Efficient asymmetric synthesis of β-amino acid BAY 10-8888/PLD-118, a novel antifungal for the treatment of yeast infections

Article abstract of DOI:10.1055/s-2003-36265

The β-amino acid BAY 10-8888/PLD-118 is currently being investigated in phase II clinical studies as a novel antifungal for the treatment of yeast infections. An efficient asymmetric synthesis of this compound is described. The key step employed a highly enantioselective, quinine-mediated alcoholysis of a mesoanhydride intermediate.

Full text of DOI:10.1055/s-2003-36265

136
PAPER
Efficient Asymmetric Synthesis of -Amino Acid BAY 10-8888/PLD-118,
a Novel Antifungal for the Treatment of Yeast Infections
Synthesis
o
of -Amino A
a
cid BA
Y
c
10-8888/PL
h
D
-118,
a
N
o
i
ve
l
A
n
m
tifungal Mittendorf,*a,b Jordi Benet-Buchholz,c Peter Fey,b Klaus-Helmut Mohrsb
a
Medicinal Chemistry, Business Group Pharma, Bayer AG, 42096 Wuppertal, Germany
b
Chemical Development, Business Group Pharma, Bayer AG, 42096 Wuppertal, Germany
Fax +49(202)365461; E-mail: joachim.mittendorf.jm@bayer-ag
c
BSD-ZA Strukturforschung X-ray, Geb. Q18, Bayer AG, 51368 Leverkusen, Germany
Received 16 September 2002; revised 24 October 2002
Abstract: The -amino acid BAY 10-8888/PLD-118 is currently
being investigated in phase II clinical studies as a novel antifungal
for the treatment of yeast infections. An efficient asymmetric syn-
thesis of this compound is described. The key step employed a high-
ly enantioselective, quinine-mediated alcoholysis of a meso-
anhydride intermediate.
Key words: amino acids, antifungal agents, asymmetric synthesis,
desymmetrization, quinine
Major increases in the incidence of systemic fungal infec-
tions caused by the yeast Candida albicans have been ob-
served during the last two decades, particularly in
immunocompromised patients.1 A critical need exists for
new antifungal agents to treat these life-threatening infec-
tions.2 BAY y 9379 (1) and other 1-aminocyclohexane-2-
carboxylic acids, which were originally designed at Bayer
AG as pyridoxal phosphate suicide inhibitors, turned out
to also have activity against C. albicans3 (Scheme 1). In
addition, the reported antifungal activity of the natural -
amino acid cispentacin 24 prompted us to initiate a deriva-
tization program to identify cyclic -amino acids with su-
perior efficacy and tolerability. Among more than a
thousand derivatives, BAY 10-8888 (3) exhibited the
most favourable activity–tolerability profile and was se-
lected for further development. BAY 10-8888 acts by a
unique dual mode of action.5 It was licensed to PLIVA
d.d. and is currently in phase II clinical studies as PLD-
118.
Scheme 1
enantioselective alcoholysis of meso-anhydride 7,9 fol-
lowed by a subsequent Curtius rearrangement.10 Other
published methods for the enantioselective synthesis of
cyclic -amino acids11 appeared less feasible. This can be
mainly attributed to the exo-methylene group, which
showed a distinct tendency to isomerize under acidic con-
ditions and was potentially unstable under a variety of
other reaction conditions.
The preparation of meso-anydride 7 started from commer-
cially available butanetetracarboxylic acid (4)
(Scheme 2). A four-step sequence involving esterifica-
tion, Dieckmann cyclization, hydrolysis, decarboxylation
and again esterification afforded cyclopentanone diester 5
as a mixture of diastereomers (trans/cis = 5:1) in 75%
yield. A two-step, one-pot sequence consisting of Wittig
methylenation and subsequent ester hydrolysis provided
dicarboxylic acid 6 mainly as the trans-diastereomer
(71% yield, trans/cis >50:1). Conversion of diacid 6 un-
der complete trans–cis isomerization to meso-anhydride 7
was accomplished by treatment with propionic anhydride
at 135 °C. Following a distillative work-up and recrystal-
lization from diisopropyl ether, anhydride 7 was obtained
in 75% yield.
For this purpose, multikilogram quantities of enantiomer-
ically pure BAY 10-8888 (3) were required. The other
stereoisomers showed significantly lower antifungal ac-
tivity. Our initial laboratory synthesis6 of -amino acid 3
did not allow for the preparation of kilogram amounts due
to a lengthy 13 step sequence including reagents undesir-
able for large-scale work, hazardous reaction conditions
and a low yield classical resolution. Here we describe a
shorter and more efficient large-scale asymmetric synthe-
sis of BAY 10-8888 (3).
Encouraged by previously published results7,8 the asym-
metric synthesis of -amino acid 3 centered around the
Several other routes for the construction of 4-methylene-
1,2-cyclopentanedicarboxylate derivatives have been de-
scribed.12 Among these routes, only Binger’s palladium-
catalyzed [3 + 2] cycloaddition12a of methylenecyclopro-
pane to diethyl fumarate offered a valuable alternative for
us and will be considered for further technical scale syn-
thesis. All other routes were regarded as less suitable for
Synthesis 2003, No. 1, Print: 30 12 2002.
Art Id.1437-210X,E;2003,0,01,0136,0140,ftx,en;T09902SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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Synthesis of -Amino Acid BAY 10-8888/PLD-118, a Novel Antifungal
137
Scheme 2 Synthesis of meso-anhydride 7
large-scale work mainly due to low yields and undesirable
reagents in terms of availability or safety.
Following the published conditions8 (3 equiv of MeOH in
toluene, 0.5 equiv quinine at 25 °C), methanolysis of an-
hydride 7 provided the corresponding methyl hemiester
with low enantiomeric excess (max. 35% ee). After inves-
tigating various reaction conditions, it was found that the
enantiomeric excess of the quinine-mediated alcoholysis
of anhydride 7 could be significantly improved by lower-
ing the temperature and by using stoichiometric amounts
of the chiral auxiliary. While screening different alcohols
for the ring-opening step, trans-cinnamyl alcohol (8)
proved to be the best choice with regard to yield, enantio-
meric excess, crystallization properties of products in sub-
sequent steps and ester cleavage conditions. Alcoholysis
of anhydride 7 with cinnamyl alcohol (8) in the presence
of stoichiometric amounts of quinine (9) in toluene at
–15 °C afforded crude hemiester 10 with 85% ee. When
this material was stirred with a small amount of toluene,
approx. 10% of crystalline racemic hemiester rac-10 pre-
cipitated. The filtrate contained cinnamyl ester 10 (84%
yield) with > 97% ee and was used without further purifi-
cation in the next step (Scheme 3). The racemic hemiester
10, as well as the chiral auxiliary 9, could be easily recov-
ered making this process highly efficient and economical.
Recently, Deng and coworkers13 described an enantiose-
lective methanolysis of various cyclic meso-anhydrides
catalyzed by modified bis-cinchona alkaloids. Following
this protocol the anhydride 7 was treated with 5 mol% of
the dihydroquinidine-based (DHQD)2AQN14 and 10
equivalents of cinnamyl alcohol (8) in diethyl ether at r.t.
for 72 h. Extractive work-up and chromatographic separa-
tion of excess 8 afforded hemiester ent-10 in 54% yield
and with 89% ee. As the reaction was still not complete af-
ter 72 h, this method appeared less attractive for a large-
scale production of cinnamyl ester 10.
Scheme 3
reaction of the intermediate isocyanate with cinnamyl al-
cohol (8) gave the protected -amino acid ester 11, which
after cooling precipitated from the reaction mixture in
pure form with >99.5% ee (80% yield). This reaction was
successfully carried out in a controlled manner on a pilot
plant scale to produce 26 kg of protected -amino acid
11.15
In the final step the ester and carbamate protecting groups
of 11 were removed by treatment with palladium acetate
(0.05 mol%)–triphenyl phosphine and morpholine in re-
fluxing ethanol. The crude product 3 crystallized from the
reaction mixture and was further purified by recrystalliza-
tion from aqueous ethanol (Scheme 3). 3-Mercapto-1,2,4-
triazole was added prior to each crystallization to reduce
the Pd-content of the product. -Amino acid 3 was ob-
tained in 85% yield with >99.5% ee and with a Pd-content
of <0.5 ppm. The (1R,2S)- configuration of 3 could be de-
termined by a single crystal X-ray structure determination
using CuK -radiation as X-ray source (Figure 1).16
The next step was a Curtius rearrangement using diphenyl
phosphoryl azide–triethylamine in toluene. Subsequent
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138
J. Mittendorf et al.
PAPER
110 °C. Toluene (5.0 L) was added and the mixture was heated to
reflux for 5 h. During this period H2O (approx. 480 mL) was re-
moved using a Dean–Stark trap. After cooling to 80 °C, EtOH (5.0
L) was added and the mixture was stirred at reflux for 1.5 h. The sol-
vent (approx. 8.0 L) was distilled off until the temperature reached
105 °C. Toluene (6.0 L) was added and the mixture was heated to
reflux for 0.5 h. During this period H2O (approx. 30 mL) was re-
moved. The reaction mixture was cooled to r.t. and washed with
H2O (0.5 L). The H2O layer was extracted with toluene (0.5 L) and
the combined toluene layers were washed with aq Na2CO3 (15%;
3.75 L). The solvent was removed in vacuo and the remaining crude
tetraethyl 1,2,3,4-butanetetracarboxylate was dissolved in MeOH
(3.2 L) in a 20 L reactor. A solution of sodium methylate (30%) in
MeOH (5.19 kg, 28.8 mol) was added at r.t. over a period of 15 min.
After stirring at r.t. for 1 h, aq HCl (50%; 5.95 L) was added where-
by the temperature raised to 57 °C. After addition of concd aq HCl
(1.6 L) the reaction mixture was heated to reflux and the solvent
(approx. 12.4 L) was distilled off until the temperature reached
100 °C. The mixture was stirred at 100 °C for 5 h and cooled to r.t.
Toluene (7.0 L) was added and the mixture was heated to reflux.
H2O (approx. 4.3 L) was removed using a Dean–Stark trap until the
temperature reached 110 °C (approx. 5.5 h). Toluene (2 L) was re-
moved by distillation and the mixture cooled to 80 °C. EtOH (9.0 L)
was added and the slurry cooled to r.t. Precipitated salts were re-
moved by filtration and washed with EtOH (5 L). The filtrate was
transferred into the 20 L reactor and concd sulfuric acid (626 g) was
added at r.t. The mixture was heated to reflux and solvent (7.5 L)
was distilled off. After stirring for 2 h at reflux further solvent (8.5
L) was removed until the temperature reached 105 °C. Toluene (5.0
L) was added and the mixture was heated to reflux for 2 h. During
this period H2O (approx. 165 mL) was removed using a Dean–Stark
trap. The reaction mixture was cooled to r.t. and washed with H2O
(1 L). The H2O layer was extracted with toluene (0.5 L) and the
combined toluene layers were washed successively with aq Na2CO3
(15%; 3.75 L) and H2O (2.2 L). The solvent was removed in vacuo
and the remaining crude product (2.02 kg) was purified by distilla-
tion using a thin film evaporator (1.4 mbar, bath temp. 178 °C) to
afford diester 5.
Figure 1 Ortep plot of -amino acid 3
In conclusion, we have developed a short and efficient
asymmetric synthesis of the antifungal clinical candidate
BAY 10-8888/PLD-118 (3) in a 23% overall yield, start-
ing from commercially available butanetetracarboxylic
acid (4). The described process was successfully used on
a pilot plant scale.
In recent years, there has been an increasing interest in -
amino acids also for other applications.11,16 Our process
offers an attractive approach for the synthesis of further
conformationally restricted -amino acids.10,17
Mps were determined on a Büchi capillary mp apparatus and are un-
corrected. Optical rotations were determined using a Perkin–Elmer
241 MC polarimeter. 1H and 13C NMR spectra were recorded on a
Bruker WM 250, AM 300 and AV 500C spectrometers in either
CDCl3, DMSO-d6, or D2O solution using TMS (CDCl3, DMSO-d6),
sodium 3-(trimethylsilyl)proponoate (1H NMR in D2O) and 1,4-di-
oxane (13C NMR in D2O) as an internal standard. Microanalyses
were obtained using a Perkin–Elmer 240 element analyser. Mass
spectra were obtained on the following mass spectrometers: elec-
tron ionization (EI) and desorption chemical ionisation (DCI) on a
Finnigan MAT 95; high resolution mass spectra (HRMS) on a
Finnigan MAT 90 under FAB conditions. Chemical purities were
determined by HPLC quantitative and qualitative methods with a
HP 1090 series instrument. Enantiomeric excesses of compounds
10, 11, and 3 were determined by chiral HPLC on HP 1050 and HP
1090 series instruments. All reactions were performed under a pos-
itive atmosphere of argon or nitrogen. The Pd-content of 3 was de-
termined by ICP-MS following wet decomposition at Central
Analytics, Bayer AG, Leverkusen. Reactions were monitored by
analytical TLC using 5 10 cm plates: silica gel 60 F-254, layer
thickness 0.25 mm (E. Merck). All chemicals were purchased from
commercial sources and were used without further purification.
Yield: 1.72 kg (75%); colorless oil; trans–cis, 5: 1 [HPLC, Nucleo-
sil C 8, 250 mm 3 mm, 5 m, detection at 210 nm, 45 °C, flow rate
0.5 mL /min, gradient 100–20% of aq phosphoric acid (0.2%)– 0 –
80% MeCn, tR trans-5, 15.10 min; cis-5, 14.40 min; the cis-config-
uration of the minor diastereomer could be confirmed by compari-
son with material obtained following the procedure of Gais et al.12c].
1H NMR (CDCl3, 250 MHz; cf. lit.18): = 1.21–1.33 (m, 3 H, CH3),
2.42–2.82 (m, 4 H, CH2COCH2), 3.31–3.48 (m, 2 H, CHCH), 4.11–
4.26 (m, 4 H, OCH2).
MS (EI): m/z (%) = 228 (M+, 15), 183 (20), 154 (35), 128 (100), 100
(65), 55 (60).
HRMS: m/z calcd for C11H20NO5 [M + NH4]: 246.1346; found:
246.1341.
4-Methylene-1,2-cyclopentanedicarboxylic Acid (6)
To a solution of methyl(triphenyl)phosphonium bromide (493 g,
1.38 mol) in THF (1.7 L), t-BuOK (151 g, 1.35 mol) was added at
r.t. After stirring for 2 h at r.t., the mixture was cooled to –12 to
–15 °C. Diethyl 4-oxo-1,2-cyclopentanedicarboxylate (5) (274 kg,
1.20 mol) was added dropwise over a period of 1 h, while maintain-
ing the temperature of the reaction mixture at –12 to –15 °C. After
further stirring for 1 h at this temperature, the reaction mixture was
allowed to warm to 10 °C over 1 h. A solution of KOH (168 g, 3.00
mol) in H2O (840 mL) was then added, while keeping the tempera-
ture below 30 °C. The reaction mixture was stirred at r.t. overnight.
THF was evaporated in vacuo, precipitated solids were removed by
filtration and washed with H2O (100 mL). The combined aq solu-
tions were washed with EtOAc (2 1000 mL) and a small amount
Diethyl 4-Oxo-1,2-cyclopentanedicarboxylate (5)
To a solution of 1,2,3,4-butanetetracarboxylic acid (4) (2.34 kg,
10.0 mol) in EtOH (7.5 L) and toluene (5.0 L) in a 20 L reactor,
concd H2SO4 (553 g) was added over a period of 15 min. The mix-
ture was heated to reflux and stirred for 2 h. The solvent (approx.
8.2 L) was removed by distillation until the temperature reached
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Synthesis of -Amino Acid BAY 10-8888/PLD-118, a Novel Antifungal
139
of organic solvent was removed in vacuo. The aq solution was acid-
ified under ice cooling to pH 2.0 with concd hydrochloric acid (ap-
prox. 250 mL). Precipitated product was collected by filtration,
washed with H2O (3 140 mL) and dried in vacuo at 50 °C to afford
diacid 6.
1H NMR (CDCl3, 300 MHz): = 2.58–2.88 (m, 4 H, 3-CH2, 5-
CH2), 3.05–3.25 (m, 2 H, CHCH), 4.71 (d, 2 H, J = 6.4 Hz, OCH2),
4.91–4.97 (m, 2 H, =CH2), 6.23 (dt, 1 H, J = 15.9 Hz, 6.4 Hz,
CH=CHPh), 6.62 (dd, 1 H, J = 15.9 Hz, 1 Hz, CH=CHPh), 7.20–
7.42 (m, 5 H, CHarom.), 11.1 (br s, 1 H, COOH).
Yield: 145 g (71%); colorless crystals; mp 178 °C (lit.19 mp 178–
179 °C);
13C NMR (CDCl3, 125 MHz): = 34.82 (3-CH2), 35.38 (5-CH2),
46.11 (1-CH, 2-CH), 65.40 (OCH2), 107.76 (C=CH2), 122.86
(CH=CHPh), 126.64, 127.98, 128.53 (arom. CH), 134.07
(CH=CHPh), 136.17 (arom. C), 146.98 (C=CH2), 172.95
(COOCH2), 179.92 (COOH).
Trans– cis > 50: 1 [HPLC, Nucleosil C 8, 250 mm 3 mm, 5 m, de-
tection at 210 nm, 45 °C, flow rate 0.5 mL/min, gradient 100–20%
phophoric acid (0.2%) 0–80% MeCN, tR trans-6, 11.80 min; cis-
6, 10.10 min].
MS (DCI/NH3): m/z (%) = 304 (M + NH4, 100), 188 (15), 151 (10).
1H NMR (DMSO-d6, 300 MHz): = 2.34–2.48 (m, 2 H, CH2),
2.49–2.73 (m, 2 H, CH2), 2.92–3.04 (m, 2 H, CHCH), 4.84–4.88 (m,
2 H, =CH2), 12.33 (br s, 2 H, COOH).
Anal. Calcd for C17H18O4 (286.33): C, 71.3; H, 6.3; O, 22.4. Found:
C, 71.5; H, 6.3; O, 22.5.
(2E)-3-Phenyl-2-propenyl (1R,2S)-4-Methylene-2-{[(2E)-3-phe-
nyl-2-propenyloxycarbonyl]amino}cyclopentanecarboxylate
(11)
Anal. Calcd for C8H10O4 (170.16): C, 56.5; H, 5.9; O, 37.6. Found:
C, 56.8; H, 5.8; O, 37.8.
To a solution of (1S,2R)-4-methylene-2-[(2E)-3-phenyl-2-prop-
enyloxycarbonyl]cyclopentanecarboxylic acid (10) (53.3 g, 186
mmol) in toluene (370 mL) was added Et3N (26.0 mL, 18.8 g, 186
mmol). Diphenyl azidophosphate (51.2 g, 186 mmol) was added
dropwise at r.t. over a period of 10 min and the mixture was heated
to 90 °C until no further nitrogen escaped (approx. 30 min). (2E)-3-
Phenyl-2-propan-1-ol (8) (30.0 g, 223 mmol) was added and the
mixture was heated at reflux overnight. The reaction mixture was
allowed to cool to r.t., while stirring, and was then cooled to 3 °C
and stirred for 30 min. Precipitated crystals were collected by filtra-
tion, washed with cold toluene (250 mL) and dried in vacuo at 50 °C
to afford title compound 11.
5-Methylenetetrahydrocyclopenta[c]furan-1,3-dione (7)
A mixture of 4-methylene-1,2-cyclopentanedicarboxylic acid (6)
(649 g, 3.81 mol) and propanoic anhydride (1.5 L) was stirred at
135 °C for 8 h. Excess propanoic anhydride and propanoic acid
were removed by thin film evaporation (1 mbar, bath temperature
84 °C). Subsequent distillation using a thin film evaporator (1 mbar,
bath temp. 165 °C) afforded crude anhydride 7 (595 g), which was
dissolved in diisopropyl ether (500 mL) at r.t. The mixture was
cooled to –20 °C and stirred for 30 min at this temperature. The
crystals were collected by filtration, washed with cold diisopropyl
ether (250 mL) and dried in vacuo at r.t. to afford anhydride 7.
Yield: 437 g (75%); colorless crystals; mp 50–52 °C (lit.19 mp 50–
51 °C).
1H NMR (CDCl3, 300 MHz): = 2.70–2.90 (m, 4 H, CH2), 3.48–
3.60 (m, 2 H, CH), 5.02 (s, 2 H, =CH2).
20
Yield: 62.0 g, 80%; colourless crystals; mp 137 °C; [ ]D – 6.6
(c 1.0, CH2Cl2); > 99.5% ee [HPLC, Chiracel OD-H, 250 mm
2
mm, 8 m, detection at 215 nm, 45 °C, flow rate 0.2 mL/min, n-hep-
tane–EtOH (95:5), tR (1R,2S)-11, 7.58 min; (1S,2R)-11, 9.22min].
1H NMR (DMSO-d6, 500 MHz): = 2.35–2.75 (m, 4 H, 3-CH2, 5-
CH2), 3.16 (dd, 1 H, J = 7.3, 7.2 Hz, 1-CH), 4.27 (dd, 1 H, J = 7.2,
7.1 Hz, 2-CH), 4.50, 4.60 (AB of ABX, JAB = 13 Hz, JAX = 5.8 Hz,
2 H, COOCH2), 4.63, 4.69 (AB of ABX, JAB = 13.5 Hz, JAX = 5.8
Hz, 2 H, NHCOOCH2), 4.86–4.93 (m, 2 H, =CH2), 6.20–6.40 (m, 2
H, CH=CHPh), 6.58, 6.62 (2 d, 2 H, J = 16, 16 Hz, CH=CHPh),
7.20–7.54 (m, 11 H, NH, CHarom.).
13C NMR (DMSO-d6, 125 MHz): = 33.19 (5-CH2), 37.71 (3-
CH2), 47.13 (CHCO), 53.38 (CHNH), 64.08, 64.24 (OCH2), 106.89
(C=CH2), 123.87, 124.61 (CH=CHPh), 126.23, 126.33, 127.74,
127.80, 128.54, 128.56 (arom. CH), 131.98, 132.31 (CH=CHPh),
135.96 (arom. C), 147.37 (C=CH2), 155.50 (NHCO), 171.85
(CHCO).
Anal. Calcd for C8H8O3 (152.15): C, 63.2; H, 5.3; O, 31.1. Found:
C, 63.6; H, 5.5; O, 31.6.
(+)-(1S,2R)-4-Methylene-2-[(2E)-3-phenyl-2-propenyloxycar-
bonyl]cyclopentanecarboxylic Acid (10)
A mixture of quinine (9) (960 g, 2.96 mol, contains 8% dihydroqui-
nine) in toluene (12 L) was cooled to –15 °C. 5-Methylenetetrahy-
drocyclopenta[c]furan-1,3-dione (7) (450 g, 2.96 mol) was added
and the mixture stirred for 10 min at –15 °C. Then (2E)-3-phenyl-
2-propan-1-ol (8) (595 g, 4.44 mol) was added and the reaction mix-
ture stirred overnight at –15 °C. The mixture was allowed to warm
to r.t. and washed with aq HCl (1 N; 2 4.5 L) and H2O (4.5 L). The
organic layer was extracted with aq K2CO3 (2%) (22.5 L + 7.5 L).
After washing of the combined aqueous solutions with EtOAc
(2 5 L), toluene (5 L) was added and the mixture was acidified un-
der vigorous stirring to pH 2.0 with aq HCl (10%; approx. 3.4 L).
The aq layer was separated and extracted with toluene (5 L). The
combined toluene solutions were washed with H2O (2 2.5 L) and
evaporated in vacuo at (20 mbar, bath 55 °C). The oily residue (889
g, 85% ee) was stirred with toluene (1.0 L) at r.t. for 1 h. The pre-
cipitated solid was collected by filtration, washed with toluene (300
mL) and dried in vacuo to afford almost racemic 10.
MS (FAB): m/z (%) = 440 (M + Na, 20), 418 (M + H, 15), 307 (5),
154 (30), 117 (100).
Anal. Calcd for C26H27NO4 (417.50): C, 74.8; H, 6.5; N, 3.4; O,
15.3. Found: C, 74.8; H, 6.7; N, 3.4; O, 15.3.
(–)-(1R,2S)-2-Amino-4-methylenecyclopentanecarboxylic Acid
(3)
To a suspension of (2E)-3-phenyl-2-propenyl (1R,2S)-4-methylene-
2-{[(2E)-3-phenyl-2-propenyloxycarbonyl]amino}cyclopentane-
carboxylate (11) (352 g, 843 mmol) in EtOH (970 mL) was added
Ph3P (2.21 g, 8.43 mmol) and the mixture was stirred for 30 min at
r.t., while N2 was bubbled through. Morpholine (147 mL, 147 g,
1.69 mol) was added and the mixture was stirred at r.t. for 10 min,
while N2 was bubbled through. Palladium(II)acetate (95 mg, 42
mmol) was added and the mixture was heated at reflux for 2 h. 3-
Mercapto-1,2,4-triazole (8.50 g, 84.3 mmol) was added, the mixture
heated at reflux for 1 h and then allowed to cool to r.t., while stir-
ring. It was then further cooled to 3 °C and stirred for 30 min. Pre-
Yield: 84.3 g (10%); (1S, 2R)-10–(1R, 2S)-10 = 55: 45; colorless
crystals; mp 101 °C.
The filtrate was evaporated in vacuo to afford (+)-(1S, 2R)-10. The
product was stored as a 35% solution in toluene.
Yield: 714.6 g (84%); slightly yellow oil, which slowly crystallizes
upon standing; mp 50–51 °C; [ ]D20 +6.8 (c 1.0, EtOAc); 97.3% ee
[HPLC, Chiracel OD-H, 250 mm 2 mm, 8 m, detection at 215 nm,
45 °C, flow rate 0.3 mL/min, 97% n-heptane containing TFA (0.2
mL/L)– 3% EtOH, tR (1S,2R)-10, 6.90 min; (1R,2S)-10, 9.10 min].
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J. Mittendorf et al.
PAPER
cipitated crystals were collected by filtration, washed with cold
EtOH (320 mL) and dried in vacuo at 45 °C to afford crude -amino
acid 3 (109 g). The crude product was recrystallized from hot EtOH
(915 mL)–H2O (160 mL) in the presence of 3-mercapto-1,2,4-tria-
zole (3.81 g, 37.7 mmol) to afford -amino acid 3.
(5) Ziegelbauer, K.; Babczinski, P.; Schoenfeld, W. Antimicrob.
Agents Chemother. 1998, 42, 2197.
(6) Mittendorf, J.; Kunisch, F.; Plempel, M. Ger. Offen. DE
4217776 A1, 1993; Chem. Abstr. 1994, 121, 83988.
(7) (a) Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Chem.
Commun. 1985, 1717. (b) Hiratake, J.; Inagaki, M.;
Yamamoto, Y.; Oda, J. J. Chem. Soc., Perkin Trans. 1 1987,
1053.
(8) (a) Aitken, R. A.; Gopal, J.; Hirst, J. A. J. Chem. Soc., Chem.
Commun. 1988, 632. (b) Aitken, R. A.; Gopal, J.
Tetrahedron: Asymmetry 1990, 1, 517.
Yield: 102 g (85%); colourless crystals; mp 219 °C (decomp.);
[ ]D20 – 31.6 (c 1.0, H2O); > 99.5% ee [HPLC, Chiracel OD-H, 250
mm 2 mm, 5 m, detection at 210 nm, 40 °C, flow rate 2 mL/min,
n-heptane–EtOH (9:1) containing camphersulfonic acid (20 g/L), tR
(1R,2S)-3, 13.3 min; (1S,2R)-3, 14.5 min].
1H NMR (D2O, 300 MHz): = 2.41–2.59, 2.64–2.71 (2 m, 4 H, 3-
CH2, 5-CH2), 2.93–3.05 (m, 1 H, 1-CH), 3.72–3.82 (m, 1 H, 2-CH),
4.95–5.08 (m, 2 H, =CH2).
(9) For leading references, see: Spivey, A. C.; Andrews, B. I.
Angew. Chem. Int. Ed. 2001, 40, 3131; Angew. Chem. 2001,
113, 3227.
13C NMR (D2O, 125 MHz): = 34.84 (5-CH2), 37.39 (3-CH2),
47.84 (CHCO), 53.27 (CHNH2), 109.94 (C=CH2), 146.19 (C=CH2),
180.70 (CO).
(10) (a) Mittendorf, J.; Arold, H.; Fey, P.; Matzke, M.; Militzer,
H.-C.; Mohrs, K.-H. Ger. Offen. DE 4400749 A1, 1995;
Chem. Abstr. 1995, 124, 9443. (b) Mittendorf, J. Eur. Pat.
Appl. EP 805145 A1, 1997; Chem. Abstr. 1997, 127,
359100.
(11) (a) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A.
Curr. Med. Chem. 1999, 6, 955. (b) Juaristi, E.; López-
Ruiz, H. Curr. Med. Chem. 1999, 6, 983. (c) Fülöp, F.
Chem. Rev. 2001, 101, 2181.
MS (DCI/NH3): m/z (%) = 159 (M + NH4, 55), 14 (M + H, 100).
ICP-MS: Pd < 0.5 ppm.
Anal. Calcd for C7H11NO2 (141.17): C, 59.6; H, 7.9; N, 9.9; O, 22.7.
Found: C, 59.4; H, 7.7; N, 10.0; O, 23.0.
(12) (a) Binger, P.; Schuchardt, U. Chem. Ber. 1981, 114, 3313.
(b) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1983,
105, 2315. (c) Gais, H.-J.; Buelow, G.; Zatorski, A.; Jentsch,
M.; Maidonis, P.; Hemmerle, H. J. Org. Chem. 1989, 54,
5115. (d) Furuta, K.; Ikeda, N.; Yamamoto, H. Tetrahedron
Lett. 1984, 25, 675. (e) Lu, Y.-W.; Nédélec, J.-Y.; Folest, J.-
C.; Périchon, J. J. Org. Chem. 1990, 55, 2503.
(13) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000,
122, 9542.
(14) (DHQD)2AQN: 1,4-bis(dihydroquinidyl)anthraquinone
(15) Unpublished results.
(16) (a) Seebach, S.; Albert, M.; Arvidsson, P. I.; Rueping, M.;
Schreiber, J. V. Chimia 2001, 55, 345. (b) Gellman, S. H.
Acc. Chem. Res. 1998, 31, 173.
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