz, ³J ϭ 10.6 Hz, ³J ϭ 6.5 Hz, 1 H, H10), 5.12Ϫ5.04

2-(methylamino)phenyl]-1,2,3,4-tetrahydroisoquinoline

tartrate,

purchased from Aldrich.^[15]All the standard-condition catalyses

were carried out with dried, distilled solvents under nitrogen.

3

(m, 2 H, H11a, H11b), 4.68 (d, J ϭ 9.9 Hz, 1 H, H9), 3.97 (s, 3

H, OCH₃), 3.10Ϫ2.90 (m, 5 H, H2, H6, H8), 2.33Ϫ2.22 (m, 1 H,

H3), 2.15 (s, 2 H, NH₂), 1.61Ϫ1.51 (m, 3 H, H4, H5), 1.19Ϫ1.10

(m, 1 H, H7a), 1.00Ϫ0.88 (m, 1 H, H7b). Ϫ ¹³C NMR (CDCl₃):

δ ϭ 157.6 (C6Ј), 147.8 (C2Ј), 147.5 (C4Ј), 144.7 (C10Ј), 140.8 (C10),

131.8 (C8Ј), 128.7 (C9Ј), 121.5 (C7Ј), 119.9 (C3Ј), 114.4 (C11),

101.6 (C5Ј), 62.4 (C8), 55.4 (OCH₃), 51.8 (C9), 49.5 (C2), 47.5 (C6),

39.4 (C3), 27.6 (C4), 26.7 (C5), 25.0 (C7). Ϫ MS (EI, 70 eV); m/z

(%): 323 [M]^ϩ(59). Ϫ C₂₀H₂₅N₃O (323.4): calcd. C 74.27, H 7.79,

N 12.99; found C 73.85, H 7.87, N 12.84.

2-Cyano-2-(6-methoxynaphth-2-yl)propionic Acid (2): Ethyl 2-cy-

ano-2-(6-methoxynaphth-2-yl)propionate^[33,38]

(5)

(5.00 g,

17.6 mmol) was suspended in

a solution of KOH (4.95 g,

88.2 mmol) in water (50 mL) and EtOH (12.5 mL). After the mix-

ture was stirred for 24 h, the alcohol was removed in vacuo at room

temp. Water was added to fully dissolve the potassium salt and the

solution was saturated with NaCl. The water phase was extracted

four times with ether (ether extracts discarded) and was then acidi-

fied with 2  H₂SO₄at 0 °C. The product was isolated by being

extracted with ether three times; the organic layer was decolorized

with charcoal and was dried with Na₂SO₄. After the solvent was

removed at room temp, the resulting solid was dissolved in ether.

Addition of hexane and cooling to Ϫ30 °C afforded 18 (4.05 g,

90%) as colorless crystals, m.p. 139Ϫ141 °C (dec., ϪCO₂). Ϫ IR

(KBr): ν˜ ϭ 2260 (CϵN), 1725 cm^Ϫ1(CϭO). Ϫ ¹H NMR (CDCl₃):

δ ϭ 7.97 (d, ⁴J ϭ 2.0 Hz, 1 H, H1), 7.78 (d, ³J ϭ 8.8 Hz, 1 H, H4),

General Procedure for the Preparation of the Amides ‘‘a’’ of 11 and

‘‘b’’ of 12

Variant A (Amides from Carboxylic Acid Chlorides and Amines):

The 9-amino-9-deoxyepicinchona alkaloid was dissolved in CH₂Cl₂

and 7 mL of abs. triethylamine. The carboxylic acid chloride in

4 mL of CH₂Cl₂was added dropwise at 0 °C. After the reaction

mixture was stirred for 10 h at room temperature, the organic phase

was diluted with CH₂Cl₂, washed three times with a half-concen-

trated Na₂CO₃solution, dried with Na₂CO₃and the solvent was re-

moved.

3

7.77 (d, ³J ϭ 9.0 Hz, 1 H, H8), 7.55 (dd, J ϭ 8.8 Hz, ⁴J ϭ 2.0 Hz,

3

4

1 H, H3), 7.20 (dd, J ϭ 9.0 Hz, J ϭ 2.4 Hz, 1 H, H7), 7.13 (d,

⁴J ϭ 2.4 Hz, 1 H, H5), 6.94 (br. s, 1 H, COOH), 3.93 (s, 3 H,

OCH₃), 2.06 (s, 3 H, CH₃). Ϫ MS (EI, 70 eV); m/z (%): 211

[M Ϫ CO₂]^ϩ(92). Ϫ C₁₅H₁₃NO₃(255.3): calcd. C 70.58, H 5.13,

N 5.49; found C 70.56, H 5.16, N 5.51.

In most cases, for purification, the hydrochloride was formed: The

base was stirred with a fivefold excess of HCl in ethanol for 10 h.

The solvent was removed and the hydrochloride was recrystallized.

The base was liberated when the salt was dissolved in water, an

excess of Na₂CO₃solution was added, and extraction with CH₂Cl₂

occurred. Chromatography on silica gel with MeOH as eluent was

carried out (column 40 ϫ 6 cm). For further details, see the indi-

vidual compounds (if filtration through Al₂O₃is described, a

Pasteur pipette filled with the adsorbent was used).

2-Cyano-2-phenylpropionic Acid (40): Ethyl 2-cyano-2-phenylpropio-

nate^[38](20.00 g, 98.4 mmol) was hydrolyzed in a solution of KOH

(16.5 g, 294 mmol) in water (200 mL) and EtOH (50 mL), accord-

ing to the method for the saponification of 5. The crude product

was purified by filtration through SiO₂with ether. Concentration

of the ether solution and addition of pentane gave the title com-

pound at Ϫ30 °C as colorless crystals (12.4 g, 72%), m.p. 97Ϫ100

°C (dec., CO₂). Ϫ IR (KBr): ν˜ ϭ 2240 (CϵN), 1710 cm^Ϫ1(CϭO).

Variant B (Amides from Carboxylic Acid Esters and Amines): The

9-amino-9-deoxyepicinchona alkaloid was dissolved in abs. toluene

under nitrogen. The stirred mixture was treated with a 1.2-fold

molar amount of a solution of AlMe₃in toluene or hexane and

stirring was continued for 15 min at room temp. (evolution of

CH₄). Then, a 1.1-fold molar amount (with respect to the alkaloid)

of carboxylic acid ester dissolved in toluene was added and the

mixture was heated at 80 °C for 10 h. Water (1 mL) was added to

the cold solution (gas evolution). Then the mixture was diluted

with toluene, filtered, washed with a diluted Na₂CO₃solution,

dried (Na₂CO₃), and the solvent was removed. For further purifica-

tion (chromatography) see Variant A.

1

Ϫ H NMR (CDCl₃): δ ϭ 7.60Ϫ7.52 (m, 2 H, Ar-H), 7.48Ϫ7.36

(m, 3 H, Ar-H), 7.17 (br. s, 1 H, COOH), 1.99 (s, 3 H, CH₃). Ϫ

MS (CI, NH₃); m/z (%): 193 [M ϩ NH₄]^ϩ(12). Ϫ C₁₀H₉NO₂

(175.2): calcd. C 68.56, H 5.18, N 8.00; found C 68.43, H 5.22,

N 7.96.

9-Amino-9-deoxyepiquinidine (12): A solution of hydrazoic acid^[53]

in benzene (96 mL, 93.1 mmol, 0.97 mol/l) was added at 10 °C un-

der nitrogen to a stirred mixture of quinidine (10) (25.0 g,

77.1 mmol) and triphenylphosphane (24.3 g, 92.6 mmol) in abs.

THF (400 mL). After 5 min, the reaction mixture was cooled to

Ϫ5 to Ϫ10 °C, and diisopropyl azodicarboxylate (DIAD; 16.5 mL,

17.1 g, 84.8 mmol) in abs. THF (80 mL) was added dropwise. The

mixture was stirred for 4 h at room temp. Then triphenylphosphane

N-(9-Deoxyepicinchonin-9-yl)cyclohexylcarboxamide (14a): Variant

A was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

(20.2 g, 77.1 mmol) in abs. THF (80 mL) was added in one portion. 3.41 mmol) in CH₂Cl₂(18 mL) and cyclohexanecarbonyl chloride

The mixture was heated at 45 °C until gas evolution ceased (ap-

(14c) (733 mg, 5.00 mmol). The hydrochloride was dissolved in hot

prox. 5 h). Water (8 mL) was added and the solution was stirred

MeOH (3 mL) and was treated with acetone (100 mL). Cooling to

Eur. J. Org. Chem. 2000, 2119Ϫ2133

2127

H. Brunner, P. Schmidt

FULL PAPER

Ϫ30 °C gave a solid which was recrystallized. The free base was

dissolved in ether and filtered through Al₂O₃. Colorless powder

(630 mg, 46%), m.p. 69Ϫ70 °C. Ϫ [α]²_D²ϭ 196 (c ϭ 0.89, CHCl₃).

(900 mg, 4.15 mmol). The base was dissolved in toluene and filtered

through Al₂O₃. Colorless solid (970 mg, 60%), m.p. 168Ϫ170 °C.

Ϫ [α]²_D²ϭ 151 (c ϭ 0.61, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3420, 3380

1

Ϫ IR (KBr): ν˜ ϭ 3255 (NϪH), 1535 cm^Ϫ1(amide). Ϫ H NMR

(NϪH), 1795 (CϭO, camphane), 1680, 1515 cm^Ϫ1(amide). Ϫ H

(CDCl₃): δ ϭ 8.85 (d, ³J ϭ 4.6 Hz, 1 H, H2Ј), 8.36 (dd, ³J ϭ 8.6 Hz,

NMR (CDCl₃): δ ϭ 8.88 (d, J ϭ 4.5 Hz, 1 H, H2Ј), 8.34 (d, J ϭ

3

4

3

4

⁴J ϭ 0.8 Hz, 1 H, H5Ј), 8.11 (dd, J ϭ 8.4 Hz, J ϭ 1.0 Hz, 1 H, 8.3 Hz, 1 H, H5Ј), 8.14 (dd, J ϭ 8.4 Hz, J ϭ 1.0 Hz, 1 H, H8Ј),

H8Ј), 7.73Ϫ7.66 (m, 1 H, H7Ј), 7.60Ϫ7.53 (m, 1 H, H6Ј), 7.38 (d,

7.80Ϫ7.66 (m, 2 H, H7Ј, CONH), 7.63Ϫ7.57 (m, 1 H, H6Ј), 7.40

3

³J ϭ 4.6 Hz, 1 H, H3Ј), 7.04 (br. s, 1 H, CONH), 5.91 (ddd, J ϭ (d, J ϭ 4.5 Hz 1 H, H3Ј), 5.93 (ddd, J ϭ 17.1 Hz, J ϭ 10.5 Hz,

17.1 Hz, ³J ϭ 10.5 Hz, ³J ϭ 6.6 Hz, 1 H, H10), 5.21 (br. s, 1 H, ³J ϭ 6.5 Hz, 1 H, H10), 5.40 (br. s, 1 H, H9), 5.15 (td, ³J ϭ 10.5 Hz,

H9), 5.16 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11a),

³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11a), 5.10 (td, ³J ϭ 17.1 Hz, ³J ϭ

5.12 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b), 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b), 3.11Ϫ2.68 (m, 5 H, H2, H6, H8),

3.00Ϫ2.90 (m, 4 H, quinuclidine-H), 2.82Ϫ2.73 (m, 1 H, quinuclid-

ine-H), 2.36Ϫ2.24 (m, 1 H, H3), 2.20Ϫ2.09 (m, 1 H, cyclohexyl-

H), 1.79Ϫ1.10 (m, 14 H, H4, H5, H7a, cyclohexyl-H), 0.98Ϫ0.87

2.38Ϫ2.21 (m, 2 H, H3, camphane-H), 1.11 (s, 3 H, camphane-

CH₃), 1.04 (s, 3 H, camphane-CH₃), 0.99 (s, 3 H, camphane-CH₃),

1.93Ϫ0.85 (m, 8 H, H4, H5, H7, 3 camphane-H). Ϫ MS (EI,

(m, 1 H, H7b). Ϫ MS (EI, 70 eV); m/z (%): 403 [M]^ϩ(47). Ϫ 70 eV); m/z (%): 473 [M]^ϩ(17). Ϫ C₂₉H₃₅N₃O₃(473.6): calcd. C

C₂₆H₃₃N₃O (403.6): calcd. C 77.38, H 8.24, N 10.41; found C 73.54, H 7.45, N 8.87; found C 73.33, H 7.51, N 8.75.

76.96, H 8.51, N 10.17.

N-(9-Deoxyepicinchonin-9-yl)coumarin-3-carboxamide (18a): Vari-

ant A was followed, with 9-amino-9-deoxyepicinchonine (11)

(1.00 g, 3.41 mmol) in CH₂Cl₂(20 mL) and coumarin-3-carbonyl

chloride (18c) (1.04 g, 5.00 mmol). The hydrochloride was dissolved

in MeOH and precipitated at Ϫ30 °C by addition of acetone. The

free base was dissolved in CH₂Cl₂and filtered through Al₂O₃.

Ether was added to the concentrated solution; after approx. 2

weeks at Ϫ30 °C, 18a was obtained as colorless crystals (110 mg,

7%), m.p. 182Ϫ184 °C. Ϫ [α]²_D²ϭ 266 (c ϭ 0.31, CHCl₃). Ϫ IR

(KBr): ν˜ ϭ 3320 (NϪH), 1720 (CϭO, coumarin), 1660, 1570, 1530

cm^Ϫ1(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ 9.75 (br. s, 1 H, CONH),

N-(9-Deoxyepicinchonin-9-yl)-4-phenylbutyramide (15a): Variant A

was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

3.41 mmol) in CH₂Cl₂(18 mL) and 4-phenylbutyric acid chloride

(15c) (913 mg, 5.00 mmol). The base was dissolved in ether and

filtered through Al₂O₃. Colorless powder (830 mg, 55%), m.p.

53Ϫ55 °C. Ϫ [α]²_D²ϭ 180 (c ϭ 0.51, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3380

1

(NϪH), 1655, 1515 cm^Ϫ1(amide). Ϫ H NMR (CDCl₃): δ ϭ 8.85

3

(d, J ϭ 4.5 Hz, 1 H, H2Ј), 8.36 (d, J ϭ 8.5 Hz, 1 H, H5Ј), 8.12

(dd, ³J ϭ 8.4 Hz, ⁴J ϭ 1.1 Hz, 1 H, H8Ј), 7.74Ϫ7.67 (m, 1 H, H7Ј),

7.62Ϫ7.55 (m, 1 H, H6Ј), 7.38 (d, ³J ϭ 4.5 Hz, 1 H, H3Ј),

7.29Ϫ7.11 (m, 5 H, phenyl-H), 6.89 (br. s, 1 H, CONH), 5.91 (ddd,

3

³J ϭ 17.1 Hz, J ϭ 10.5 Hz, ³J ϭ 6.5 Hz, 1 H, H10), 5.29 (br. d, 1

8.89 (d, J ϭ 4.6 Hz, 1 H, H2Ј), 8.72 (s, 1 H, H4ЈЈ), 8.44 (d, J ϭ

3

4

H, H9), 5.16 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H,

H11a), 5.11 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H,

H11b), 3.01Ϫ2.79 (m, 5 H, H2, H6, H8), 2.58 (t, 2 H, ³J ϭ 7.5 Hz,

PhCH₂CH₂CH₂CO), 2.34Ϫ2.14 (m, 3 H, H3, CH₂), 1.95Ϫ1.80 (m,

2 H, CH₂), 1.64Ϫ1.25 (m, 4 H, H4, H5, H7a), 0.98Ϫ0.87 (m, 1 H,

H7b). Ϫ MS (EI, 70 eV); m/z (%): 439 [M]^ϩ(93). Ϫ C₂₉H₃₃N₃O

(439.6): calcd. C 79.24, H 7.57, N 9.56; found C 78.84, H 7.77,

N 9.46.

8.4 Hz, 1 H, H5Ј), 8.14 (dd, J ϭ 8.3 Hz, J ϭ 1.2 Hz, 1 H, H8Ј),

3

7.76Ϫ7.55 (m, 4 H, H6Ј, H7Ј, coumarin-H), 7.49 (d, J ϭ 4.6 Hz,

1 H, H3Ј), 7.40Ϫ7.28 (m, 2 H, coumarin-H), 5.92 (ddd, ³J ϭ

17.0 Hz, ³J ϭ 10.7 Hz, ³J ϭ 6.4 Hz, 1 H, H10), 5.67 (br. s, 1 H,

H9), 5.14 (td, ³J ϭ 10.7 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11a),

5.12 (td, ³J ϭ 17.0 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b),

3.20Ϫ2.92 (m, 5 H, H2, H6, H8), 2.35Ϫ2.25 (m, 1 H, H3),

1.65Ϫ1.46 (m, 4 H, H4, H5, H7a), 1.04Ϫ0.89 (m, 1 H, H7b). Ϫ

MS (EI, 70 eV); m/z (%): 465 [M]^ϩ(46). Ϫ C₂₉H₂₇N₃O₃(465.6):

calcd. C 74.82, H 5.85, N 9.03; found C 74.62, H 5.84, N 8.74.

N-(9-Deoxyepicinchonin-9-yl)-2,2-diphenylacetamide (16a): Variant

A was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

3.41 mmol) in CH₂Cl₂(18 mL) and diphenylacetyl chloride (16c)

(1.15 g, 4.99 mmol). The hydrochloride was dissolved in hot MeOH

(4 mL) and was precipitated by the addition of ethyl acetate. After

being cooled at Ϫ30 °C, a solid was obtained, which was recrystal-

lized. The free base was dissolved in ether and filtered through

Al₂O₃. Concentration and addition of hexane at Ϫ30 °C gave col-

orless crystals (380 mg, 23%), m.p. 82Ϫ84 °C. Ϫ [α]²_D²ϭ 183 (c ϭ

1.04, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3300 (NϪH), 1645, 1520 cm^Ϫ1

(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ 8.82 (d, ³J ϭ 4.5 Hz, 1 H, H2Ј),

8.26 (br. d, ³J ϭ 8.4 Hz, 1 H, H5Ј), 8.12 (dd, ³J ϭ 8.5 Hz, ⁴J ϭ

0.9 Hz, 1 H, H8Ј), 7.73Ϫ7.66 (m, 1 H, H7Ј), 7.55Ϫ7.49 (m, 1 H,

H6Ј), 7.30Ϫ7.15 (m, 12 H, H3Ј, CONH, phenyl-H), 5.89 (ddd, ³J ϭ

17.1 Hz, ³J ϭ 10.5 Hz, ³J ϭ 6.5 Hz, 1 H, H10), 5.24 (br. s, 1 H,

H9), 5.15 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11a),

5.09 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b), 4.93

(s, 1 H, HCϪCO), 2.92Ϫ2.66 (m, 5 H, H2, H6, H8), 2.30Ϫ2.21

(m, 1 H, H3), 1.62Ϫ1.25 (m, 4 H, H4, H5, H7a), 0.98Ϫ0.79 (m, 1

H, H7b). Ϫ MS (EI, 70 eV); m/z (%): 487 [M]^ϩ(54). Ϫ C₃₃H₃₃N₃O

(487.6): calcd. C 81.28, H 6.82, N 8.62; found C 81.15, H 7.10,

N 8.61.

N-(9-Deoxyepicinchonin-9-yl)-α-methylcinnamamide (19a): Variant

A was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

3.41 mmol) in CH₂Cl₂(18 mL) and α-methylcinnamoyl chloride

(19c) (813 mg, 4.50 mmol). The hydrochloride was dissolved in hot

MeOH and precipitated at Ϫ30 °C by the addition of acetone. The

free base was dissolved in ether and was filtered through Al₂O₃.

Addition of hexane to the concentrated solution and storage at

Ϫ30 °C afforded a colorless solid (660 mg, 44%), m.p. 70Ϫ72 °C.

Ϫ [α]²_D²ϭ 301 (c ϭ 0.70, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3290 (NϪH),

1

3

1650, 1515 cm^Ϫ1(amide). Ϫ H NMR (CDCl₃): δ ϭ 8.88 (d, J ϭ

3

4.5 Hz, 1 H, H2Ј), 8.42 (d, J ϭ 8.5 Hz, 1 H, H5Ј), 8.14 (dd, J ϭ

8.3 Hz, ⁴J ϭ 1.1 Hz, 1 H, H8Ј), 7.75Ϫ7.69 (m, 1 H, H7Ј),

3

7.64Ϫ7.58 (m, 1 H, H6Ј), 7.53 (br. s, 1 H, CONH), 7.47 (d, J ϭ

4.5 Hz, 1 H, H3Ј), 7.37 (q, ⁴J ϭ 1.4 Hz, 1 H, HCϭCCH₃),

7.37Ϫ7.25 (m, 5 H, phenyl-H), 5.94 (ddd, ³J ϭ 17.1 Hz, ³J ϭ

3

10.5 Hz, J ϭ 6.5 Hz, 1 H, H10), 5.34 (br. d, 1 H, H9), 5.18 (td,

³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11a), 5.13 (td, ³J ϭ

17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b), 3.12Ϫ2.81 (m, 5

4

H, H2, H6, H8), 2.37Ϫ2.27 (m, 1 H, H3), 2.09 (d, J ϭ 1.4 Hz, 3

H, HCϭCCH₃), 1.67Ϫ1.33 (m, 4 H, H4, H5, H7a), 1.03Ϫ0.92 (m,

1 H, H7b). Ϫ MS (EI, 70 eV); m/z (%): 437 [M]^ϩ(42). Ϫ

C₂₉H₃₁N₃O (437.6): calcd. C 79.60, H 7.14, N 9.59; found C 79.43,

H 7.39, N 9.29.

(1S)-N-(9-Deoxyepicinchonin-9-yl)camphanamide (17a): Variant A

was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

3.41 mmol) in CH₂Cl₂(18 mL) and (1S)-camphanoyl chloride (17c)

2128

Eur. J. Org. Chem. 2000, 2119Ϫ2133

Asymmetric Catalysis, 131

FULL PAPER

N-(9-Deoxyepicinchonin-9-yl)naphthalene-1-carboxamide

(20a): 3.20Ϫ2.84 (m, 5 H, H2, H6, H8), 2.37Ϫ2.27 (m, 1 H, H3),

Variant A was followed, with 9-amino-9-deoxyepicinchonine (11)

(1.00 g, 3.41 mmol) in CH₂Cl₂(18 mL) and naphthalene-1-car-

bonyl chloride (20c) (953 mg, 5.00 mmol). The hydrochloride was

dissolved in hot MeOH (4 mL) and was precipitated at Ϫ30 °C by

the addition of acetone (100 mL). The free base was filtered

through Al₂O₃with ether, concentrated, and crystallized after addi-

tion of petroleum ether (40Ϫ60 °C) at Ϫ30 °C. Colorless solid

(540 mg, 35%), m.p. 105Ϫ107 °C. Ϫ [α]²_D²ϭ 145 (c ϭ 0.43, CHCl₃).

Ϫ IR (KBr): ν˜ ϭ 3280 (NϪH), 1650, 1515 cm^Ϫ1(amide). Ϫ ¹H

NMR (CDCl₃): δ ϭ 8.92 (d, J ϭ 4.5 Hz, 1 H, H2Ј), 8.51 (d, J ϭ

8.5 Hz, 1 H, H5Ј), 8.24 (br. s, 1 H, CONH), 8.17 (dd, ³J ϭ 8.4 Hz,

⁴J ϭ 1.2 Hz, 1 H, H8Ј), 7.91Ϫ7.81 (m, 2 H, naphthyl-H), 7.78Ϫ7.72

(m, 1 H, H7Ј), 7.67Ϫ7.61 (m, 2 H, H6Ј, naphthyl-H), 7.54 (d, ³J ϭ

4.5 Hz, 1 H, H3Ј), 7.56Ϫ7.42 (m, 4 H, naphthyl-H), 5.98 (ddd, ³J ϭ

17.1 Hz, ³J ϭ 10.5 Hz, ³J ϭ 6.6 Hz, 1 H, H10), 5.57 (br. s, 1 H,

H9), 5.20 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11a),

5.16 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b),

3.16Ϫ2.90 (m, 5 H, H2, H6, H8), 2.37Ϫ2.28 (m, 1 H, H3),

1.69Ϫ1.38 (m, 4 H, H4, H5, H7a), 1.09Ϫ0.98 (m, 1 H, H7b). Ϫ

MS (EI, 70 eV); m/z (%): 447 [M^ϩ] (23). Ϫ C₃₀H₂₉N₃O (447.6):

calcd. C 80.51, H 6.53, N 9.39; found C 80.23, H 6.65, N 9.26.

1.68Ϫ1.34 (m, 4 H, H4, H5, H7a), 1.05Ϫ0.94 (m, 1 H, H7b). Ϫ

MS (EI, 70 eV); m/z (%): 505 [M]^ϩ(31). Ϫ C₃₀H₃₁FeN₃O (505.4):

calcd. C 71.29, H 6.18, N 8.31; found C 71.19, H 6.39, N 8.28.

N-(9-Deoxyepicinchonin-9-yl)indole-2-carboxamide (23a): Variant B

was followed, with 9-amino-9-deoxyepicinchonine (11) (1.28 g,

4.36 mmol) in toluene (15 mL) and ethyl indole-2-carboxylate

(23d). The base was dissolved in CH₂Cl₂and filtered through

Al₂O₃. Recrystallization from ether afforded a colorless solid

(560 mg, 29%), m.p. 165Ϫ167 °C. Ϫ [α]²_D²ϭ 358 (c ϭ 0.34, CHCl₃).

Ϫ IR (KBr): ν˜ ϭ 3280 (NϪH), 1640, 1540, 1515 cm^Ϫ1(amide). Ϫ

¹H NMR (CDCl₃): δ ϭ 10.05 (br. s, 1 H, NH), 8.81 (d, ³J ϭ 4.5 Hz,

1 H, H2Ј), 8.45 (dd, ³J ϭ 8.7 Hz, ⁴J ϭ 0.8 Hz, 1 H, H5Ј), 8.17 (dd,

³J ϭ 8.4 Hz, ⁴J ϭ 1.1 Hz, 1 H, H8Ј), 8.04 (br. s, 1 H, NH),

7.76Ϫ7.69 (m, 1 H, H7Ј), 7.62Ϫ7.50 (m, 2 H, H6Ј, indole-H), 7.48

(d, ³J ϭ 4.5 Hz 1 H, H3Ј), 7.10Ϫ6.99 (m, 2 H, indole-H), 6.86 (br.

s, 1 H, indole-H), 6.67Ϫ6.62 (m, 1 H, indole-H), 5.95 (ddd, ³J ϭ

3

17.2 Hz, J ϭ 10.5 Hz, J ϭ 6.4 Hz, 1 H, H10), 5.49 (br. d, 1 H,

H9), 5.19 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ 1.4 Hz, 1 H, H11a),

5.13 (td, ³J ϭ 17.2 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ 1.4 Hz, 1 H, H11b),

3.18Ϫ2.85 (m, 5 H, H2, H6, H8), 2.38Ϫ2.28 (m, 1 H, H3),

1.70Ϫ1.38 (m, 4 H, H4, H5, H7a), 1.06Ϫ0.94 (m, 1 H, H7b). Ϫ

MS (EI, 70 eV); m/z (%): 436 [M]^ϩ(100). Ϫ C₂₈H₂₈N₄O (436.6):

calcd. C 77.04, H 6.46, N 12.83; found C 76.50, H 6.61, N 12.67.

N-(9-Deoxyepicinchonin-9-yl)naphthalene-2-carboxamide

(21a):

Variant A was followed, with 9-amino-9-deoxyepicinchonine (11)

(900 mg, 3.07 mmol) in CH₂Cl₂(20 mL) and naphthalene-2-car-

bonyl chloride (21c) (1.00 g, 5.25 mmol). The hydrochloride was

dissolved in MeOH/EtOH (1:10) and was precipitated at Ϫ30 °C

after the addition of acetone. The free base was dissolved in ether

and was crystallized after the addition of petroleum ether (40Ϫ60

°C) at Ϫ30 °C. Colorless solid (310 mg, 23%), m.p. 116Ϫ118 °C.

Ϫ [α]²_D²ϭ 316 (c ϭ 0.79, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3277 (NϪH),

1636, 1533, 1508 cm^Ϫ1(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ 8.89 (d,

N-(9-Deoxyepicinchonin-9-yl)furan-2-carboxamide (24a): Variant A

was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

3.41 mmol) in CH₂Cl₂(18 mL) and furan-2-carbonyl chloride (24c)

(653 mg, 5.00 mmol). The base was dissolved in CH₂Cl₂and was

filtered through Al₂O₃. Colorless solid (980 mg, 74%), m.p.

197Ϫ199 °C. Ϫ [α]²_D²ϭ 317 (c ϭ 0.38, CHCl₃). Ϫ IR (KBr): ν˜ ϭ

1

3260 (NϪH), 1640 cm^Ϫ1(amide). Ϫ H NMR (CDCl₃): δ ϭ 8.87

3

4

(d, J ϭ 4.6 Hz, 1 H, H2Ј), 8.41 (dd, J ϭ 8.4 Hz, J ϭ 0.9 Hz, 1

3

³J ϭ 4.5 Hz, 1 H, H2Ј), 8.49 (d, J ϭ 8.5 Hz, 1 H, H5Ј), 8.32 (br.

3

4

H, H5Ј), 8.13 (dd, J ϭ 8.4 Hz, J ϭ 1.0 Hz, 1 H, H8Ј), 7.75Ϫ7.69

s, 1 H, naphthyl-H), 8.15 (dd, ³J ϭ 8.3 Hz, ⁴J ϭ 1.3 Hz, 1 H, H8Ј),

8.01 (br. s, 1 H, CONH), 7.95Ϫ7.82 (m, 4 H, naphthyl-H),

(m, 2 H, H7Ј, CONH), 7.64Ϫ7.57 (m, 1 H, H6Ј), 7.47 (d, ³J ϭ

3

4

4.6 Hz, 1 H, H3Ј), 7.47 (dd, J ϭ 1.8 Hz, J ϭ 0.9 Hz, 1 H, furan-

H), 6.98 (dd, ³J ϭ 3.5 Hz, ⁴J ϭ 0.9 Hz, 1 H, furan-H), 6.45 (dd,

3

7.76Ϫ7.70 (m, 1 H, H7Ј), 7.66Ϫ7.59 (m, 1 H, H6Ј), 7.55 (d, J ϭ

4.5 Hz, 1 H, H3Ј), 7.56Ϫ7.50 (m, 2 H, naphthyl-H), 5.95 (ddd, ³J ϭ

³J ϭ 3.5 Hz, J ϭ 1.8 Hz, 1 H, furan-H), 5.92 (ddd, J ϭ 17.1 Hz,

4

3

17.1 Hz, J ϭ 10.5 Hz, J ϭ 6.5 Hz, 1 H, H10), 5.47 (br. d, ³J ϭ

³J ϭ 10.6 Hz, J ϭ 6.4 Hz, 1 H, H10), 5.45 (br. d, 1 H, H9), 5.17

3

10.3 Hz, 1 H, H9), 5.19 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ 1.4 Hz,

3

4

(td, J ϭ 10.6 Hz, J ϭ 1.5 Hz, J ϭ 1.5 Hz, 1 H, H11a), 5.12 (td,

³J ϭ 17.2 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b), 3.17Ϫ2.84

(m, 5 H, H2, H6, H8), 2.36Ϫ2.26 (m, 1 H, H3), 1.79Ϫ1.26 (m, 4

H, H4, H5, H7a), 1.04Ϫ0.93 (m, 1 H, H7b). Ϫ MS (EI, 70 eV); m/

z (%): 387 [M]^ϩ(31). Ϫ C₂₄H₂₅N₃O₂(387.5): calcd. C 74.39, H

6.50, N 10.84; found C 74.17, H 6.65, N 10.76.

1 H, H11a), 5.16 (td, J ϭ 17.1 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ 1.4 Hz, 1 H,

3

H11b), 3.20Ϫ2.83 (m, 5 H, H2, H6, H8), 2.38Ϫ2.28 (m, 1 H, H3),

1.69Ϫ1.39 (m, 4 H, H4, H5, H7a), 1.09Ϫ0.97 (m, 1 H, H7b). Ϫ

MS (EI, 70 eV); m/z (%): 447 [M]^ϩ(22). Ϫ C₃₀H₂₉N₃O (447.6):

calcd. C 80.51, H 6.53, N 9.39; found C 80.16, H 6.38, N 9.21.

N-(9-Deoxyepicinchonin-9-yl)ferrocenecarboxamide (22a): Variant

A was followed, with 9-amino-9-deoxyepicinchonine (11) (1.25 g,

3,5-Di-tert-butyl-N-(9-deoxyepicinchonin-9-yl)benzamide

Variant A was followed, with 9-amino-9-deoxyepicinchonine (11)

(25a):

4.26 mmol) in CH₂Cl₂(20 mL) and ferrocenecarbonyl chloride (1.00 g, 3.41 mmol) in CH₂Cl₂(18 mL) and 3,5-di-tert-butylbenzoyl

(22c) (1.06 g, 4.27 mmol). A small amount of charcoal was added

to a solution of the base in CH₂Cl₂; this was followed by filtration

and removal of the solvent. Orange crystals were obtained at Ϫ30

°C when a solution of the product in ether/CH₂Cl₂(1:1) was co-

chloride (25c) (1.07 g, 4.23 mmol). The hydrochloride was dissolved

in MeOH and was precipitated at Ϫ30 °C by the addition of ether.

Recrystallization of the free base from ether afforded a colorless

solid (780 mg, 45%), m.p. 209Ϫ210 °C. Ϫ [α]²_D²ϭ 242 (c ϭ 0.30,

vered with a layer of pentane (1.58 g, 73%), m.p. 193Ϫ194 °C. Ϫ CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3320 (NϪH), 1630, 1535, 1520 cm^Ϫ1

[α]²_D²ϭ 110 (c ϭ 0.42, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3240 (NϪH),

1630, 1540, 1520 cm^Ϫ1(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ 8.87 (d,

(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ 8.87 (d, ³J ϭ 4.5 Hz, 1 H, H2Ј),

8.42 (dd, ³J ϭ 8.5 Hz, ⁴J ϭ 1.0 Hz, 1 H, H5Ј), 8.13 (dd, ³J ϭ

8.3 Hz, ⁴J ϭ 1.2 Hz, 1 H, H8Ј), 7.88 (br. s, 1 H, CONH), 7.75Ϫ7.68

3

³J ϭ 4.5 Hz, 1 H, H2Ј), 8.45 (d, J ϭ 8.5 Hz, 1 H, H5Ј), 8.13 (dd,

³J ϭ 8.3 Hz, ⁴J ϭ 1.2 Hz, 1 H, H8Ј), 7.75Ϫ7.68 (m, 1 H, H7Ј), (m, 1 H, H7Ј), 7.63 (d, ⁴J ϭ 1.8 Hz, 2 H, phenyl-H), 7.64Ϫ7.60 (m,

7.65Ϫ7.58 (m, 1 H, H6Ј), 7.49 (d, ³J ϭ 4.5 Hz, 1 H, H3Ј), 7.33 (br. 1 H, H6Ј), 7.56 (t, ⁴J ϭ 1.8 Hz, 1 H, phenyl-H), 7.52 (d, ³J ϭ

s, 1 H, CONH), 5.94 (ddd, ³J ϭ 17.1 Hz, ³J ϭ 10.5 Hz, ³J ϭ 4.5 Hz 1 H, H3Ј), 5.94 (ddd, ³J ϭ 17.1 Hz, ³J ϭ 10.6 Hz, ³J ϭ

6.5 Hz, 1 H, H10), 5.34 (br. s, 1 H, H9), 5.17 (td, ³J ϭ 10.5 Hz, 6.5 Hz, 1 H, H10), 5.41 (br. d, 1 H, H9), 5.17 (td, J ϭ 10.6 Hz,

3

³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11a), 5.12 (td, ³J ϭ 17.1 Hz, ³J ϭ

1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b), 4.71Ϫ4.66 (m, 2 H, ferrocene-H), 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b), 3.16Ϫ2.82 (m, 5 H, H2, H6, H8),

3

4.32 (t, J ϭ 1.9 Hz, 2 H, ferrocene-H), 4.14 (s, 5 H, ferrocene-H),

2.37Ϫ2.27 (m, 1 H, H3), 1.68Ϫ1.25 (m, 4 H, H4, H5, H7a), 1.33

Eur. J. Org. Chem. 2000, 2119Ϫ2133

2129

H. Brunner, P. Schmidt

FULL PAPER

(s, 18 H, tert-butyl-H), 1.07Ϫ0.94 (m, 1 H, H7b). Ϫ MS (EI, 70 eV);

[M]^ϩ(23). Ϫ C₂₇H₂₉N₃O₂(427.6): calcd. C 75.85, H 6.84, N 9.83;

m/z (%): 509 [M]^ϩ(37). Ϫ C₃₄H₄₃N₃O (509.7): calcd. C 80.12, H found C 75.60, H 7.04, N 9.72.

8.50, N 8.24; found C 79.90, H 8.47, N 8.19.

N-(9-Deoxyepicinchonin-9-yl)-3-methoxybenzamide (29a): Variant

A was followed, with 9-amino-9-deoxyepicinchonine (11) (1.50 g,

was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g, 5.11 mmol), in CH₂Cl₂(25 mL) and 3-methoxybenzoyl chloride

N-(9-Deoxyepicinchonin-9-yl)-2-fluorobenzamide (26a): Variant A

3.41 mmol) in CH₂Cl₂(18 mL) and 2-fluorobenzoyl chloride (26c)

(793 mg, 5.00 mmol). The hydrochloride was dissolved in CH₂Cl₂

and was precipitated by the addition of acetone. The free base was

filtered through Al₂O₃with ether. Recrystallization from ether gave

colorless crystals (590 mg, 42%), m.p. 163Ϫ164 °C. Ϫ [α]²_D²ϭ 294

(29c) (1.50 g, 8.79 mmol). The hydrochloride was dissolved in hot

methanol and precipitated at Ϫ30 °C by the addition of acetone

(100 mL). Filtration of the free base through Al₂O₃with ether gave

a colorless solid (1.09 g, 50%), m.p. 81Ϫ83 °C. Ϫ [α]²_D²ϭ 281 (c ϭ

0.52, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3300 (NϪH), 1650, 1520 cm^Ϫ1

(c ϭ 0.48, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3420 (NϪH), 1660, 1510 cm^Ϫ1(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ 8.86 (d, ³J ϭ 4.5 Hz, 1 H, H2Ј),

(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ 8.88 (d, ³J ϭ 4.5 Hz, 1 H, H2Ј), 8.44 (d, ³J ϭ 8.2 Hz, 1 H, H5Ј), 8.13 (dd, ³J ϭ 8.5 Hz, ⁴J ϭ 1.0 Hz,

8.43 (dd, ³J ϭ 8.4 Hz, ⁴J ϭ 0.8 Hz, 1 H, H5Ј), 8.29 (br. d, 1 H, 1 H, H8Ј), 7.91 (br. s, 1 H, CONH), 7.73Ϫ7.69 (m, 1 H, H7Ј),

3

4

CONH), 8.14 (dd, J ϭ 8.5 Hz, J ϭ 1.0 Hz, 1 H, H8Ј), 7.92 (dd,

7.63Ϫ7.59 (m, 1 H, H6Ј), 7.48 (d, ³J ϭ 4.5 Hz 1 H, H3Ј), 7.38Ϫ7.30

(m, 3 H, phenyl-H), 7.03Ϫ7.00 (m, 1 H, phenyl-H), 5.93 (ddd, ³J ϭ

³J ϭ 7.9 Hz, ⁴J ϭ 1.9 Hz, 1 H, phenyl-H), 7.75Ϫ7.69 (m, 1 H,

H7Ј), 7.64Ϫ7.58 (m, 1 H, H6Ј), 7.50 (d, ³J ϭ 4.5 Hz 1 H, H3Ј), 17.1 Hz, ³J ϭ 10.6 Hz, ³J ϭ 6.5 Hz, 1 H, H10), 5.40 (br. s, 1 H,

7.49Ϫ7.40 (m, 1 H, phenyl-H), 7.21Ϫ7.08 (m, 2 H, phenyl-H), 5.94 H9), 5.16 (td, ³J ϭ 10.6 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ 1.4 Hz, 1 H, H11a),

(ddd, ³J ϭ 17.1 Hz, ³J ϭ 10.6 Hz, ³J ϭ 6.5 Hz, 1 H, H10), 5.46 5.13 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ 1.4 Hz, 1 H, H11b), 3.78

3

4

(br. s, 1 H, H9), 5.17 (td, J ϭ 10.6 Hz, J ϭ 1.5 Hz, J ϭ 1.5 Hz, (s, 3 H, OCH₃), 3.10Ϫ2.82 (m, 5 H, H2, H6, H8), 2.34Ϫ2.28 (m,

1 H, H11a), 5.12 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H,

H11b), 3.15Ϫ2.83 (m, 5 H, H2, H6, H8), 2.36Ϫ2.26 (m, 1 H, H3),

1 H, H3), 1.67Ϫ1.36 (m, 4 H, H4, H5, H7a), 1.02Ϫ0.95 (m, 1 H,

H7b). Ϫ MS (EI, 70 eV); m/z (%): 427 [M]^ϩ(27). Ϫ C₂₇H₂₉N₃O₂

1.67Ϫ1.34 (m, 4 H, H4, H5, H7a), 1.03Ϫ0.87 (m, 1 H, H7b). Ϫ (427.6): calcd. C 75.85, H 6.84, N 9.83; found C 75.82, H 6.92,

MS (EI, 70 eV); m/z (%): 415 [M]^ϩ(55). Ϫ C₂₆H₂₆FN₃O (415.5): N 9.57.

calcd. C 75.16, H 6.31, N 10.11; found C 74.88, H 6.49, N 10.03.

N-(9-Deoxyepicinchonin-9-yl)-2-methoxybenzamide (30a): Variant

N-(9-Deoxyepicinchonin-9-yl)-3-nitrobenzamide (27a): Variant

B

A was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

3.41 mmol), in CH₂Cl₂(18 mL) and 2-methoxybenzoyl chloride

(30c) (853 mg, 5.00 mmol). The hydrochloride was dissolved in a

hot mixture of methanol (0.5 mL) and ethanol (4 mL) and was pre-

cipitated at Ϫ30 °C by the addition of acetone (100 mL). Filtration

of the free base through Al₂O₃(ether), concentration and addition

was followed, with 9-amino-9-deoxyepicinchonine (11) (1.55 g,

5.28 mmol) in toluene (13 mL) and ethyl 3-nitrobenzoate (27d). The

base was dissolved in CH₂Cl₂and filtered through Al₂O₃. Concen-

tration, and addition of aqueous ether gave slightly yellow crystals

at Ϫ30 °C (1.04 g, 44%), m.p. 130Ϫ132 °C. Ϫ [α]²_D²ϭ 267 (c ϭ

0.61, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3290 (NϪH), 1650, 1535 cm^Ϫ1of hexane afforded a colorless solid at Ϫ30 °C (700 mg, 48%), m.p.

(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ 8.88 (d, ³J ϭ 4.5 Hz, 1 H, H2Ј),

83Ϫ84 °C. Ϫ [α]²_D²ϭ 318 (c ϭ 0.45, CHCl₃). Ϫ IR (KBr): ν˜ ϭ

8.64Ϫ8.62 (m, 1 H, phenyl-H), 8.42 (d, ³J ϭ 8.5 Hz, 1 H, H5Ј), 3370, 3300 (NϪH), 1655, 1510 cm^Ϫ1(amide). Ϫ ¹H NMR

3

8.37Ϫ8.32 (m, 1 H, phenyl-H), 8.17Ϫ8.12 (m, 2 H, H8Ј, phenyl-

(CDCl₃): δ ϭ 9.31 (br. s, 1 H, CONH), 8.86 (d, J ϭ 4.5 Hz, 1 H,

H), 8.01 (br. s, 1 H, CONH), 7.78Ϫ7.71 (m, 1 H, H7Ј), 7.67Ϫ7.58 H2Ј), 8.45 (dd, ³J ϭ 8.5 Hz, ⁴J ϭ 0.9 Hz, 1 H, H5Ј), 8.13 (dd, ³J ϭ

(m, 2 H, H6Ј, phenyl-H), 7.49 (d, ³J ϭ 4.5 Hz 1 H, H3Ј), 5.94 (ddd, 8.4 Hz, ⁴J ϭ 1.0 Hz, 1 H, H8Ј), 7.99 (dd, ³J ϭ 8.2 Hz, ⁴J ϭ 1.8 Hz,

3

³J ϭ 17.1 Hz, J ϭ 10.5 Hz, ³J ϭ 6.5 Hz, 1 H, H10), 5.44 (br. d, 1

1 H, phenyl-H), 7.74Ϫ7.67 (m, 1 H, H7Ј), 7.62Ϫ7.55 (m, 1 H, H6Ј),

H, H9), 5.20 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, 7.48 (d, ³J ϭ 4.5 Hz 1 H, H3Ј), 7.45Ϫ7.38 (m, 1 H, phenyl-H),

H11a), 5.13 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H,

7.02Ϫ6.96 (m, 2 H, phenyl-H), 5.94 (ddd, ³J ϭ 17.1 Hz, ³J ϭ

3

H11b), 3.20Ϫ2.80 (m, 5 H, H2, H6, H8), 2.39Ϫ2.29 (m, 1 H, H3), 10.5 Hz, J ϭ 6.6 Hz, 1 H, H10), 5.49 (br. d, 1 H, H9), 5.16 (td,

1.71Ϫ1.36 (m, 4 H, H4, H5, H7a), 1.10Ϫ0.98 (m, 1 H, H7b). Ϫ ³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11a), 5.11 (td, ³J ϭ

MS (EI, 70 eV); m/z (%): 442 [M Ϫ H₂O]^ϩ(30). Ϫ C₂₆H₂₆N₄O₃17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 1.5 Hz, 1 H, H11b), 4.00 (s, 3 H, OCH₃),

H₂O (460.5): calcd. C 67.81, H 6.13, N 12.17; found C 67.46, H 3.15Ϫ2.91 (m, 5 H, H2, H6, H8), 2.36Ϫ2.25 (m, 1 H, H3),

6.28, N 12.05.

1.67Ϫ1.25 (m, 4 H, H4, H5, H7a), 1.01Ϫ0.90 (m, 1 H, H7b). Ϫ

MS (EI, 70 eV); m/z (%): 427 [M]^ϩ(24). Ϫ C₂₇H₂₉N₃O₂(427.6):

calcd. C 75.85, H 6.84, N 9.83; found C 75.84, H 6.98, N 9.81.

N-(9-Deoxyepicinchonin-9-yl)-4-methoxybenzamide (28a): Variant

A was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

3.41 mmol) in CH₂Cl₂(18 mL) and 4-methoxybenzoyl chloride N-(9-Deoxyepiquinidin-9-yl)-2-methoxybenzamide (30b): Variant B

(28c) (853 mg, 5.00 mmol). The hydrochloride was recrystallized

from methanol. Filtration of the free base through Al₂O₃with

was followed, with 9-amino-9-deoxyepiquinidine (12) (1.00 g,

3.09 mmol) in toluene (10 mL) and ethyl 2-methoxybenzoate (30d).

CH₂Cl₂gave a colorless solid (780 mg, 54%), m.p. 135Ϫ137 °C. Ϫ The base was dissolved in ether/CH₂Cl₂(2:1) and was filtered twice

[α]²_D²ϭ 297 (c ϭ 0.64, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3300 (NϪH),

through Al₂O₃. Colorless solid (560 mg, 40%), m.p. 94Ϫ96 °C. Ϫ

1

3

1640, 1510 cm^Ϫ1(amide). Ϫ H NMR (CDCl₃): δ ϭ 8.86 (d, J ϭ [α]²_D²ϭ 335 (c ϭ 0.37, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3380, 3310 (NϪH),

3

1

4.6 Hz, 1 H, H2Ј), 8.45 (d, J ϭ 8.3 Hz, 1 H, H5Ј), 8.13 (dd, J ϭ

1660, 1515 cm^Ϫ1(amide). Ϫ H NMR (CDCl₃): δ ϭ 9.28 (br. s, 1

4

3

8.4 Hz, J ϭ 1.1 Hz, 1 H, H8Ј), 7.77 (d, J ϭ 8.9 Hz, 2 H, phenyl-

H, CONH), 8.71 (d, ³J ϭ 4.7 Hz, 1 H, H2Ј), 8.03 (dd, ³J ϭ 7.8 Hz,

H), 7.80Ϫ7.66 (m, 2 H, H7Ј, CONH), 7.63Ϫ7.57 (m, 1 H, H6Ј), ⁴J ϭ 1.9 Hz, 1 H, phenyl-H), 8.01 (d, J ϭ 9.2 Hz, 1 H, H8Ј), 7.69

3

7.49 (d, J ϭ 4.6 Hz 1 H, H3Ј), 6.91 (d, J ϭ 8.9 Hz, 2 H, phenyl-

H), 5.93 (ddd, ³J ϭ 17.2 Hz, ³J ϭ 10.5 Hz, ³J ϭ 6.5 Hz, 1 H, H10), 7.45Ϫ7.33 (m, 2 H, H7Ј, phenyl-H), 7.03Ϫ6.95 (m, 2 H, phenyl-

5.40 (br. d, 1 H, H9), 5.17 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ H), 5.95 (ddd, ³J ϭ 17.7 Hz, ³J ϭ 10.1 Hz, ³J ϭ 6.2 Hz, 1 H, H10),

1.5 Hz, 1 H, H11a), 5.12 (td, ³J ϭ 17.2 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ 5.47 (br. d, 1 H, H9), 5.17Ϫ5.09 (m, 2 H, H11a, H11b), 3.98 (s, 3

1.5 Hz, 1 H, H11b), 3.83 (s, 3 H, OCH₃), 3.13Ϫ2.80 (m, 5 H, H2, H, OCH₃), 3.96 (s, 3 H, OCH₃), 3.16Ϫ2.98 (m, 5 H, H2, H6, H8),

(d, ³J ϭ 2.7 Hz, 1 H, H5Ј), 7.43 (d, ³J ϭ 4.7 Hz, 1 H, H3Ј),

H6, H8), 2.36Ϫ2.26 (m, 1 H, H3), 1.77Ϫ1.36 (m, 4 H, H4, H5, 2.37Ϫ2.27 (m, 1 H, H3), 1.70Ϫ1.69 (m, 1 H, H4), 1.59Ϫ1.18 (m,

H7a), 1.04Ϫ0.93 (m, 1 H, H7b). Ϫ MS (EI, 70 eV); m/z (%): 427 3 H, H5, H7a), 1.09Ϫ0.97 (m, 1 H, H7b). Ϫ MS (EI, 70 eV); m/z

2130

Eur. J. Org. Chem. 2000, 2119Ϫ2133

Asymmetric Catalysis, 131

FULL PAPER

(%): 457 [M]^ϩ(16). Ϫ C₂₈H₃₁N₃O₃(457.6): calcd. C 73.50, H 6.83, ³J ϭ 7.3 Hz, 3 H, OCH₂CH₂CH₂CH₃), 0.98Ϫ0.86 (m, 1 H, H7b).

N 9.18; found C 73.21, H 7.11, N 8.98.

Ϫ MS (EI, 70 eV); m/z (%): 469 [M]^ϩ(39). Ϫ C₃₀H₃₅N₃O₂(469.6):

calcd. C 76.73, H 7.51, N 8.95; found C 76.61, H 7.42, N 8.94.

N-(9-Deoxyepicinchonin-9-yl)-2-ethoxybenzamide (31a): Variant A

was followed, with 9-amino-9-deoxyepicinchonine (11) (1.00 g,

3.41 mmol) in CH₂Cl₂(18 mL) and 2-ethoxybenzoyl chloride (31c)

(830 mg, 4.51 mmol). The base was filtered through Al₂O₃

(CH₂Cl₂). Two recrystallizations from ether gave colorless crystals

(830 mg, 55%), m.p. 137Ϫ138 °C. Ϫ [α]²_D²ϭ 343 (c ϭ 1.13, CHCl₃).

Ϫ IR (KBr): ν˜ ϭ 3350 (NϪH), 1705, 1580 cm^Ϫ1(amide). Ϫ ¹H

N-(9-Deoxyepicinchonin-9-yl)-2-hydroxybenzamide (33a): Variant B

was followed, with 9-amino-9-deoxyepicinchonine (11) (1.03 g,

3.51 mmol), in toluene (13 mL) and methyl 2-hydroxybenzoate

(33d). Filtration of the base through Al₂O₃with CH₂Cl₂and two

recrystallizations from ether afforded a colorless solid (450 mg,

31%), m.p. 199Ϫ201 °C (dec.). Ϫ [α]²_D²ϭ 302 (c ϭ 0.79, CHCl₃).

NMR (CDCl₃): δ ϭ 9.26 (br. s, 1 H, CONH), 8.86 (d, ³J ϭ 4.6 Hz, Ϫ IR (KBr): ν˜ ϭ 3400Ϫ2600 (OϪH), 3280 (NϪH), 1655, 1515

1

3

1 H, H2Ј), 8.48 (dd, ³J ϭ 8.5 Hz, ⁴J ϭ 1.0 Hz, 1 H, H5Ј), 8.12 (dd,

cm^Ϫ1(amide). Ϫ H NMR (CDCl₃): δ ϭ 8.88 (d, J ϭ 4.6 Hz, 1

4

3

4

3

4

³J ϭ 8.4 Hz, J ϭ 1.1 Hz, 1 H, H8Ј), 8.03 (dd, J ϭ 8.0 Hz, J ϭ

H, H2Ј), 8.38 (dd, J ϭ 8.7 Hz, J ϭ 1.0 Hz, 1 H, H5Ј), 8.16 (dd,

1.9 Hz, 1 H, phenyl-H), 7.74Ϫ7.68 (m, 1 H, H7Ј), 7.67Ϫ7.56 (m, 1 ³J ϭ 8.4 Hz, ⁴J ϭ 1.1 Hz, 1 H, H8Ј), 8.19Ϫ8.00 (br. s, 1 H, CONH),

3

H, H6Ј), 7.47 (d, ³J ϭ 4.6 Hz, 1 H, H3Ј), 7.42Ϫ7.35 (m, 1 H,

7.78Ϫ7.71 (m, 1 H, H7Ј), 7.66Ϫ7.60 (m, 1 H, H6Ј), 7.55 (dd, J ϭ

phenyl-H), 6.99Ϫ6.93 (m, 2 H, phenyl-H), 5.94 (ddd, ³J ϭ 17.1 Hz, 7.9 Hz, ⁴J ϭ 1.4 Hz, 1 H, phenyl-H), 7.47 (d, ³J ϭ 4.6 Hz, 1 H,

3

³J ϭ 10.5 Hz, J ϭ 6.5 Hz, 1 H, H10), 5.53 (br. d, 1 H, H9), 5.16

H3Ј), 7.41Ϫ7.34 (m, 1 H, phenyl-H), 6.93Ϫ6.85 (m, 2 H, phenyl-

(td, J ϭ 10.5 Hz, J ϭ 1.5 Hz, J ϭ 1.5 Hz, 1 H, H11a), 5.11 (td, H), 5.94 (ddd, ³J ϭ 17.1 Hz, ³J ϭ 10.5 Hz, ³J ϭ 6.5 Hz, 1 H, H10),

3

4

³J ϭ 17.1 Hz, ³J ϭ 1.5 Hz, J ϭ 1.5 Hz, 1 H, H11b), 4.23 (q, J ϭ

5.35 (br. d, 1 H, H9), 5.20 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ

4

3

7.0 Hz, 2 H, OCH₂CH₃), 3.16Ϫ3.04 (m, 1 H, H8), 3.01Ϫ2.94 (m, 1.4 Hz, 1 H, H11a), 5.13 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ

3

4 H, H2, H6), 2.31Ϫ2.27 (m, 1 H, H3), 1.61 (t, J ϭ 7.0 Hz, 3 H, 1.4 Hz, 1 H, H11b), 3.07Ϫ2.78 (m, 5 H, H2, H6, H8), 2.39Ϫ2.29

OCH₂CH₃), 1.66Ϫ1.45 (m, 3 H, H4, H5), 1.39Ϫ1.33 (m, 1 H, (m, 1 H, H3), 1.70Ϫ1.39 (m, 4 H, H4, H5, H7a), 1.07Ϫ0.97 (m, 1

H7a), 0.97Ϫ0.86 (m, 1 H, H7b). Ϫ MS (EI, 70 eV); m/z (%): 441 H, H7b). Ϫ MS (EI, 70 eV); m/z (%): 413 [M]^ϩ(100). Ϫ

[M]^ϩ(39). Ϫ C₂₈H₃₁N₃O₂(441.6): calcd. C 76.16, H 7.08, N 9.52; C₂₆H₂₇N₃O₂(413.5): calcd. C 75.52, H 6.58, N 10.16; found C

found C 76.05, H 7.27, N 9.54.

75.15, H 6.72, N 10.11.

N-(9-Deoxyepiquinidin-9-yl)-2-ethoxybenzamide (31b): Variant A

was followed, with 9-amino-9-deoxyepiquinidine (12) (1.00 g,

N-(9-Deoxyepicinchonin-9-yl)-2-(methoxymethyl)benzamide (34a):

Variant B was followed, with 9-amino-9-deoxyepicinchonine (11)

3.09 mmol) in CH₂Cl₂(18 mL) and 2-ethoxybenzoyl chloride (31c) (1.80 g, 6.13 mmol), in toluene (8 mL) and methyl 2-(methoxyme-

(738 mg, 4.00 mmol). The base was dissolved in ether and filtered

through Al₂O₃. Concentration and cooling to Ϫ30 °C gave a color-

less solid (690 mg, 47%), m.p. 127Ϫ128 °C. Ϫ [α]²_D²ϭ 357 (c ϭ

thyl)benzoate^[50,51](35d). The base was dissolved in ether and fil-

tered through Al₂O₃. Concentration, addition of pentane and cool-

ing to Ϫ30 °C gave a colorless powder (810 mg, 30%), m.p. 90Ϫ92

0.82, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3320 (NϪH), 1650, 1510 cm^Ϫ1°C. Ϫ [α]²_D²ϭ 177 (c ϭ 0.37, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3250

1

(amide). Ϫ H NMR (CDCl₃): δ ϭ 9.26 (br. s, 1 H, CONH), 8.71

(NϪH), 1630, 1540, 1510 cm^Ϫ1(amide). Ϫ ¹H NMR (CDCl₃): δ ϭ

3

4

(d, J ϭ 4.6 Hz, 1 H, H2Ј), 8.06 (dd, J ϭ 7.8 Hz, J ϭ 1.8 Hz, 1 8.90 (d, ³J ϭ 4.5 Hz, 1 H, H2Ј), 8.49 (dd, ³J ϭ 8.4 Hz, ⁴J ϭ 0.9 Hz,

H, phenyl-H), 8.01 (d, ³J ϭ 9.2 Hz, 1 H, H8Ј), 7.71 (d, ³J ϭ 2.7 Hz, 1 H, H5Ј), 8.14 (dd, ³J ϭ 8.3 Hz, ⁴J ϭ 1.2 Hz, 1 H, H8Ј), 8.14 (br.

1 H, H5Ј), 7.42 (d, ³J ϭ 4.6 Hz, 1 H, H3Ј), 7.40Ϫ7.34 (m, 2 H,

s, 1 H, CONH), 7.77Ϫ7.70 (m, 1 H, H7Ј), 7.68Ϫ7.60 (m, 2 H, H6Ј,

H7Ј, phenyl-H), 6.99Ϫ6.93 (m, 2 H, phenyl-H), 5.95 (ddd, ³J ϭ phenyl-H), 7.49 (d, ³J ϭ 4.5 Hz, 1 H, H3Ј), 7.44Ϫ7.31 (m, 3 H,

17.0 Hz, ³J ϭ 10.8 Hz, ³J ϭ 6.2 Hz, 1 H, H10), 5.53 (br. s, 1 H,

phenyl-H), 5.93 (ddd, J ϭ 17.1 Hz, J ϭ 10.5 Hz, J ϭ 6.5 Hz, 1

3

H9), 5.15Ϫ5.10 (m, 2 H, H11a, H11b), 4.21 (q, J ϭ 7.0 Hz, 2 H, H, H10), 5.65 (br. s, 1 H, H9), 5.16 (td, ³J ϭ 10.5 Hz, ³J ϭ 1.5 Hz,

3

OCH₂CH₃), 3.97 (s, 3 H, OCH₃), 3.08Ϫ2.92 (m, 5 H, H2, H6, H8),

⁴J ϭ 1.5 Hz, 1 H, H11a), 5.14 (td, ³J ϭ 17.1 Hz, ³J ϭ 1.5 Hz, ⁴J ϭ

2.33Ϫ2.27 (m, 1 H, H3), 1.70Ϫ1.65 (m, 1 H, H4), 1.57 (t, ³J ϭ 1.5 Hz, 1 H, H11b), 4.61, 4.52 (d_AB, ²J ϭ 11.6 Hz, 2 H, CH₂OCH₃),

7.0 Hz, 3 H, OCH₂CH₃), 1.54Ϫ1.47 (m, 2 H, H5), 1.42Ϫ1.34 (m, 3.37 (s, 3 H, CH₂OCH₃), 3.20Ϫ2.88 (m, 5 H, H2, H6, H8),

1 H, H7a), 1.02Ϫ0.95 (m, 1 H, H7b). Ϫ MS (EI, 70 eV); m/z (%):

2.34Ϫ2.24 (m, 1 H, H3), 1.66Ϫ1.45 (m, 3 H, H4, H5), 1.37Ϫ1.26

471 [M]^ϩ(32). Ϫ C₂₉H₃₃N₃O₃(471.6): calcd. C 73.86, H 7.05, N (m, 1 H, H7a), 1.07Ϫ0.96 (m, 1 H, H7b). Ϫ MS (EI, 70 eV); m/z

8.91; found C 74.02, H 7.11, N 8.86.

(%): 441 [M]^ϩ(39). Ϫ C₂₈H₃₁N₃O₂(441.6): calcd. C 76.10, H 7.08,

N 9.52; found C 75.87, H 7.11, N 9.48.

2-Butoxy-N-(9-deoxyepicinchonin-9-yl)benzamide (32a): Variant B

was followed, with 9-amino-9-deoxyepicinchonine (11) (922 mg,

2-(Acetylamino)-N-(9-deoxyepicinchonin-9-yl)benzamide

(35a):

3.14 mmol), in toluene (12 mL) and ethyl 2-butoxybenzoate^[49]Variant B was followed, with 9-amino-9-deoxyepicinchonine (11)

(32d). Filtration of the base through Al₂O₃with ether gave a color-

(1.20 g, 4.09 mmol), in toluene (7 mL) and methyl 2-(acetamido)-

less solid (690 mg, 47%), m.p. 53Ϫ56 °C. Ϫ [α]²_D²ϭ 320 (c ϭ 0.84, benzoate (34d). The base was dissolved in CH₂Cl₂and filtered

CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3370 (NϪH), 1650, 1510 cm^Ϫ1(amide). through Al₂O₃. Recrystallization from ether gave a colorless solid

1

3

Ϫ H NMR (CDCl₃): δ ϭ 9.17 (br. s, 1 H, CONH), 8.86 (d, J ϭ

(690 mg, 37%), m.p. 105Ϫ107 °C. Ϫ [α]²_D²ϭ 187 (c ϭ 0.29, CHCl₃).

4.5 Hz, 1 H, H2Ј), 8.49 (d, J ϭ 8.5 Hz, 1 H, H5Ј), 8.12 (dd, J ϭ Ϫ IR (KBr): ν˜ ϭ 3300 (NϪH), 1690, 1645, 1520 cm^Ϫ1(amide). Ϫ

3

8.4 Hz, ⁴J ϭ 0.9 Hz, 1 H, H8Ј), 8.04 (dd, ³J ϭ 7.9 Hz, ⁴J ϭ 1.9 Hz,

¹H NMR (CDCl₃): δ ϭ 10.89 (br. s, 1 H, CONH), 8.90 (d, J ϭ

3

4

1 H, phenyl-H), 7.73Ϫ7.68 (m, 1 H, H7Ј), 7.62Ϫ7.57 (m, 1 H, H6Ј), 4.5 Hz, 1 H, H2Ј), 8.56 (dd, J ϭ 8.4 Hz, J ϭ 0.8 Hz, 1 H, H5Ј),

7.46 (d, ³J ϭ 4.5 Hz 1 H, H3Ј), 7.42Ϫ7.35 (m, 1 H, phenyl-H),

8.40 (dd, ³J ϭ 8.4 Hz, ⁴J ϭ 0.5 Hz, 1 H, phenyl-H), 8.17 (dd, J ϭ

3

6.99Ϫ6.93 (m, 2 H, phenyl-H), 5.94 (ddd, ³J ϭ 17.1 Hz, ³J ϭ 8.4 Hz, ⁴J ϭ 1.1 Hz, 1 H, H8Ј), 7.99 (br. s, 1 H, CONH), 7.78Ϫ7.72

10.5 Hz, ³J ϭ 6.5 Hz, 1 H, H10), 5.58 (br. s, 1 H, H9), 5.16 (td,

³J ϭ 10.5 Hz, ³J ϭ 1.3 Hz, ⁴J ϭ 1.3 Hz, 1 H, H11a), 5.12 (td, ³J ϭ

(m, 1 H, H7Ј), 7.66Ϫ7.60 (m, 2 H, H6Ј, phenyl-H), 7.49 (d, J ϭ

4.5 Hz 1 H, H3Ј), 7.50Ϫ7.43 (m, 1 H, phenyl-H), 7.14Ϫ7.08 (m, 1

3

17.1 Hz, ³J ϭ 1.3 Hz, ⁴J ϭ 1.3 Hz, 1 H, H11b), 4.16 (t, ³J ϭ 6.8 Hz, H, phenyl-H), 5.96 (ddd, ³J ϭ 17.1 Hz, ³J ϭ 10.5 Hz, ³J ϭ 6.5 Hz,

2 H, OCH₂CH₂CH₂CH₃), 3.15Ϫ2.94 (m, 5 H, H2, H6, H8),

1 H, H10), 5.32 (br. d, 1 H, H9), 5.19 (td, ³J ϭ 10.5 Hz, ³J ϭ

2.34Ϫ2.24 (m, 1 H, H3), 2.07Ϫ1.87 (m, 2 H, OCH₂CH₂CH₂CH₃), 1.4 Hz, ⁴J ϭ 1.4 Hz, 1 H, H11a), 5.13 (td, ³J ϭ 17.1 Hz, ³J ϭ

1.69Ϫ1.30 (m, 6 H, H4, H5, H7a, OCH₂CH₂CH₂CH₃), 1.09 (t, 1.4 Hz, ⁴J ϭ 1.4 Hz, 1 H, H11b), 3.11Ϫ2.74 (m, 5 H, H2, H6, H8),

Eur. J. Org. Chem. 2000, 2119Ϫ2133

2131

H. Brunner, P. Schmidt

FULL PAPER

2.40Ϫ2.27 (m, 1 H, H3), 2.04 (s, 3 H, CH₃), 1.70Ϫ1.33 (m, 4 H,

methanol (12 mL) and precipitated at Ϫ30 °C by addition of acet-

H4, H5, H7a), 1.06Ϫ0.95 (m, 1 H, H7b). Ϫ MS (EI, 70 eV); m/z one (100 mL). Recrystallization of the free base from methanol

(%): 454 [M]^ϩ(56). Ϫ C₂₈H₃₀N₄O₂(454.6): calcd. C 73.98, H 6.65, gave colorless crystals (790 mg, 55%), m.p. Ͼ250 °C. Ϫ [α]²_D²ϭ 21

N 12.33; found C 73.88, H 6.73, N 12.26.

(c ϭ 0.33, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 1710 cm^Ϫ1(imide). Ϫ ¹H

NMR (CDCl₃): δ ϭ 8.97 (d, J ϭ 4.6 Hz, 1 H, H2Ј), 8.51 (d, J ϭ

3

N-(9-Deoxyepidihydrocinchonin-9-yl)-2-ethoxybenzamide (36): N-(9-

Deoxyepicinchonin-9-yl)-2-ethoxybenzamide

3

4

8.5 Hz, 1 H, H5Ј), 8.14 (dd, J ϭ 8.3 Hz, J ϭ 1.2 Hz, 1 H, H8Ј),

(30a)

(1.00 g,

8.00 (d, ³J ϭ 4.6 Hz, 1 H, H3Ј), 7.80Ϫ7.61 (m, 6 H, H7Ј, H6Ј,

phthalyl-H), 5.84 (ddd, J ϭ 17.2 Hz, J ϭ 10.4 Hz, J ϭ 6.6 Hz,

2.26 mmol) was dissolved in a mixture of water (10 mL) and conc.

HCl (0.6 mL), then PdCl₂(11.8 mg, 0.07 mmol) was added. After

being stirred for 1 h under hydrogen pressure (30 bar), the base

was liberated by the addition of an excess of Na₂CO₃solution and

extraction with CH₂Cl₂(3 ϫ 50 mL). After drying (Na₂CO₃) and

removal of the solvent, the resulting solid was dissolved in ether/

CH₂Cl₂(10:1) and filtered through a Pasteur pipette filled with

Al₂O₃. Addition of pentane to a solution of the base in ether gave

36 at Ϫ30 °C as a colorless solid (710 mg, 71%), m.p. 126Ϫ127 °C.

Ϫ [α]²_D²ϭ 321 (c ϭ 0.61, CHCl₃). Ϫ IR (KBr): ν˜ ϭ 3350 (NϪH),

3

4

1 H, H10), 5.12 (td, J ϭ 10.4 Hz, J ϭ 1.4 Hz, J ϭ 1.4 Hz, 1 H,

H11a), 5.07 (td, ³J ϭ 17.2 Hz, ³J ϭ 1.4 Hz, ⁴J ϭ 1.4 Hz, 1 H,

H11b), 3.08Ϫ2.79 (m, 5 H, H2, H6, H8), 2.28Ϫ2.22 (m, 1 H, H3),

1.68Ϫ1.44 (m, 4 H, H4, H5, H7a), 1.09Ϫ1.04 (m, 1 H, H7b). Ϫ

MS (EI, 70 eV); m/z (%): 423 [M]^ϩ(65). Ϫ C₂₇H₂₅N₃O₂(423.5):

calcd. C 76.57, H 5.95, N 9.92; found C 76.49, H 6.04, N 9.88.

Enantioselective Decarboxylation of 2-Cyano-2-(6-methoxynaphth-

2-yl)propionic Acid (2) (Standard Procedure): 2-Cyano-2-(6-me-

thoxynaphth-2-yl)propionic acid (2) (170 mg, 0.67 mmol) and 10

mol-% of optically active base were stirred in abs. THF (10 mL)

under nitrogen for 24 h at 15 °C. After removal of the solvent, the

residue was dissolved in ether (50 mL) and the base was separated

by being shaken with 2  HCl (50 mL). The organic phase was

washed with water (2 ϫ 50 mL) and dried with Na₂SO₄. The con-

version was determined by ¹H-NMR analysis (decarboxylation was

quantitative in most cases). Chromatography on silica with ether/

petroleum ether (40Ϫ60 °C) (2:1) afforded the pure product 6 as a

colorless solid. The enantiomeric excess was determined by GC.

1

1650, 1510 cm^Ϫ1(amide). Ϫ H NMR (CDCl₃): δ ϭ 9.30 (br. s, 1

3

H, CONH), 8.86 (d, J ϭ 4.5 Hz, 1 H, H2Ј), 8.50 (d, J ϭ 8.5 Hz,

1 H, H5Ј), 8.13 (dd, ³J ϭ 8.3 Hz, ⁴J ϭ 1.1 Hz, 1 H, H8Ј), 8.03 (dd,

³J ϭ 8.1 Hz, ⁴J ϭ 1.9 Hz, 1 H, phenyl-H), 7.74Ϫ7.67 (m, 1 H,

H7Ј), 7.63Ϫ7.57 (m, 1 H, H6Ј), 7.48 (d, ³J ϭ 4.5 Hz, 1 H, H3Ј),

7.41Ϫ7.34 (m, 1 H, phenyl-H), 6.98Ϫ6.92 (m, 2 H, phenyl-H), 5.51

3

(br. s, 1 H, H9), 4.23 (q, J ϭ 7.0 Hz, 2 H, OCH₂CH₃), 3.11Ϫ2.85

(m, 5 H, H2, H6, H8), 2.63Ϫ2.55 (m, 1 H, H3), 1.61 (t, ³J ϭ 7.0 Hz,

3 H, OCH₂CH₃), 1.66Ϫ1.22 (m, 6 H, H4, H5, H7a, H10),

3

0.94Ϫ0.84 (m, 1 H, H7b), 0.89 (t, J ϭ 7.1 Hz, 3 H, H11). Ϫ MS

(EI, 70 eV); m/z (%): 443 [M]^ϩ(40). Ϫ C₂₈H₃₃N₃O₂(443.6): calcd.

Enantioselective Decarboxylation of 2-Cyano-2-phenylpropionic

Acid (40) (Standard Procedure): The reaction was carried out with

148.0 mg (0.84 mmol) of 2-cyano-2-phenylpropionic acid (40) ac-

cording to the decarboxylation of 2 which gave the product 41 as

a colorless oil.

C 75.82, H 7.50, N 9.47; found C 75.67, H 7.55, N 9.47.

N-(9-Deoxy-1Ј-oxyepidihydrocinchonin-9-yl)-2-ethoxybenzamide

(37):

N-(9-Deoxyepidihydrocinchonin-9-yl)-2-ethoxybenzamide

(36) (1.45 g, 3.27 mmol), and 3-chloroperoxybenzoic acid (3.45 g,

20.0 mmol) were dissolved in CHCl₃(50 mL) and stirred for 5 d at

room temperature. After being filtered and diluted with 100 mL

CHCl₃, the organic phase was washed with a half-concentrated

Na₂CO₃solution (4 ϫ 50 mL) and then dried (Na₂CO₃). The res-

idue was purified by chromatography on silica with MeOH (col-

umn 30 ϫ 2.5 cm). Filtration through a Pasteur pipette filled with

Al₂O₃gave the N,NЈ-dioxide (950 mg, 61%), of which 800 mg

(1.68 mmol) was dissolved in MeOH (25 mL). Then, SO₂gas was

passed through the solution for 3 h, followed by removal of the

solvent. After the residue was dissolved in CH₂Cl₂, the organic

phase was washed with half-concentrated Na₂CO₃solution (3 ϫ

50 mL) and water (1 ϫ 50 mL), the solution was concentrated to

approx. 5 mL and filtered through Al₂O₃. Two recrystallizations

from ether gave 320 mg (41%, with respect to the N,NЈ-dioxide) of

colorless 37, m.p. 181Ϫ182 °C. Ϫ [α]²_D²ϭ 321 (c ϭ 0.29, CHCl₃).

Ϫ IR (KBr): ν˜ ϭ 3380 (NϪH), 1650, 1570 cm^Ϫ1(amide). Ϫ ¹H

NMR (CDCl₃): δ ϭ 9.31 (br. s, 1 H, CONH), 8.83 (dd, ³J ϭ 8.3 Hz,

⁴J ϭ 1.7 Hz, 1 H, H8Ј), 8.54Ϫ8.45 (m, 1 H, H5Ј), 8.48 (d, ³J ϭ

6.4 Hz, 1 H, H2Ј), 8.02 (dd, ³J ϭ 8.0 Hz, ⁴J ϭ 1.9 Hz, 1 H, phenyl-

H), 7.80Ϫ7.68 (m, 2 H, H6Ј, H7Ј), 7.43Ϫ7.35 (m, 1 H, phenyl-H),

7.38 (d, ³J ϭ 6.4 Hz, 1 H, H3Ј), 7.00Ϫ6.94 (m, 2 H, phenyl-H),

5.40 (br. s, 1 H, H9), 4.29Ϫ4.17 (m, 2 H, OCH₂CH₃), 3.08Ϫ2.86

(m, 5 H, H2, H6, H8), 2.59Ϫ2.51 (m, 1 H, H3), 1.60 (t, ³J ϭ

7.0 Hz, 3 H, OCH₂CH₃), 1.63Ϫ1.22 (m, 6 H, H4, H5, H7a, H10),

GC Conditions: 30-m Rt-β DEX cst fused silica capillary column

(0.32 mm inner diameter, from Restek), injector temp. 260 °C, de-

tector temp. 260 °C [flame ionisation]; 6 (41): column temp. 177

°C (120 °C), H₂pressure 1.0 bar (0.7 bar), retention times for the

enantiomers [(S)/(R)] 24.5/25.5 min (6.7/7.3 min). Ϫ ¹H NMR: Ap-

prox. 10 mg dissolved in 0.8 mL of CDCl₃, conversion determined

by comparison of the singlet of 2 (40) at δ ϭ 2.06 (1.99) with the

doublet of 6 (41) at δ ϭ 1.71 (1.65).

Acknowledgments

Generous financial support by the Bayerischer Forschungsverbund

Katalyse (FORKAT II) and the Hermann-Schlosser-Stiftung

(DegussaϪHüls AG) are gratefully acknowledged. We thank Dr.

Chris Welch (Regis Technologies Inc., U.S.A.) for the separation of

the enantiomers of ester 5 by HPLC. We are grateful to Prof. Dr.

Gerhard Hübner and Jonathan Müller (Institut für Biochemie,

Martin-Luther-Universität Halle-Wittenberg, Germany) for carry-

ing out the decarboxylation experiments with pyruvate decarb-

oxylase.

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Received December 21, 1999

[O99682]

Eur. J. Org. Chem. 2000, 2119Ϫ2133

2133

Article Doi

Asymmetric catalysis, 131([≠]) - Naproxen derivatives by enantioselective decarboxylation

DOI: 10.1002/1099-0690(200006)2000:11<2119::aid-ejoc2119>3.0.co;2-5

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