Stereocontrolled approach to δ-amino acids by asymmetric hydrogenation of 5-acetylaminopent-4-enoic acid derivatives

Article abstract of DOI:10.1007/s11172-010-0263-4

Asymmetric hydrogenation of the C=C bond in 5-acetylamino-5-phenylpent-4- enoic acid methyl ester or N,N-dimethylamide catalyzed by rhodium complexes with chiral bisphosphine ligands (1 mol.% of the catalyst, 20 atm. of H2, MeOH, 50°C) gives the correspon

Full text of DOI:10.1007/s11172-010-0263-4

Russian Chemical Bulletin, International Edition, Vol. 59, No. 7, pp. 1463—1466, July, 2010
1463
Stereocontrolled approach to δꢀamino acids by asymmetric hydrogenation
of 5ꢀacetylaminopentꢀ4ꢀenoic acid derivatives
E. V. Starodubtseva,a O. V. Turova,a O. M. Antipova,a M. G. Vinogradov,a Zh. R. Sagirova,b
O. R. Malyshev,a and M. I. Struchkovaa
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: ving@ioc.ac.ru
bSamara State University,
1 ul. Akad. Pavlova, 443011 Samara, Russian Federation
Asymmetric hydrogenation of the C=C bond in 5ꢀacetylaminoꢀ5ꢀphenylpentꢀ4ꢀenoic acid
methyl ester or N,Nꢀdimethylamide catalyzed by rhodium complexes with chiral bisphosphine
ligands (1 mol.% of the catalyst, 20 atm. of H2, MeOH, 50 °C) gives the corresponding saturatꢀ
ed derivatives with enantioselectivity up to 40% ee.
Key words: asymmetric hydrogenation, rhodium complexes, bisphosphine chiral ligands,
nonracemic 5ꢀacetylaminoꢀ5ꢀphenylpentanoic acid.
Amino acids and their derivatives are important natuꢀ
ral objects and are widely used in the synthesis of various
pharmacologically active compounds and ligands for
asymmetric catalysis.1—3 Widespread methods for the synꢀ
thesis of chiral amino acids, including asymmetric hydroꢀ
genation of unsaturated precursors intensively developed
in the last years,4—6 in fact are mainly used for obtaining
acids with the amino group in αꢀ or βꢀposition. Amino
acids with more remote amino group, viz., chiral γꢀ and
δꢀamino acids, are significantly less available. It is noteꢀ
worthy that the absolute configuration of one of the simꢀ
plest chiral δꢀamino acids, i.e., levorotating δꢀaminocaꢀ
prylic acid, was unambiguously established7 only in 1965.
As a rule, laborious multiꢀstep schemes involving stoichiꢀ
ometric amounts of inconvenient in handling organomeꢀ
tallic reagents and expensive chiral inductors are required
for the synthesis of chiral γꢀ and δꢀamino acids.8—11 There
are also known separate examples of solving the same probꢀ
lem by asymmetric hydrogenation of the C=N bond in
imino carboxylic acid derivatives with the use of complex
catalytic systems.12
presence of Ac2O and AcOH is the key step in the syntheꢀ
sis of both enamides. Earlier, only simple keto oximes
containing no other functional groups have been used in
this reaction17—21 with just rare exceptions.19,21 In the
present work, reductive Nꢀacetylation, as far as we known,
was for the first time accomplished for oximes with an
ester and amide functional groups, and the earlier undeꢀ
scribed enamide 4 was isolated in the crystalline form as
1
an individual Eꢀisomer. Its twoꢀdimensional H NMR
spectrum (500 MHz, the NOESY procedure) contains an
intensive crossꢀsignal, corresponding to the spatial interꢀ
action of the phenyl protons (δ 7.3) with the protons of the
methylene group (a broad singlet at δ 2.35). At the same
time, the spectrum contains no crossꢀsignal responsible
for the spatial interaction of the phenyl group with the
olefin proton (δ 6.3). Unlike enamide 4, enamide 9 was
not isolated in the isomerically pure form, and it was used
in the asymmetric hydrogenation reaction as a mixture of
Zꢀ and Eꢀisomers (~1 : 2).
Comparison of rhodiumꢀcontaining catalysts and catꢀ
alytic systems Rhꢀ1—Rhꢀ5 (see Scheme 1) in their activity,
as well as enamides 4 and 9 in their reactivity in the hydroꢀ
genation reactions studied (30—50 °C, 20 atm of H2) shows
the absence of serious differences in both cases: the 50—100%
conversion of these substrates in both the polar (MeOH)
and nonpolar (toluene) solvents can be reached within
20—48 h (Table 1). At the same time, the ee value changes
from virtually nonexistent to 40% depending on the strucꢀ
ture of the catalyst and the nature of the solvent.
Earlier, we have studied asymmetric catalytic hydroꢀ
genation of prochiral substrates containing a keto
group.13—16 In the present work, we made an attempt to
use similar approach to the synthesis of chiral δꢀamino
acids starting from available δꢀketo acids. 5ꢀOxoꢀ5ꢀ
phenylpentanoic acid (1) has been chosen as the starting
compound (Scheme 1), which gave rise to two model subꢀ
strates, viz., ωꢀenamides 4 and 9.
Reductive Nꢀacetylation of the corresponding keto
oximes 3 and 8 with finely dispersed iron metal in the
Assignment of the absolute configuration for the preꢀ
dominant enantiomers of 5 and 10 was made based on the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1430—1433, July, 2010.
1066ꢀ5285/10/5907ꢀ1463 © 2010 Springer Science+Business Media, Inc.

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Starodubtseva et al.
Scheme 1
Reagents: i. MeOH, H2SO4; ii. NH2OH•HCl, AcONa, MeOH, H2O; iii. Fe(0), Ac2O, AcOH, PhMe; iv. H2, catalyst*; v. Ac2O;
vi. 33% aq. Me2NH.
*Catalysts: [((S,S)ꢀMeꢀDuPHOS)Rh(COD)]BF4 (Rhꢀ1); [((R,R)ꢀEtꢀDuPHOS)Rh(COD)]OTf (Rhꢀ2);
[((R,R)ꢀMeꢀBPE)Rh(COD)]OTf (Rhꢀ3); [Rh(COD)2]OTf + (R)ꢀSYNPHOS (Rhꢀ4); [Rh(COD)2]OTf + (R)ꢀBINAP (Rhꢀ5).
known data on stereochemistry of asymmetric hydrogeꢀ
nations of the structurally similar enamides in the presꢀ
ence of the same or similar rhodium catalysts with ligands
of the type DuPHOS and ВРE.17—19 The ee values for
nonracemic hydrogenation products 5 and 10 were deterꢀ
1
mined by H NMR in the presence of chiral solvating
shiftꢀreagent 11,22 with the *CH signal of the enantiomer
(+)ꢀ(R)ꢀ10, which forms a solvate diastereomeric comꢀ
plex with reagent 11, being shifted to the high field (Fig. 1).
Table 1. Asymmetric hydrogenation of enamides 4 and 9a
Entry Cataꢀ
lyst
Solꢀ
vent
Т
τ
Converꢀ Proꢀ
eec
(%)
/°C /h sionb (%) duct
Hydrogenation 4
1
2
3
4
5
6
7
Rhꢀ1
Rhꢀ1
Rhꢀ1
Rhꢀ4
Rhꢀ4
Rhꢀ4
Rhꢀ5
MeOH
MeOH
30 45
50 20
100
90
(–)ꢀ5 14 (S)
(–)ꢀ5 18 (S)
(–)ꢀ5 20 (S)
(+)ꢀ5 36 (R)
(+)ꢀ5 21 (R)
(+)ꢀ5 17 (R)
Toluene 50 30
MeOH 50 30
Toluene 50 30
THF 50 30
Toluene 50 30
100
100
100
100
100
a
b
—
<5aaa
Hydrogenation 9
МеОН 50 20
8
9
10
11
Rhꢀ1
Rhꢀ1
Rhꢀ2
Rhꢀ3
80 (–)ꢀ10 42 (S)
90 (–)ꢀ10 40 (S)
50 (+)ꢀ10 25 (R)
60 (+)ꢀ10 38 (R)
МеОН
МеОН
МеОН
50 45
30 20
50 45
a р(H2) = 20 atm, [substrate] = 0.1 mol L–1 in entries 1—3, 8—11
and 0.2 mol L–1 in entries 4—7; [substrate]/[catalyst] = 100/1.
b According to the 1H NMR data.
c The ee values were determined by 1H NMR in the presence of
a chiral solvating shiftꢀreagent 11.
5.2
5.0
4.8
δ
5.2
5.0
4.8
δ
Fig. 1. A fragment of the 1H NMR spectrum (500 MHz, CDCl3)
of racemic Nꢀacetylꢀδꢀamino ester 5 (*CH) in the absence of the
shiftꢀreagent (a) and in the presence of chiral solvating shiftꢀ
reagent (R)ꢀ11 (0.5 equiv.) (b).

Scalemic δꢀamino acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1465
OH). 13C NMR (CDCl3), δ: 21.54 (C(O)CH2CH2); 25.25
(C(O)CH2); 33.58 (C(O)CH2CH2CH2); 51.47 (Me); 126.21
(mꢀC, Ph); 128.25 and 128.59 (oꢀC, Ph); 129.26 (pꢀC, Ph);
135.36 (C(CNOH)); 158.71 (CNOH); 173.64 (C=O). MS,
m/z: 221 [M]+.
Earlier, shiftꢀreagent 11 has been used for determinaꢀ
tion of enantiomeric composition of Sꢀstereogenic chiral
compounds.23
The results obtained look promising for the improving
enantioselectivity of catalytic hydrogenation of enamides,
precursors of δꢀamino acid derivatives, while further optiꢀ
mization of the process.
Methyl 5ꢀ(Nꢀacetylamino)ꢀ5ꢀphenylpentꢀ4(E)ꢀenoate (4).
Oxime 3 (5.54 g, 25 mmol) was dissolved under Ar in anhydrous
toluene (50 mL) in a twoꢀneck flask equipped with a stirrer and
a reflux condenser. Then, a mixture of Ac2O (7.2 mL, 75 mmol)
and AcOH (4.4 mL, 75 mmol) was added dropwise to the soluꢀ
tion, followed by addition of finely powdered iron metal (2.8 g,
50 mmol) and several drops of Me3SiCl. The reaction mixture
was stirred for 30 h. The color of the reaction solution turned
from colorless to light green, then to reddish brown. After the
reaction was complete (TLC monitoring), the reaction mixture
was filtered through celite, concentrated on a rotary evaporator,
and the residue was passed through a column with neutral alumiꢀ
na (using toluene as an eluent). A precipitate formed after partial
evaporation of toluene was filtered off and washed with toluene to
obtain a white crystalline product (2.1 g, 34%), m.p. 98—100 °C.
Found (%): C, 68.06; H, 7.11; N, 5.66. C14H17NO3. Calculatꢀ
Experimental
The following reactants were used in this work: bis(1,5ꢀ
cyclooctadiene)rhodium(I) triflate ([Rh(COD)2]OTf), (+)ꢀ1,2ꢀ
bis((2R,5R)ꢀdimethylphospholano)ethane(cyclooctadiene)rhoꢀ
dium triflate ([((R,R)ꢀMeꢀBPE)Rh(COD)]OTf) (Acros), (R)ꢀ
(+)ꢀ2,2´ꢀbis(diphenylphosphino)ꢀ1,1´ꢀbinaphthyl ((R)ꢀBINAP),
(+)ꢀ1,2ꢀbis((2S,5S)ꢀdimethylphospholano)benzene(cyclooctaꢀ
diene)rhodium tetrafluoroborate ([((S,S)ꢀMeꢀDuPHOS)Rhꢀ
(COD)]BF4), (+)ꢀ1,2ꢀbis((2R,5R)ꢀ2,5ꢀdiethylphospholano)ꢀ
benzene(cyclooctadiene)rhodium triflate ([((R,R)ꢀEtꢀDuꢀ
PHOS)Rh(COD)]OTf), (R)ꢀ(+)ꢀ6,6´ꢀbis(diphenylphosphino)ꢀ
2,2´,3,3´ꢀtetrahydroꢀ5,5´ꢀbiꢀ1,4ꢀbenzodioxine ((R)ꢀSYNPHOS)
(Strem); NH2OH•HCl (99%, Alfa Aesar); Ac2O, AcOH, Fe
(powder, 325 mesh), 5ꢀoxoꢀ5ꢀphenylpentanoic acid, Me3SiCl
(Acros).
1
ed (%): C, 68.00; H, 6.93; N, 5.66. H NMR (CDCl3), δ: 2.02
(s, 3 H, Me); 2.37 (m, 4 H, 2 CH2); 3.63 (s, 3 H, Me); 6.35 (m, 1 H,
CH); 6.71 (br.s, 1 H, NH); 7.35 (m, 5 H, Ph). 13C NMR
(CDCl3), δ: 23.90 (MeC(O)); 24.56 (C(O)CH2CH2); 34.51
(C(O)CH2); 51.56 (Me); 116.84 (CH=); 128.47 (pꢀC, Ph);
128.70 (mꢀC, Ph); 128.72 (oꢀC, Ph); 135.10 (C—CNH); 136.90
(C=CH); 168.73 (NHC(O)); 173.32 (COO). IR, ν/cm–1: 3264
(NH), 1736 (COOMe), 1660 (C=O), 1544 (C=C). MS, m/z:
247 [M]+.
Methanol was dried by reflux over magnesium with subseꢀ
quent distillation in the flow of argon. Toluene was dried by
reflux over sodium in the presence of benzophenone in the flow
of Ar with subsequent distillation.
1
Melting points were determined on a Kofler stage. H and
13C NMR spectra were recorded on a Bruker AMꢀ300 and Brukꢀ
er DRXꢀ500 spectrometers (300.13, 500.13 (1H), 75.47 MHz
(13C)) in CDCl3. Chemical shifts are given relatively to Me4Si.
IR spectra were recorded on a Specord M82 spectrometer in
KBr pellets. Mass spectra were recorded on a Kratos MSꢀ30
instrument (70 eV). Elemental analysis was performed on a Perꢀ
kin—Elmer Series II 2400 apparatus. The signs of angles of optiꢀ
cal rotation for hydrogenation products 5 and 10 (see Table 1)
were determined on a Spectropolyarimetr PUꢀ09 instrument.
Methyl 5ꢀoxoꢀ5ꢀphenylpentanoate (2). The compound was
obtained according to a standard procedure24 by esterification of
acid 1 with methanol. B.p. 146 °C (5 Torr) (Ref. 24: b.p. 137 °C
6ꢀPhenylꢀ3,4ꢀdihydropyranꢀ2ꢀone (6)26. A solution of 5ꢀoxoꢀ
5ꢀphenylpentanoic acid (1) (6.07 g, 31.6 mmol) in Ac2O (37 mL,
391 mmol) was refluxed for 5 h under Ar, then excess of Ac2O
was evaporated and the residue was heated in vacuo for 2 h (the
bath temperature was 160 °C). The compound obtained in 90%
purity was used in subsequent step without additional purificaꢀ
tion. 1H NMR (CDCl3), δ: 2.51 (m, 2 H, CH2CH); 2.68 (m, 2 H,
CH2C(O)); 5.81 (m, 1 H, CH=); 7.36 (m, 3 H, mꢀ and pꢀH, Ph);
7.61 (m, 2 H, oꢀH, Ph).
N,NꢀDimethylꢀ5ꢀoxoꢀ5ꢀphenylpentanamide (7)27. A 33% aq.
dimethylamine (30 mL) was added to lactone 6 (5.3 g,
30.6 mmol) and the mixture was vigorously stirred for 1 h. Then
dimethylamine and water were evaporated and an the oily resiꢀ
due was distilled in vacuo to yield the product (5.09 g, 76%) as an
1
(2 Torr)). H NMR (CDCl3), δ: 2.07 (m, 2 H, C(O)CH2CH2);
2.43 (t, 2 H, C(O)CH2CH2CH2, J = 7.2 Hz); 3.03 (t, 2 H,
C(O)CH2, J = 7.2 Hz); 3.67 (s, 3 H, Me); 7.49 (m, 3 H, Ph);
7.95 (d, 2 H, Ph, J = 7.5 Hz).
1
oil, b.p. 160 °C (5 Torr). H NMR (CDCl3), δ: 2.09 (m, 2 H,
C(O)CH2CH2); 2.45 (m, 2 H, C(O)CH2CH2CH2); 2.95 (s, 3 H,
C(O)N(Me)Me); 3.01 (s, 3 H, C(O)N(Me)Me); 3.11 (m, 2 H,
C(O)CH2); 7.49 (m, 3 H, Ph); 7.98 (m, 2 H, Ph).
Methyl 5ꢀhydroxyiminoꢀ5ꢀphenylpentanoate (3)25. Hydrꢀ
oxylamine hydrate hydrochloride (6.67 g, 96 mmol) and AcONa
(7.87 g, 96 mmol) were placed into a roundꢀbottom flask
equipped with a reflux condenser and a magnetic stirring bar,
followed by addition of MeOH (40 mL) and H2O (20 mL). After
stirring for 0.5 h, keto ester 2 (9.9 g, 48 mmol) was added, the
mixture was refluxed for 5 h and the solvents were evaporated.
Ethyl acetate was added to the residue and the mixture was
washed with saturated aqueous NaHCO3 and brine. The oxime
obtained was crystallized from water. The yield was 8.59 g (81%),
m.p. 49—50 °C. Found (%): C, 65.36; H, 6.93; N, 5.95. C12H15NO3.
Calculated (%): C, 65.14; H, 6.83; N, 6.33. 1H NMR (CDCl3),
δ: 1.70 (m, 2 H, C(O)CH2CH2); 2.32 (t, 2 H, C(O)CH2CH2CH2,
J = 7.3 Hz); 2.73 (t, 2 H, C(O)CH2, J = 7.5 Hz); 3.59 (s, 3 H,
Me); 7.40 (m, 3 H, Ph); 7.66 (m, 2 H, Ph); 11.21 (br.s, 1 H,
N,NꢀDimethylꢀ5ꢀhydroxyiminoꢀ5ꢀphenylpentanamide (8).
A solution of AcONa (3.19 g, 46 mmol) and NH2OH•HCl
(3.73 g, 46 mmol) in a mixture of MeOH (15 mL) and H2O
(5 mL) was mixed with a solution of keto amide 7 (4.92 g,
22.4 mmol) in MeOH (15 mL). Further, the reaction mixture
was stirred under reflux for 6 h. A solid obtained was crystallized
from water to isolate a pure oxime (3.46 g, 66%), m.p. 125—127 °C.
1H NMR (CDCl3), δ: 1.95 (m, 2 H, C(N)CH2CH2); 2.39
(m, 2 H, C(N)CH2CH2CH2); 2.93 (s, 8 H, 2 Me, C(N)CH2);
7.39 (m, 3 H, Ph); 7.68 (m, 2 H, Ph); 8.78 (br.s, 1 H, OH). IR,
ν/cm–1: 3332 (NOH), 1628 (CONMe2). MS, m/z: 234 [M]+.
N,NꢀDimethylꢀ5ꢀacetylaminoꢀ5ꢀphenylpentꢀ4ꢀenamide (9).
A mixture of Ac2O (4 mL, 42 mmol) and AcOH (2.4 mL,

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Starodubtseva et al.
42 mmol) was added dropwise to a solution of oxime 7 (3.3 g,
14 mmol) in anhydrous toluene (40 mL), followed by addition of
a powdered iron metal (1.55 g, 28 mmol) and several drops of
Me3SiCl. The reaction mixture was stirred for 30 h under Ar,
during which the solution gradually changed its color first to
light green, then to reddish brown. The reaction mixture was
filtered through celite, concentrated, and the residue was passed
through a column with neutral Al2O3 (using toluene as an eluꢀ
ent). After evaporation of toluene, the product was isolated (1.8 g,
69%, a mixture of Zꢀ and Eꢀisomers, 1 : 2) as a light yellow oil.
1H NMR (CDCl3), δ: 2.02 and 2.19 (both s, 2 H and 1 H,
MeC(O)); 2.50 (m, 4 H, CH2); 2.87, 2.91, 2.93 and 2.96 (all s,
6 H, Me2N); 5.50 (m, 0.33 H, CH=); 6.36 (m, 0.67 H, CH=);
6.71 (br.s, 0.67 H, NH); 7.37 (m, 5 H, Ph); 9.34 (br.s, 0.33 H,
NH). 13C NMR (CDCl3), δ: 22.90 and 24.06 (CH2CH); 23.49
and 24.47 (MeC(O)); 32.50 and 33.77 (CH2C(O)); 35.37 and
37.19 (Me2N); 118.15 and 121.47 (CH); 127.63 (pꢀC, Ph); 128.39
(mꢀC, Ph); 128.76 (oꢀC, Ph); 133.07 and 134.45 (C—CNH);
136.95 and 137.97 (CCH); 168.53 and 169.29 (C(O)Me); 172.35
and 172.92 (C(O)NMe2).
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Results of experiments are given in Table 1.
Methyl ( )ꢀ5ꢀacetylaminoꢀ5ꢀphenylpentanoate (( )ꢀ5). This
compound was synthesized to monitor the accuracy of
determination of enantiomeric composition of nonracemic
1
compound 5 by H NMR. Racemic product was obtained by
hydrogenation with Pd (1%)ꢀonꢀsibunite at room temperature
1
for 20 h at 20 atm. of H2. H NMR (CDCl3), δ: 1.65 (m, 2 H,
C(O)CH2CH2); 1.84 (m, 2 H, C(O)CH2); 2.01 (s, 3 H, Me);
2.35 (m, 2 H, C(O)CH2CH2CH2); 3.66 (s, 3 H, Me); 4.99
(m, 1 H, NCH); 5.75 (br.s, 1 H, NH); 7.31 (m, 5 H, Ph).
( )ꢀN,NꢀDimethylꢀ5ꢀacetylaminoꢀ5ꢀphenylpentanamide
(( )ꢀ10). This compound was synthesized to monitor the acꢀ
curacy of determination of enantiomeric composition of
1
1
nonracemic compound 10 by H NMR. H NMR (CDCl3), δ:
1.66 (m, 2 H, C(O)CH2CH2); 1.78 (m, 2 H, C(O)CH2); 1.96
(s, 3 H, Me); 2.31 (m, 2 H, C(O)CH2CH2CH2); 2.92 (s, 6 H,
2 Me); 4.93 (m, 1 H, NCH); 6.73 (br.s, 1 H, NH); 7.26
(m, 5 H, Ph).
27. M. Yasuda, N. Ohigashi, I. Shibata, A. Baba, J. Org. Chem.,
1999, 64, 2180.
Received March 30, 2010;
in revised form May 12, 2010