α-amino acid derivatives by enantioselective decarboxylation

Article abstract of DOI:10.1002/ejoc.200300206

The methodology of enantioselective decarboxylation was applied to 2-aminomalonic acid derivatives in order to obtain enantio-enriched amino acid derivatives. Full conversion was achieved stirring racemic N-acetylated 2-aminomalonic hemiesters in THF at 70 °C with 10 mol % of a chiral base for 24 h. The catalyst may be recycled. Whereas the commercially available cinchona alkaloids gave poor results, benzamide and benzenesulfonamide derivatives of 9-amino(9-deoxy)epicinchonine turned out to be effective catalysts. The best result was obtained with 2-N-acetylamino-2-ethoxy-carbonyl-3-phenylpropionic acid as the starting material and N-(9-deoxyepicinchonine-9-yl)-4-methoxybenzamide as the chiral base to give ethyl N-acetyl-L-phenylalaninate in 70% ee. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300206

FULL PAPER
α-Amino Acid Derivatives by Enantioselective Decarboxylation[‡]
Henri Brunner*[a] and Markus A. Baur[a]
Keywords: Amino acids / Asymmetric catalysis / Enantioselective decarboxylation / Alkaloids / Amides
The methodology of enantioselective decarboxylation was
applied to 2-aminomalonic acid derivatives in order to obtain
enantio-enriched amino acid derivatives. Full conversion was
achieved stirring racemic N-acetylated 2-aminomalonic
hemiesters in THF at 70 °C with 10 mol % of a chiral base
oxy)epicinchonine turned out to be effective catalysts. The
best result was obtained with 2-N-acetylamino-2-ethoxy-
carbonyl-3-phenylpropionic acid as the starting material
and N-(9-deoxyepicinchonine-9-yl)-4-methoxybenzamide as
the chiral base to give ethyl N-acetyl-L-phenylalaninate in
for 24 h. The catalyst may be recycled. Whereas the commer- 70% ee.
cially available cinchona alkaloids gave poor results, benza- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
mide and benzenesulfonamide derivatives of 9-amino(9-de-
Germany, 2003)
Introduction
chona alkaloid bases, this methodology was set up for ala-
nine derivatives. Varying the substituents we also arrived at
valine and phenylalanine derivatives.[22,23]
It was in 1904 when Marckwald reported on the first en-
antioselective decarboxylation reactions.[1,2] In the follow-
ing decades, only few publications followed, all with disap-
pointing results.[3,4] In 1986 Toussaint revitalized interest in
enantioselective decarboxylation reactions, using copper()
salts and cinchona alkaloids.[5,6] Later it was shown that the
reaction was not copper()-catalyzed, but base-
catalyzed.[7Ϫ10] Recently, we applied the enantioselective de-
carboxylation with substoichiometric amounts of chiral
bases as catalysts in the synthesis of derivatives of Nap-
roxen with up to 72% ee.[11,12] Parallel to these studies,
Results and Discussion
Diethyl 2-N-acetylaminomalonate, commercially avail-
able and important in industrial amino acid synthesis,[23]
was the precursor for the synthesis of substrates 1, 2, 3
and 4. Hemiesters 1,[25] 2, 3[26] were synthesized first by
alkylation with the appropriate alkyl halide and second by
partial saponification. Diacid 4 was prepared by full
saponification. Cyanopropionic acid
5 was prepared
´
Henin and Muzart prepared optically active linear and cyc-
analogously by starting from ethyl 2-N-acetylamino-2-
lic ketones via palladium-induced cascade reactions includ-
ing enantioselective decarboxylation steps.[13Ϫ17] The group
of Kim tried to get optically active β-hydroxyisobutyric acid
by enantioselective decarboxylation.[18]
cyanopropionate.[27]
The catalytic decarboxylation of the racemic substrates
1Ϫ5 (prochiral in case of 4) afforded the corresponding am-
ino acid derivatives 6Ϫ10 (Scheme 1). Standard reactions
were carried out with 10 mol % optically active base in abs.
THF at 70 °C under nitrogen. After 24 h the reactions were
stopped by cooling and evaporating the solvent at room
temp. The residue was dissolved in diluted hydrochloric acid
The synthesis of amino acids, proteinogenic and non-pro-
teinogenic of both configurations, continues to be a chal-
lenge, although there are many synthetic approaches avail-
able. Not taking into account enzymatic processes, enanti-
oselective catalytic decarboxylation has rarely been used to
obtain enantio-enriched amino acids. A preparative ap-
proach to optically active amino acids by enantioselective
decarboxylation was based on stoichiometric amounts of
trans-dichlorocobalt() complexes.[19Ϫ21] In this paper, we
report on our studies concerning the decarboxylation of N-
acetylaminomalonic acid derivatives. Using different cin-
[‡]
Asymmetric Catalysis, 152. Part 151: H. Brunner, C. Zettler,
M. Zabel, Z. Anorg. Allg. Chem., in press.
[a]
Institut für Anorganische Chemie der Universität
93040 Regensburg, Germany
Fax: (internat.) ϩ49-(0)941-943-4439
E-mail: henri.brunner@chemie.uni-regensburg.de
Scheme 1. Decarboxylation of 1Ϫ5 leading to amino acid deriva-
tives 6Ϫ10
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α-Amino Acid Derivatives by Enantioselective Decarboxylation
FULL PAPER
and extracted with ethyl acetate. The base stayed in the
At 15 °C no decarboxylation of 2-N-acetylamino-2-
water phase and could be recycled. The organic layer was ethoxycarbonylpropionic acid (1) with 10 mol % cinchonine
evaporated and the conversion was determined by 1H NMR (11) occurred within 3 days (Table 1, Entry 1). Increasing
spectroscopy. Usually, conversion was quantitative. The en- the temperature to 35 °C increased the conversion after 3
antiomeric excess of the products was determined by GC.
days to 65% (Table 1, Entry 2). Higher temperatures short-
In order to find suitable reaction conditions for the ca- ened the reaction times improving the enantiomeric excess
talysis, the parameters reaction temperature and time were slightly (Table 1, Entries 3Ϫ7). Therefore, as standard con-
varied, using the commercially available cinchona alkaloid ditions 70 °C in refluxing THF were chosen.
cinchonine 11 (Scheme 2) in the solvent THF, which had
been the best solvent for the decarboxylations in the Nap-
roxen system.[11,12]
The results with the cinchona alkaloids 11؊14 under
standard conditions are given in Entries 7Ϫ10 of Table 1.
Obviously, the configurations at positions 8 and 9 of the
cinchona alkaloid and the presence or absence of the meth-
oxy group in 6Ј-position of the quinoline ring determine the
direction of induction. With respect to positions 8 and 9,
cinchonine (11) and cinchonidine (12) as well as quinidine
(13) and quinine (14) are mirror image isomers. Conse-
quently, cinchonine (11) and cinchonidine (12) (Table 1, En-
tries 7 and 8) as well as quinidine (13) and quinine (14)
(Table 1, Entries 9 and 10) gave different configurations of
product 6. On the other hand, the pairs cinchonine (11)/
quinidine (13) and cinchonidine (12)/quinine (14) have the
same configurations at position 8 and 9. They just differ in
the absence or presence of a methoxy group in the quinoline
system. Surprisingly, the components of the pairs afforded
opposite configurations in product 6. N-(9-Deoxyepicin-
chonine-9-yl)-2-ethoxybenzamide (15), the best base in the
Naproxen system,[11,12] gave better enantioselectivities
than the commercially available alkaloids (Table 1, Entry
11).
Base 15 was also tested with the starting materials 2-N-
acetylamino-2-methylmalonic acid (4) and 2-N-acetylamino-
2-cyanopropionate (5) (Table 1, Entries 12 and 13). As 2-N-
acetylamino-2-ethoxycarbonylpropionic acid (1) (Table 1,
Entry 11) gave much better results, further catalyses were
carried out with hemiester 1 as the starting material.
In addition to THF, other solvents were tested in the de-
carboxylation of 1 with 10 mol % 15 (Table 1, Entries 14
Scheme 2. Optically active bases 11Ϫ15
Table 1. Variation of temperature, reaction time, base and solvent in the decarboxylation of substrates 1, 4 and 5
[a]
Not determined.
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H. Brunner, M. A. Baur
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and 15). Acetonitrile had turned out to be a suitable solvent system,[11,12] in addition to benzamide 15 the amides 17Ϫ37
for
enantioselective
decarboxylations
in
recent were screened as catalysts in the decarboxylation of hemi-
publications.[9,13Ϫ16] However, in the decarboxylation of 1 ester 1. The amides were prepared in two steps, illustrated
the enantiomeric excess decreased dramatically (Table 1, in Scheme 3. In the first step, 9-amino(9-deoxy)epicinchon-
Entry 14). Dioxane gave similar results as THF (Table 1, ine (16) was prepared from cinchonine via a Mitsunobu re-
Entry 15). In diethyl ether both, starting material 1 and action leading to an inversion at C-9.[28,29] Amine 16 was
base 15 were almost insoluble.
converted into amides 17Ϫ37 using the appropriate acid
Since benzamides of the cinchona alkaloids had been the chlorides analogous to the literature.[11] Amides 21, 24,
best bases in decarboxylation reactions of the Naproxen 25 and 36 included water affecting elemental analyses but
Scheme 3. Preparation of amides 17Ϫ37 of 9-amino(9-deoxy)epicinchonine (16)
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α-Amino Acid Derivatives by Enantioselective Decarboxylation
FULL PAPER
Table 2. Decarboxylation of 1 with cinchona alkaloid derivatives 17Ϫ45 (THF, T ϭ 70 °C, t ϭ 24 h, 100% conversion)
showing up in the 1H NMR spectra. Compounds 23, Entry 11). As expected on the basis of the steric hindrance
28Ϫ35, 37 (and 41) were available from the previous argument, the 1-naphthyl derivative 28 gave a lower ee than
study.[11]
the 2-naphthyl derivative 29 (Table 2, Entries 12 and 13).
In the decarboxylation of hemiester 1 to the acetylated The 2-furanylamide 30 and the ferrocenylamide 31 provided
alanine ester 6, the unsubstituted benzamide 17 gave pro- similar results as the parent benzamide 17 (Table 2, Entries
mising results with about 50% ee (Table 2, Entry 1). The 14 and 15).
ortho-, meta- and para-methoxy-substituted benzamides
Amides 32Ϫ37 lacking the aromatic substituent were
18Ϫ20 were tested to see whether there were steric and elec- much less efficient in the decarboxylation of 1. While the α-
tronic effects. In fact, the ortho-substituted derivative 18 af- methylcinnamic acid amide 32 yielded about 45% ee
forded only about 18% ee (Table 2, Entry 2) compared to (Table 2, Entry 16), the aralkyl and alkyl derivatives 33Ϫ37
the meta- and para-substituted derivatives 18 and 19 with afforded only low enantioselectivities (Table 2, Entries
about 52% ee (Entries 3 and 4) indicating steric hindrance 17Ϫ21) including the adamantane derivative 36 and the
of ortho-substituents. This was corroborated by the low en- (1S)-(Ϫ)-camphanic acid derivative 37 in which even group
antioselectivities of the ortho-ethoxy derivative 15 and the R was chiral.
ortho-fluoro derivative 23 (Table 1, Entry 11; Table 2, En-
try 7).
In addition, compounds 38Ϫ45 (Scheme 4) were tested in
the decarboxylation of hemiester 1. Similar to the phenyl-
21 with a tert-butyl group in para-position gave 54% ee and di-tert-butylphenyl-substituted benzamides 17 and 27,
(Table 2, Entry 5) and the dibenzamide 22[29] 44% ee the corresponding sulfonamides 38 and 39, derived from 9-
(Table 2, Entry 6). Compounds 24, 25, 26, containing amino(9-deoxy)epicinchonine (16), afforded 55 and 52% ee
1
strongly electron-withdrawing and electron-attracting sub- (Table 2, Entries 22 and 23). The complex H NMR spec-
stituents in 3,5-position led to an enantiomeric excess in a trum of 38 simplified at 110 °C in C2D2Cl4 (see Exp. Sect.).
range between 50 and 54% ee (Table 2, Entries 8Ϫ10), Amine 40 and phthalimide 41 gave poor results (Table 2,
showing that there was no pronounced inductive effect. Entries 24 and 25), whereas the urea derivative 42 led to
N-(9-Deoxyepicinchonine-9-yl)-3,5-di-tert-butylbenzamide 30% ee (Table 2, Entry 26). The carbamate and sulfonate
(27) afforded the best result (59% ee) in this series (Table 2, esters 43 and 44 of cinchonine achieved only low enantiose-
Scheme 4. Compounds 38Ϫ45
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H. Brunner, M. A. Baur
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lectivities as did compound 45, a successful catalyst in the
BaylisϪHillman reaction (Table 2, Entries 27Ϫ29).[30]
The screening was extended to the decarboxylation of 2
affording valine derivative 7. With the unsubstituted benza-
mide 17 15% ee was obtained (Table 3, Entry 1). Again the
ortho-methoxy-substituted base 18 gave a bad result, in this
case a racemate (Table 3, Entry 2), whereas the meta- and
para derivatives 19 and 20 matched the unsubstituted
benzamide 17 with about 13% ee (Table 3, Entries 3 and 4).
Table 4. Variation of catalyst concentration and temperature in the
decarboxylation of 1 to give 6. 100% conversion in all cases except
for Entry 11 with 85% conversion
Table 3. Decarboxylation of 2 and 3 with different bases (THF,
T ϭ 70 °C, t ϭ 24 h, 100% conversion)
was almost complete after 12 h (Figure 1). At the beginning
of the catalysis the enantiomeric excess of ethyl N-acetylal-
aninate (6) was a little lower. After 5 h it reached 60% ee and
stayed constant then. A similar observation had been made
in the Naproxen system.[11] This is in contradiction to a
computational study recently published in this journal,[30]
denying a two-step decarboxylation/protonation mecha-
nism and suggesting a concerted mechanism according to
which each enantiomer of the starting material transforms
into its own product enantiomer. In such a case, kinetic
resolution should occur. This was not observed, neither in
the Naproxen system[11] nor in the present study. Moreover,
in the Naproxen system it had been shown that both
enantiomers of the resolved starting material 2-cyano-2-(6-
methoxynaphth-2-yl)propionic acid gave the same product
enantioselectivity of about 68% ee, which is incompatible
with a concerted mechanism. Thus, we continue to favor
the two-step decarboxylation/protonation mechanism via
planar intermediates, such as the enolate of ethyl N-acetyla-
laninate in the decarboxylation of 1, and their stereoselec-
tive protonation.
An unexpected increase to 48% enantiomeric excess was
observed with N-(9-deoxyepicinchonine-9-yl)-3,5-di-tert-
butylbenzamide (27) (Table 3, Entry 5), also the best base
in the system 1 Ǟ 6.
Enantioselectivities were much higher in the decar-
boxylation of 3 to give ethyl N-acetylphenylalaninate 8. The
unsubstituted benzamide 17 afforded 67% ee (Table 3, En-
try 6). Again, the ortho-substituted methoxybenzamide 18
gave only 38% ee (Table 3, Entry 7), whereas the meta- and
para-substituted methoxybenzamides 19 and 20 achieved
65% and 70% ee (Table 3, Entries 8 and 9). With 21 and 27
close to 70% ee were obtained (Table 3, Entries 10 and 11).
The sulfonamides 38 and 39 resulted in 63% and 65% ee
(Table 3, Entries 12 and 13).
With 15, the effect of varying the amount of catalyst in
the decarboxylation of hemiester 1 was tested (Table 4, En-
tries 1Ϫ8). Increasing the amount of 15 gave rise to an in-
crease of the enantiomeric excess, reaching 41.5% ee with
60 mol % base (Table 4, Entry 7). Use of a stoichiometric
amount of base did not improve the results (Table 4, Entry
8). In contrast, with 27 the enantiomeric excess could not
be improved with higher amounts of base (Table 4, Entries
9 and 10). A decrease of the reaction temperature to 30 °C
made the reaction sluggish. After 18 days there was only
85% conversion with decreased enantioselectivity (Table 4,
Entry 11).
Figure 1. Kinetics of the decarboxylation of 1Ǟ6 with base 27
A kinetic study of the decarboxylation of 1 was per-
formed with base 27, which had been the most successful
catalyst in the system 1 Ǟ 6. The twelvefold standard reac-
Conclusion
The enantioselective decarboxylation methodology was
tion was analyzed taking samples each hour. Conversion extended to amino acid derivatives (10 mol % catalyst,
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C6H9NO5 (175.1): calcd. C 41.15, H 5.18, N 8.00; found C 40.58,
H 5.16, N 7.53.
THF, 70 °C, 100% conversion). The best catalysts, epicin-
chonine benzamides and benzenesulfonamides (lacking or-
tho-substituents!) afforded 60% ee in the decarboxylation 1
Ǟ 6 and 70% ee in the decarboxylation 3 Ǟ 8.
2-N-Acetylamino-2-cyanopropionic Acid (5): To a suspension of
ethyl 2-N-acetylamino-2-cyanopropionate[27] (1.00 g, 5.43 mmol) in
EtOH (2.8 mL), KOH (0.91 g, 16.2 mmol) dissolved in water
(11 mL) was added at 0 °C. After stirring at room temp. for 10 h,
workup was as for 4, except that 2  HCl was used for acidification
and the product did not precipitate. Dissolution in THF, precipi-
tation with PE 40/60 and storage at Ϫ30 °C gave 5 (170 mg, 20%)
as a colorless solid, m.p. 125Ϫ128 °C (dec., ȆCO2). IR (KBr): ν˜ ϭ
3340 (NϪH), 1730 cmϪ1 (CϭO). 1H NMR (250 MHz,
[D6]DMSO): δ ϭ 1.69 (s, 3 H, CH3), 1.93 (s, 3 H, COCH3), 8.99
(s, 1 H, NH), 13.80 (br. s, 1 H, COOH) ppm. MS (CI, NH3): m/z
(%) ϭ 130.0 (100) [M ϩ NH4 Ϫ CO2]. C6H8N2O3 (156.1): calcd.
C 46.15, H 5.16, N 17.94; found C 46.19, H 5.25, N 17.56.
Experimental Section
General: 1H NMR: Bruker AC 250, Bruker Avance 300 and Bruker
Avance 400. EI MS: Finnigan MAT 311 A, CI and FD MS: Finni-
gan MAT 95. Only the most intense peak of a cluster is given. GC:
HewlettϪPackard HP 5890 series II and Thermoquest 8130Ϫ10,
Spectra Physics SP 4270 integrator. IR: Beckman IR 4240. Optical
rotations: PerkinϪElmer polarimeter 241 (1-dm cell), measurement
at room temp. Melting points: Büchi SMP 20 (uncorrected). El-
emental analysis: Vario EL III.
General Procedure for the Synthesis of the Amides of 9-Amino(9-
deoxy)epicinchonine (16): 16 was dissolved in the given amount of
CH2Cl2 and NEt3. Then a solution of the appropriate benzoyl chlo-
ride in CH2Cl2 was added dropwise at 0 °C. After stirring at room
temp. for 10 h, the reaction mixture was diluted with CH2Cl2 and
washed 3 ϫ with half-concentrated Na2CO3 solution, dried with
Na2CO3 and the solvents were evaporated. All the amides were
purified by chromatography on silica gel with MeOH as eluent.
Further details are given for the individual compounds.
The precursors for the substrates diethyl 2-N-acetylamino-2-meth-
ylmalonate[25], diethyl 2-N-acetylamino-2-isopropylmalonate,[32] di-
ethyl 2-N-acetylamino-2-benzylmalonate[33] and ethyl 2-N-acetyl-
amino-2-cyanopropionate[27] and the substrates 2-N-acetylamino-
2-ethoxycarbonylpropionic acid (1)[25] and 2-N-acetylamino-2-
ethoxycarbonyl-3-phenylpropionic acid (3)[26] were prepared ac-
cording to the literature. 3,5-Dimethoxybenzoyl chloride was ob-
tained by refluxing the corresponding acid for 2 h in SOCl2, fol-
lowed by bulb-to-bulb distillation in vacuo. 4-tert-Butylbenzoyl
chloride, 3,5-difluorobenzoyl chloride, 3,5-dinitrobenzoyl chloride
and 1-adamantanecarboxylic acid chloride were purchased from
ACROS. Compounds 16, 17, 22 (ref.[29]) and 15, 18, 19, 20, 27
(ref.[11]) were prepared as described. Furthermore, 3,5-di-tert-butyl-
benzenesulfonyl chloride[34] and (3R,8R,9S)-10,11-dihydro-3,9-ep-
oxy-6Ј-hydroxycinchonane (45)[30] were synthesized as described.
N-(9-Deoxyepicinchonine-9-yl)-4-tert-butylbenzamide
(21):
16
(908 mg, 3.09 mmol), CH2Cl2 (16 mL), NEt3 (6.4 mL) and 4-tert-
butylbenzoyl chloride (755 mg, 3.84 mmol), CH2Cl2 (4 mL). After
dissolution in Et2O the product was precipitated with PE 40/60 and
stored at Ϫ30 °C. Colorless solid (390 mg, 28%), m.p. 122Ϫ124 °C.
[α]D ϭ 266 (c ϭ 0.53, CHCl3). IR (KBr): ν˜ ϭ 3280 (NϪH), 1640,
1
1515 cmϪ1 (amide). H NMR (250 MHz, CDCl3): δ ϭ 0.90Ϫ1.10
(m, 1 H, Hb7), 1.32 (s, 9 H, CH3), 1.19Ϫ1.71 (m, 4 H, H4, H5,
Ha7), 2.23Ϫ2.38 (m, 1 H, H3), 2.76Ϫ3.17 (m, 5 H, H2, H6, H8),
2-N-Acetylamino-2-ethoxycarbonyl-3-methylbutyric Acid (2): Diethyl
2-N-acetylamino-2-isopropylmalonate[32] (4.96 g, 19.1 mmol) was dis-
solved in EtOH (10 mL). A solution of KOH (1.28 g, 19.4 mmol)
in water (1.3 mL) and EtOH (5.2 mL) was added dropwise. After
stirring for 48 h at room temp., the solvents were removed in vacuo
at room temp. The aqueous solution of the residue was washed 3
ϫ with EtOAc to remove the starting material from the product.
The water phase was acidified with half-concentrated HCl at 0 °C.
The precipitating product was extracted 3 ϫ with EtOAc. The or-
ganic layers were dried with Na2SO4 adding charcoal to remove a
pink color. Evaporation of the organic solvent yielded 2 as a color-
less solid (1.5 g, 34%), m.p. 130Ϫ132 °C (dec., ȆCO2). IR (KBr):
ν˜ ϭ 3360 (NϪH), 1780 cmϪ1 (CϭO). 1H NMR (250 MHz,
[D6]DMSO): δ ϭ 0.84, 0.87 [2 d, 3J ϭ 6.9 Hz, 6 H, CH(CH3)2],
1.11 (t, 3J ϭ 7.1 Hz, 3 H, CH2CH3), 1.89 (s, 3 H, COCH3),
2.40Ϫ2.57 [m, 1 H, CH(CH3)2], 3.93Ϫ4.17 (m, 2 H, CH2CH3), 7.94
(s, 1 H, NH), 13.27 (br. s, 1 H, COOH) ppm. MS (CI, NH3): m/z
(%) ϭ 188.1 (100) [MH Ϫ CO2]. C10H17NO5 (231.3): calcd. C
51.94, H 7.41, N 6.06; found C 52.10, H 7.25, N 6.20.
3
2
5.12 (td, J ϭ 17.2, J ϭ 1.5, 4J ϭ 1.5 Hz, 1 H, H11b), 5.17 (td,
3J ϭ 10.6, 2J ϭ 1.5, 4J ϭ 1.5 Hz, 1 H, H11a), 5.38 (br. d, 1 H,
H9), 5.93 (ddd, J ϭ 17.1, 3J ϭ 10.6, 3J ϭ 6.5 Hz, 1 H, H10), 7.45
3
3
3
(d, J ϭ 8.7 Hz, 2 H, H3ЈЈ, H5ЈЈ), 7.49 (d, J ϭ 4.6 Hz, 1 H, H3Ј),
3
7.55Ϫ7.65 (m, 1 H, H6Ј), 7.67Ϫ7.75 (m, 1 H, H7Ј), 7.75 (d, J ϭ
8.7 Hz, 2 H, H2ЈЈ, H6ЈЈ), 7.90 (s, 1 H, NH), 8.13 (dd, 3J ϭ 8.4,
4J ϭ 1.2 Hz, 1 H, H8Ј), 8.45 (dd, 3J ϭ 8.5, 4J ϭ 1.0 Hz, 1 H, H5Ј),
3
8.86 (d, J ϭ 4.6 Hz, 1 H, H2Ј) ppm. MS (EI, 70 eV): m/z (%) ϭ
161.3 (100) [4-tert-butylbenzoyl], 453.6 (38) [M]. C30H35N3O
(453.6)·1.2H2O: calcd. C 75.82, H 7.93, N 8.84; found C 75.45, H
8.17, N 8.84.
N-(9-Deoxyepicinchonine-9-yl)-3,5-difluorobenzamide
(24):
16
(848 mg, 2.89 mmol), CH2Cl2 (15 mL), NEt3, (6 mL) and 3,5-di-
fluorobenzoyl chloride (748 mg, 4.24 mmol), CH2Cl2 (4 mL).
Recrystallization from Et2O. Colorless solid (326 mg, 26%), m.p.
134Ϫ137 °C. [α]D ϭ 243 (c ϭ 0.54, CHCl3). IR (KBr): ν˜ ϭ 3320
(NϪH), 1640, 1515 cmϪ1 (amide). 1H NMR (250 MHz, CDCl3):
δ ϭ 0.95Ϫ1.09 (m, 1 H, Hb7), 1.30Ϫ1.71 (m, 4 H, H4, H5, Ha7),
2.25Ϫ2.41 (m, 1 H, H3), 2.89Ϫ3.18 (m, 5 H, H2, H6, H8), 5.12
2-N-Acetylamino-2-methylmalonic Acid (4): Diethyl 2-N-acetylam-
3
2
4
3
ino-2-methylmalonate[25] (5.0 g, 21.6 mmol) was added to a solu- (td, J ϭ 17.6, J ϭ 1.7, J ϭ 1.7 Hz, 1 H, H11b), 5.18 (td, J ϭ
tion of KOH (4.90 g, 87.0 mmol) in EtOH (20 mL) and water
10.8, 2J ϭ 1.7, 4J ϭ 1.7 Hz, 1 H, H11a), 5.36 (br. d, 1 H, H9), 5.93
(10 mL). After stirring for 6 d at room temp., the solvents were (ddd, 3J ϭ 17.1, 3J ϭ 10.6, 3J ϭ 6.4 Hz, 1 H, H10), 6.93 (tt,
4
removed at room temp. in vacuo. Workup as described for 2. For
purification, the crude product was dissolved in THF, precipitated
with PE 40/60 and stored at Ϫ30 °C. Colorless solid (0.74 g, 20%),
3JH4ЈЈ,F ϭ 8.6, J ϭ 2.3 Hz, 1 H, H4ЈЈ), 7.27Ϫ7.34 (m, 2 H, H2ЈЈ),
7.46 (d, 3J ϭ 4.4 Hz, 1 H, H3Ј), 7.56Ϫ7.67 (m, 1 H, H6Ј),
3
7.68Ϫ7.79 (m, 1 H, H7Ј), 7.87 (br. s, 1 H, NH), 8.15 (dd, J ϭ 8.3,
m.p. 135 °C (dec., ȆCO2). IR (KBr): ν˜ ϭ 3350 (NϪH), 1750 cmϪ1
4J ϭ 1.2 Hz, 1 H, H8Ј), 8.39 (d, J ϭ 7.9 Hz, 1 H, H5Ј), 8.88 (d,
3
(CϭO). H NMR (250 MHz, [D6]DMSO): δ ϭ 1.51 (s, 3 H, CH3), 3J ϭ 4.4 Hz, 1 H, H2Ј) ppm. MS (EI, 70 eV): m/z (%) ϭ 136.3
1
1.86 (s, 3 H, COCH3), 8.02 (s, 1 H, NH), 12.98 (br. s, 2 H, COOH)
(100) [quinuclidine], 433.1 (10) [M]. C26H25F2N3O (433.5)·2.2H2O:
ppm. MS (CI, NH3): m/z (%) ϭ 129.9 (100) [M Ϫ COOH].
calcd. C 69.22, H 6.57, N 9.31; found C 68.94, H 6.09, N 9.16.
Eur. J. Org. Chem. 2003, 2854Ϫ2862
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2859

H. Brunner, M. A. Baur
FULL PAPER
N-(9-Deoxyepicinchonine-9-yl)-3,5-dimethoxybenzamide (25): 16
(590 mg, 2.01 mmol), CH2Cl2 (12 mL), NEt3 (4.1 mL) and 3,5-di-
N-(9-Deoxyepicinchonine-9-yl)-4-methylbenzenesulfonamide (38): 16
(960 mg, 3.27 mmol), p-toluenesulfonyl chloride (938 mg,
methoxybenzoyl chloride (522 mg, 2.60 mmol), CH2Cl2 (3 mL). 4.92 mmol) and K2CO3 (540 mg, 3.90 mmol) were stirred in
The hydrochloride was formed by stirring with an excess of etha- CH2Cl2 (20 mL) at room temp. for 10 h. The reaction mixture was
nolic HCl for 10 h. After removal of the solvent, the hydrochloride diluted with CH2Cl2, K2CO3 was removed by filtration and the
was dissolved in MeOH, precipitated with acetone and stored at
Ϫ30 °C. Then the free base was liberated by dissolving the hydro-
chloride in water, adding an excess of Na2CO3 solution and extrac-
tion with CH2Cl2. The free base was chromatographed and after-
solution was washed 3 ϫ with saturated Na2CO3 solution. Chro-
matography on SiO2 with EtOAc/MeOH (9:1). Colorless solid
(460 mg, 31%), m.p. 190Ϫ192 °C. [α]D ϭ 52 (c ϭ 0.51, CHCl3). IR
(KBr): ν˜ ϭ 3440 (NϪH), 1390, 1330, 1170 cmϪ1 (sulfonamide). 1H
wards recrystallized from Et2O. Colorless solid (330 mg, 36%), m.p. NMR (250 MHz, CDCl3): δ ϭ 0.71Ϫ0.93 (m, 1 H, Hb7), 1.08Ϫ1.68
123Ϫ125 °C. [α]D ϭ 267 (c ϭ 0.52, CHCl3). IR (KBr): ν˜ ϭ 3340 (m, 4 H, H4, H5, Ha7), 2.35 (s, 3 H, CH3), 2.13Ϫ2.42 (m, 1 H,
(NϪH), 1645, 1515 cmϪ1 (amide). 1H NMR (300 MHz, CDCl3):
H3), 2.62Ϫ2.97 (m, 3.7 H, H2, H6, H8), 3.17Ϫ3.31 (m, 0.3 H, H8),
δ ϭ 0.91Ϫ1.07 (m, 1 H, Hb7), 1.46Ϫ1.73 (m, 4 H, H4, H5, Ha7), 4.20 (br. d, J ϭ 10.7 Hz, 0.3 H, H11b), 4.82Ϫ4.96 (m, 1.7 H, H9,
2.24Ϫ2.38 (m, 1 H, H3), 2.76Ϫ3.15 (m, 5 H, H2, H6, H8), 3.79 (s, H11b), 5.12 (td, 3J ϭ 10.6, 2J ϭ 1.4, 4J ϭ 1.4 Hz, 1 H, H11a), 5.76
3
6 H, OCH3), 5.12 (td, 3J ϭ 17.3, 2J ϭ 1.5, 4J ϭ 1.5 Hz, 1 H, H11b), (ddd, J ϭ 17.2, J ϭ 10.6, J ϭ 5.8 Hz, 1 H, H10), 6.83 (d, J ϭ
3
3
3
3
3
3
2
5.18 (td, J ϭ 10.6, J ϭ 1.4, J ϭ 1.4 Hz, 1 H, H11a), 5.93 (ddd, 8.1 Hz, 0.6 H, H3ЈЈ, H5ЈЈ), 7.07 (d, 3J ϭ 8.0 Hz, 1.4 H, H3ЈЈ, H5ЈЈ),
3J ϭ 17.2, 3J ϭ 10.6, 3J ϭ 6.4 Hz, 1 H, H10), 6.57 (t, 4J ϭ 1.8 Hz, 7.17 (d, 3J ϭ 4.3 Hz, 0.3 H, H3Ј), 7.33 (d, 3J ϭ 8.4 Hz, 0.6 H, H2ЈЈ,
1 H, H4ЈЈ), 6.95 (d, J ϭ 2.2 Hz, 2 H, H2ЈЈ), 7.48 (d, J ϭ 4.4 Hz, H6ЈЈ), 7.39Ϫ7.46 (m, 2.4 H, H2ЈЈ, H3Ј, H6ЈЈ, H7Ј), 7.55Ϫ7.64 (m,
1 H, H3Ј), 7.55Ϫ7.66 (m, 1 H, H6Ј), 7.67Ϫ7.77 (m, 1 H, H7Ј), 7.90 1 H, H6Ј), 7.68Ϫ7.77 (m, 0.7 H, H7Ј), 7.98 (d, 3J ϭ 8.4 Hz, 0.3 H,
4
3
3
4
3
3
4
(br. s, 1 H, NH), 8.13 (dd, J ϭ 8.4, J ϭ 1.0 Hz, 1 H, H8Ј), 8.47 H8Ј), 8.04 (d, J ϭ 8.5 Hz, 0.7 H, H8Ј), 8.10 (dd, J ϭ 8.5, J ϭ
(d, J ϭ 8.0 Hz, 1 H, H5Ј), 8.87 (d, J ϭ 4.7 Hz, 1 H, H2Ј) ppm. 0.9 Hz, 0.7 H, H5Ј), 8.41 (d, 3J ϭ 8.4 Hz, 0.3 H, H5Ј), 8.71 (d,
3
3
3
MS (EI, 70 eV): m/z (%) ϭ 165.2 (100) [3,5-dimethoxybenzoyl],
457.2 (45) [M]. C28H31N3O3 (457.6)·H2O: calcd. C 70.71, H 6.99,
N 8.84; found C 70.30, H 6.94, N 8.76.
3J ϭ 4.6 Hz, 0.7 H, H2Ј), 8.74 (d, J ϭ 4.2 Hz, 0.3 H, H2Ј) ppm.
1H NMR (400 MHz, C2D2Cl4, 110 °C): δ ϭ 0.77Ϫ0.92 (m, 1 H,
Hb7), 1.12Ϫ1.23 (m, 1 H, Ha7), 1.37Ϫ1.64 (m, 3 H, H4, H5),
2.15Ϫ2.31 (m, 1 H, H3), 2.24 (s, 3 H, CH3), 2.43Ϫ2.57 (m, 1 H,
H2), 2.76Ϫ3.12 (m, 4 H, H2, H6, H8), 4.75 (br. s, 1 H, H9), 4.95
N-(9-Deoxyepicinchonine-9-yl)-3,5-dinitrobenzamide (26): As the
acid chloride is almost insoluble in CH2Cl2, CHCl3 was used for
this batch. 16 (500 mg, 1.70 mmol), CHCl3 (9 mL), NEt3 (3.5 mL)
and 3,5-dinitrobenzoyl chloride (575 mg, 2.49 mmol), CHCl3
(20 mL). Purification via the hydrochloride as described for 25, but
precipitation was done with Et2O instead of acetone. Yellow-brown
solid (190 mg, 23%), m.p. 196Ϫ199 °C. [α]D ϭ 236 (c ϭ 0.51,
CHCl3). IR (KBr): ν˜ ϭ 3320 (NϪH), 1660, 1640, 1540 cmϪ1 (am-
3
3
2
3
(td, J ϭ 17.4, J ϭ 1.5, J ϭ 1.5 Hz, 1 H, H11b), 5.12 (td, J ϭ
10.6, 2J ϭ 1.4, 4J ϭ 1.4 Hz, 1 H, H11a), 5.76 (ddd, 3J ϭ 17.3, 3J ϭ
10.7, 3J ϭ 5.9 Hz, 1 H, H10), 6.92 (d, 3J ϭ 7.9 Hz, 2 H, H3ЈЈ,
3
H5ЈЈ), 7.21Ϫ7.38 (m, 1 H, H3Ј), 7.33 (d, J ϭ 8.3 Hz, 2 H, H2ЈЈ,
H6ЈЈ), 7.43Ϫ7.54 (m, 1 H, H6Ј), 7.57Ϫ7.68 (m, 1 H, H7Ј), 8.03 (d,
4
3J ϭ 8.4, J ϭ 0.3 Hz, 1 H, H8Ј), 8.06Ϫ8.20 (m, 1 H, H5Ј), 8.68
3
(d, J ϭ 4.5 Hz, 1 H, H2Ј) ppm. MS (EI, 70 eV): m/z (%) ϭ 136.3
(100) [quinuclidine], 447.1 (17) [M]. C26H29N3O2S (447.6): calcd. C
69.77, H 6.53, N 9.39; found C 69.20, H 6.92, N 9.32.
1
ide). H NMR (250 MHz, CDCl3): δ ϭ 0.77Ϫ0.97 (m, 1 H, Hb7),
0.97Ϫ1.76 (m, 4 H, H4, H5, Ha7), 2.27Ϫ2.42 (m, 1 H, H3),
2.73Ϫ3.28 (m, 5 H, H2, H6, H8), 5.14 (td, 3J ϭ 17.2, 2J ϭ 1.5,
4J ϭ 1.5 Hz, 1 H, H11b), 5.21 (td, 3J ϭ 10.5, 2J ϭ 1.4, 4J ϭ 1.4 Hz,
N-(9-Deoxyepicinchonine-9-yl)-3,5-di-tert-butylbenzenesulfonamide
(39): 16 (650 mg, 2.22 mmol), 3,5-di-tert-butylbenzenesulfonyl
chloride (962 mg, 3.33 mmol) and K2CO3 (360 mg, 2.60 mmol) in
CH2Cl2 (20 mL) were stirred at room temp. for 10 h. The reaction
mixture was diluted with CH2Cl2 and K2CO3 was filtered off. The
organic layer was washed 3 ϫ with saturated Na2CO3 solution. The
crude product was chromatographed on SiO2 with MeOH. Color-
less solid (340 mg, 28%), m.p. 95Ϫ98 °C. [α]D ϭ 57 (c ϭ 0.55,
CHCl3). IR (KBr): ν˜ ϭ 3420 (NϪH), 1370, 1335, 1170 cmϪ1 (sul-
fonamide). 1H NMR (250 MHz, CDCl3): δ ϭ 0.65Ϫ0.88 (m, 1.7
H, Ha7, Hb7), 0.94Ϫ1.01 (m, 0.3 H, Ha7), 1.04Ϫ1.66 (m, 3 H, H4,
H5), 1.3 (s, 18 H, CH3), 2.11Ϫ2.34 (m, 1 H, H3), 2.58Ϫ2.78 (m, 4.7
H, H2, H6, H8), 3.13Ϫ3.34 (m, 0.3 H, H8), 4.12 (d, 3J ϭ 10.7 Hz, 1
H, H11b), 4.75Ϫ4.92 (m, 2 H, H9, H11b), 5.00Ϫ5.11 (m, 1 H,
3
3
1 H, H11a), 5.46 (br. s, 1 H, H9), 5.94 (ddd, J ϭ 17.1, J ϭ 10.5,
3J ϭ 6.5 Hz, 1 H, H10), 7.46 (d, 3J ϭ 4.4 Hz, 1 H, H3Ј), 7.61Ϫ7.71
(m, 1 H, H6Ј), 7.71Ϫ7.81 (m, 1 H, H7Ј), 8.14 (dd, J ϭ 8.5, J ϭ
1.2 Hz, 1 H, H8Ј), 8.38 (dd, 3J ϭ 8.4, 4J ϭ 0.8 Hz, 1 H, H5Ј), 8.87
(d, J ϭ 4.4 Hz, 1 H, H2Ј), 8.93 (d, J ϭ 2.1 Hz, 2 H, H2ЈЈ, H6ЈЈ),
9.13 (t, J ϭ 2.1 Hz, 1 H, H4ЈЈ) ppm. MS (EI, 70 eV): m/z (%) ϭ
3
4
3
4
4
136.3 (100) [quinuclidine], 487.1 (14) [M]. C26H25N5O5 (487.5):
calcd. C 64.06, H 5.17, N 14.47; found C 63.74, H 5.60, N 14.40.
N-(9-Deoxyepicinchonine-9-yl)-adamantanecarboxamide (36): 16
(1.07 g, 3.66 mmol), CH2Cl2 (18 mL), NEt3 (7 mL) and 1-adamant-
anecarboxylic acid chloride (884 mg, 4.45 mmol), CH2Cl2 (4 mL).
Colorless solid (910 mg, 55%), m.p. 80Ϫ82 °C. [α]D ϭ 192 (c ϭ
0.51, CHCl3). IR (KBr): ν˜ ϭ 3360 (NϪH), 1650, 1510 cmϪ1 (am-
3
3
3
H11a), 5.71 (ddd, J ϭ 17.3, J ϭ 10.7, J ϭ 5.4 Hz, 1 H, H10),
7.11 (d, 3J ϭ 4.3 Hz, 0.3 H, H3Ј), 7.36Ϫ7.40 (m, 0.3 H, H4ЈЈ),
7.41Ϫ7.53 (m, 3.4 H, H2ЈЈ, H3Ј, H3ЈЈ, H4ЈЈ), 7.53Ϫ7.63 (m, 1 H,
1
ide). H NMR (250 MHz, CDCl3): δ ϭ 0.79Ϫ1.05 (m, 1 H, Hb7),
1.29Ϫ1.91 (m, 19 H, H4, H5, Ha7, adamantane-H), 2.20Ϫ2.39 (m,
1 H, H3), 2.64Ϫ2.81 (m, 1 H, H2), 2.85Ϫ3.08 (m, 4 H, H2, H6,
H8), 5.09 (br. s, 1 H, H9), 5.10 (td, 3J ϭ 17.3, 2J ϭ 1.5, 4J ϭ
3
H6Ј), 7.66Ϫ7.76 (m, 1 H, H7Ј), 8.01 (d, J ϭ 8.5 Hz, 0.3 H, H8Ј),
3
3
4
8.06 (d, J ϭ 8.1 Hz, 0.7 H, H8Ј), 8.08 (dd, J ϭ 8.4, J ϭ 0.8 Hz,
0.7 H, H5Ј), 8.53 (d, 3J ϭ 8.3 Hz, 0.3 H, H5Ј), 8.72 (d, 3J ϭ 4.6 Hz,
0.7 H, H2Ј), 8.74 (d, 3J ϭ 4.5 Hz, 0.3 H, H2Ј) ppm. MS (FD,
CH2Cl2): m/z (%) ϭ 545.6 (100) [M]. C33H43N3O2S (545.8): calcd.
C 72.62, H 7.94, N 7.70; found C 72.20, H 8.00, N 7.44.
3
2
4
1.5 Hz, 1 H, H11b), 5.16 (td, J ϭ 10.6, J ϭ 1.5, J ϭ 1.5 Hz, 1
H, H11a), 5.92 (ddd, 3J ϭ 17.1, 3J ϭ 10.4, 3J ϭ 6.6 Hz, 1 H, H10),
7.37 (d, 3J ϭ 4.8 Hz, 1 H, H3Ј), 7.50Ϫ7.61 (m, 1 H, H6Ј),
7.64Ϫ7.74 (m, 1 H, H7Ј), 8.10 (dd, 3J ϭ 8.5, 4J ϭ 1.0 Hz, 1 H,
H8Ј), 8.35 (dd, 3J ϭ 8.7, 4J ϭ 0.8 Hz, 1 H, H5Ј), 8.84 (d, 3J ϭ
N-(9-Deoxyepicinchonine-9-yl)-2,4-dinitrophenylamine (40): 16
4.4 Hz, 1 H, H2Ј) ppm. MS (FD, CH2Cl2): m/z (%) ϭ 455.5 (100) (510 mg, 1.74 mmol) and fluoro-2,4-dinitrobenzene (324 mg,
[M]. C30H37N3O (455.6)·1/3 H2O: calcd. C 78.06, H 8.22, N 9.10;
found C 78.27, H 8.45, N 8.45.
1.74 mmol) were stirred in CH2Cl2 (15 mL) at room temp. for 10 h.
A yellow powder precipitated. The solvent was removed in vacuo
2860
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2854Ϫ2862

α-Amino Acid Derivatives by Enantioselective Decarboxylation
FULL PAPER
and the residue was recrystallized from Et2O. Intensely yellow pow-
der (400 mg, 50%). m.p. 200Ϫ202 °C. [α]D ϭ 652 (c ϭ 0.51,
CHCl3). IR (KBr): ν˜ ϭ 3440, 3280 cmϪ1 (NϪH). 1H NMR
porated. The slightly brown powder was washed with MeOH and
recrystallized from Et2O. Colorless solid (300 mg, 39%), m.p.
180Ϫ182 °C. [α]D ϭ 40 (c ϭ 0.54, CHCl3). IR (KBr): ν˜ ϭ 1370,
(300 MHz, CDCl3): δ ϭ 0.87Ϫ1.08 (m, 1 H, Hb7), 1.34Ϫ1.79 (m, 1360, 1190 cmϪ1 (SϭO). 1H NMR (300 MHz, CDCl3): δ ϭ 1.07
4 H, H4, H5, Ha7), 2.28Ϫ2.45 (m, 1 H, H3), 2.65Ϫ2.84 (m, 1 H,
(s, 18 H, CH3), 1.79Ϫ2.01 (m, 5 H, H4, H5, Ha7, Hb7), 2.19Ϫ2.33
2
H2), 2.95Ϫ3.22 (m, 4 H, H2, H6, H8), 5.13 (td, 3J ϭ 17.3, J ϭ (m, 1 H, H3), 2.54Ϫ3.40 (m, 5 H, H2, H6, H8), 5.06Ϫ5.17 (m, 2
4
3
3
3
1.5, J ϭ 1.5 Hz, 1 H, H11b), 5.21 (br. td, 1 H, H 11a), 5.94 (ddd,
H, H11a, H11b), 5.98 (ddd, J ϭ 16.5, J ϭ 10.8, J ϭ 7.6 Hz, 1
3
3
3J ϭ 17.2, J ϭ 8.8, J ϭ 6.3 Hz, 1 H, 1 H, H10), 6.26 (br. s, 1 H,
H, H10), 7.14 (m, 1 H, H3Ј), 7.32 (t, 4J ϭ 1.8 Hz, 1 H, H4ЈЈ),
H9), 7.51 (d, 3J ϭ 4.5 Hz, 1 H, H3Ј), 7.65Ϫ7.93 (m, 3 H, H2ЈЈ, 7.35Ϫ7.42 (m, 2 H, H2ЈЈ), 7.50Ϫ7.58 (m, 1 H, H6Ј), 7.61Ϫ7.69 (m,
H6Ј, H7Ј), 7.85 (d, J ϭ 8.8 Hz, 1 H, H5ЈЈ), 8.23 (d, J ϭ 7.8 Hz,
1 H, H8Ј), 8.33 (dd, J ϭ 8.6, J ϭ 0.6, 1 H, H5Ј), 8.90 (d, J ϭ 4.5 Hz, 1 H, H2Ј) ppm. MS (DCI, NH3): m/z (%) ϭ 279.6 (100)
4.4 Hz, 1 H, H2Ј), 9.09 (d, J ϭ 2.7 Hz, 1 H, H3ЈЈ), 9.84 (br. s, 1 [cinchonine Ϫ OH], 547.4 (12) [MH]. C33H42N2O3S (546.8): calcd.
3
3
1 H, H7Ј), 7.99 (dd, 3J ϭ 8.5, 4J ϭ 0.9 Hz, 1 H, H5Ј), 8.61 (d, 3J ϭ
3
4
3
4
H, NH) ppm. MS (EI, 70 eV): m/z (%) ϭ 136.1 (100) [quinuclidine], C 72.49, H 7.74, N 5.12; found C 72.25, H 7.59, N 5.17.
459.1 (30) [M]. C25H25N5O4 (459.5): calcd. C 65.35, H 5.48, N
15.24; found C 65.02, H 5.49, N 14.99.
Enantioselective Decarboxylation of 1؊5 (Standard Procedure): The
substrates 1Ϫ5 (0.74 mmol) were stirred with 10 mol % optically
active base in abs. THF (9 mL) under nitrogen for 24 h at 70 °C.
Conversion was monitored with TLC (SiO2 plates) using EtOAc as
eluent. Compounds 1Ϫ10 were made visible heating with molybda-
tophosphoric acid.
N-(9-Deoxyepicinchonine-9-yl)-NЈ-phenylurea (42): 16 (276 mg,
0.94 mmol) was heated to 60 °C with phenylisocyanate (10 mL,
91.5 mmol) for 10 min. After further 15 min at room temp. the pre-
cipitate was collected, washed with PE 40/60 and recrystallized
from Et2O. Colorless solid (180 mg, 46%), m.p. 217Ϫ218 °C. [α]D ϭ
193 (c ϭ 0.29, CHCl3). IR (KBr): ν˜ ϭ 3280 (NϪH), 1690, 1510
The solvent was removed at room temp. and the residue was dis-
solved in EtOAc (25 mL). 2  HCl (15 mL) was added in order to
remove the base as the hydrochloride. After extraction with EtOAc
(3ϫ25 mL), the organic layer was dried with Na2SO4 and the sol-
vents evaporated at room temp.
1
cmϪ1 (amide). H NMR (250 MHz, CDCl3): δ ϭ 0.80Ϫ0.97 (m, 1
H, Hb7), 1.15Ϫ1.68 (m, 4 H, H4, H5, Ha7), 2.19Ϫ2.36 (m, 1 H,
2
H3), 2.77Ϫ3.06 (m, 5 H, H2, H6, H8), 5.10 (td, 3J ϭ 14.7, J ϭ
4
3
2
4
1.5, J ϭ 1.5 Hz, 1 H, H11b), 5.15 (td, J ϭ 14.7, J ϭ 1.5, J ϭ
1.5 Hz, 1 H, H11a), 5.30 (br. d, 1 H, H9), 5.89 (ddd, 3J ϭ 17.1, 3J ϭ
10.5, 3J ϭ 6.6 Hz, 1 H, H10), 6.28 (br. s, 1 H, RNH), 6.90Ϫ7.04 (m,
1 H, PhNH), 7.13Ϫ7.32 (m, 5 H, Ph-H), 7.47 (d, 3J ϭ 4.6 Hz, 1
H, H3Ј), 7.54Ϫ7.66 (m, 1 H, H6Ј), 7.67Ϫ7.77 (m, 1 H, H7Ј), 8.14
(dd, 3J ϭ 8.4, 4J ϭ 1.1 Hz, 1 H, H8Ј), 8.40 (dd, 3J ϭ 8.6, 4J ϭ
1H NMR conversion control in [D6]DMSO: The singlet of the ace-
tyl group of the starting material was compared to that of the prod-
uct, for 1/6: δ ϭ 1.86/1.82 ppm, 2/7: 1.89/1.86 ppm, 3/8: 1.92/
1.78 ppm, 4/9: 1.86/1.81 ppm, 5/10: 2.08/1.85 ppm.
GC conditions: Samples with incomplete conversion have to be
chromatographed on SiO2 with EtOAc in order to remove the start-
ing material. For 6, 9 and 10: Column Restek Rt-β DEX cst (30 m
length, 0.32 mm i.d.), injector temp. 260 °C, detector temp. 260 °C
(flame ionisation); ethyl N-acetylalaninate (6): column temp. 115 °C,
H2 pressure 0.7 bar, retention times for enantiomers / 10.9/
11.7 min; N-acetylalanine (9): column temp. 170 °C, H2 pressure
1.4 bar, retention times for enantiomers / 5.6/8.7 min; N-acetylal-
aninenitrile (10) column temp. 170 °C, H2 pressure 0.7 bar, reten-
tion times 6.3/11.8 min.
3
0.9 Hz, 1 H, H5Ј), 8.88 (d, J ϭ 4.6 Hz, 1 H, H2Ј) ppm. MS (EI,
70 eV): m/z (%) ϭ 136.1 (100) [quinuclidine], 412.0 (5) [M].
C26H28N4O (412.5): calcd. C 75.70, H 6.84, N 13.58; found C
75.52, H 6.86, N 13.48.
Cinchonine-9-yl Phenylcarbamate (43):[35] Cinchonine (1.50 g,
5.10 mmol) was heated to 80 °C in phenylisocyanate (10 mL,
91.5 mmol) for 10 h. The excess of phenylisoyanate was removed in
vacuo. The residue was stirred in boiling Et2O, cooled to Ϫ30 °C
and collected. Colorless solid (530 mg, 25%), m.p. 190Ϫ191 °C.
[α]D ϭ 53 (c ϭ 0.54, CHCl3). IR (KBr): ν˜ ϭ 3440 (NϪH), 1730
For ethyl N-acetylvalinate (7): Column MachereyϪNagel Lipodex-E
(50 m length, 0.25 mm i. d.), injector temp. 260 °C, detector temp.
260 °C (flame ionisation); column temp. 125 °C, He pressure 2 bar,
retention times for enantiomers / 25.2/27.0 min.
1
cmϪ1 (amide). H NMR (250 MHz, CDCl3): δ ϭ 1.16Ϫ1.31 (m, 1
H, Hb7), 1.41Ϫ1.97 (m, 4 H, H4, H5, Ha7), 2.20Ϫ2.34 (m, 1 H,
H3), 2.61Ϫ2.90 (m, 2 H, H2, H6), 3.24Ϫ3.41 (m, 1 H, H8), 5.08
(td, 3J ϭ 9.7, 2J ϭ 1.5, 4J ϭ 1.5 Hz, 1 H, H11b), 5.12 (td, 3J ϭ
2
4
3
3
8.9, J ϭ 1.4, J ϭ 1.4 Hz, 1 H, H11a), 6.03 (ddd, J ϭ 17.1, J ϭ
For ethyl N-acetylphenylalaninate (8): Column Chrompack Chirasil-
Val-L (25 m length, 0.25 mm i. d.), injector temp. 260 °C, detector
temp. 260 °C (flame ionisation); column temp. 155 °C, He pressure
1.2 bar, retention times for enantiomers / 12.0/13.6 min.
10.5, 3J ϭ 7.2 Hz, 1 H, H10), 6.57 (d, 3J ϭ 8.0 Hz, 1 H, Ph-H),
6.82 (br. s, 1 H, H9), 7.05 (t, J ϭ 7.2 Hz, 1 H, Ph-H), 7.19Ϫ7.39
3
3
(m, 3 H, Ph-H), 7.44 (d, J ϭ 4.5 Hz, 1 H, H3Ј), 7.54Ϫ7.64 (m, 1
H, H6Ј), 7.66Ϫ7.78 (m, 1 H, H7Ј), 8.13 (dd, 3J ϭ 8.4, 4J ϭ 0.7 Hz,
The assignment optical rotation/configuration is based on enantio-
1 H, H8Ј), 8.25 (d, J ϭ 8.5, 4J ϭ 0.9 Hz, 1 H, H5Ј), 8.89 (d, J ϭ
4.5 Hz, 1 H, H2Ј) ppm. MS (EI, 70 eV): m/z (%) ϭ 136.1 (100)
[quinuclidine], 413.1 (33) [M]. C26H27N3O2 (413.5): calcd. C 75.52,
H 6.58, N 10.16; found C 75.00, H 6.49, N 10.27.
3
3
merically enriched samples of 6,[36] 7,[37] 8[38] and 9.[39]
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2862
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2854Ϫ2862