Efficient synthesis of γ-oxo- and γ-hydroxy-α-amino acids

Article abstract of DOI:10.1055/s-1998-2203

The diastereoselective synthesis of anti-γ-oxo-α-aminocarboxylates by aminoalkylation of ketones with in situ generated ternary iminium salts from inexpensive starting materials is described. These compounds are easily transformed diastereoselectively into syn,anti- or anti,anti-γ-hydroxy-α- amino-carboxylates by the use of different reducing agents. The configuration of the products has been determined by NMR. The aminoalkylation of enamines and imines is also reported.

Full text of DOI:10.1055/s-1998-2203

SYNTHESIS
November 1998
1609
Efficient Synthesis of γ-Oxo- and γ-Hydroxy-α-amino Acids
Beatrix Merla, Hans-Joachim Grumbach, Nikolaus Risch*
Universität-GH Paderborn, Fachbereich für Chemie und Chemietechnik, Warburger Str. 100, D-33098 Paderborn, Germany
Fax +49(5251)603245; E-mail: nr@chemie.uni-paderborn.de
Received 13 March 1998; revised 10 April 1998
rived from commercially available ethyl glyoxylate12).
They are diastereoselectively reacted to give the anti-γ−
oxo-α-aminocarboxylates 6 and 7 (Scheme 1).
Abstract: The diastereoselective synthesis of anti-γ−oxo-α-
aminocarboxylates by aminoalkylation of ketones with in situ
generated ternary iminium salts from inexpensive starting materi-
als is described. These compounds are easily transformed diaste-
reoselectively into syn,anti- or anti,anti−γ-hydroxy-α-amino-
carboxylates by the use of different reducing agents. The configu-
ration of the products has been determined by NMR. The ami-
noalkylation of enamines and imines is also reported.
Key words: ternary iminium salts, aminoalkylation, diastereose-
lective reduction, γ-oxo-α-amino acids, γ-hydroxy-α-amino acids
The γ−hydroxy-α-amino acid unit plays an important role
in biologically active products, e.g. nikkomycins or
neopolyoxins,1, 2 theonellamide F,3 scytonemin A,4 and
funebrine.5 The known synthetic approaches to natural
γ−hydroxy-α-amino acid units are distinguished by the
involved formation of special key compounds, such as
substituted isoxazolines,1a–f dihydrooxazine rings,1g tet-
rahydropyrimidines,1h β-alkyl homoallylic alcohols1i or
γ−oxo-α-amino acids.6 Our goal was the development of
a new, inexpensive, and diastereoselective synthetic route
using readily available starting materials to yield γ−hy-
droxy-α-amino acids in a simple manner.
Groß et al.7 described a facile method for the formation of
γ−oxo-α-amino-carboxylates, namely the aminoalkyla-
tion of enamines and ketones with preformed ternary imi-
nium salts derived from methyl glyoxylate. However, no
information about the relative configuration of the result-
ing products and the diastereoselectivity of this type of re-
action has been described.6, 7 Furthermore, this methodol-
ogy was not pursued further, maybe due to the difficult
preparation8 and handling of the described ternary imini-
um salt.
Scheme 1
The iminium salt 3 is generated in situ by an electrophilic
attack of acetyl chloride on the aminal 2. The following
nucleophilic attack of 4 or 5 on the iminium salt 3 yields
the ethyl γ−oxo-α-aminocarboxylates 6 and 7.
The aminoalkylation of cyclohexanone (4) or tetralone (5)
with 3a proceeds with the expected high diastereoselec-
tivity. In comparison, conversion of 3b only leads to one
product in the case of 4, whereas the use of 5 results in an
anti/syn ratio of 3:1. The reaction of the iminium salt 3c
with cyclohexanone 4 produces a mixture of the two dia-
stereoisomers anti-6c and syn-6c in a ratio of 5 to 1. The
assignment of the relative configuration at the stereogenic
centers in 6 and 7 was made by comparison of the cou-
pling constant (JCHN) of the resulting lactones 12a and 13a
with those of analogous compounds.1h The results are
summarized in Table 1.
Our recent investigations10 have shown that imines 813 are
suitable compounds for aminoalkylation with ternary imi-
nium salts. The reaction of 8a and rac-8b with 3a gives 6a
with moderate yield and excellent diastereoselectivity
(Scheme 2).
Recently, we have disclosed that the aminoalkylation of
activated carbonyl compounds like enamines9 or imines10
(derivatives of aldehydes, cyclic or acyclic ketones) with
ternary iminium salts (containing alkyl and aryl groups)
provides the corresponding anti-β-amino ketones in ex-
cellent yields and diastereoselectivities (generally ≥99%
ds) after hydrolysis of the initially formed quaternary imi-
nium salts.9–11 After the simplification of the preparation
and handling of the ternary iminium salts derived from
alkyl glyoxylates, the aminoalkylation of nucleophiles
such as ketones or activated carbonyl compounds, e.g.
enamines or enol silyl ethers, should be an efficient way
to yield the γ−oxo-α-aminocarboxylates with high diaste-
reoselectivity.
Here we describe the in situ generation of the ternary imi-
nium salts 3a–c as glycine cation equivalents from easily
accessible, substituted ethyl glyoxylate aminals 2a–c (de-
The third stereogenic center of the γ−hydroxy-α-amino
acid unit is created by the diastereoselective reduction of
the carbonyl group (Scheme 3).

SYNTHESIS
Papers
1610
Table 1. Diastereoselective Synthesis of γ-Oxo-α-aminocarboxylates
by Aminoalkylation of Ketones with in situ Generated Ternary Imini-
um Salts
Entry Ketone Product
R1
R1
Yield
(%)
Ratioa
anti/syn
1
2
3
4
5
4
4
4
5
5
6a
6b
6c
7a
7b
–(CH2)5–
–(CH2)2–O–(CH2)2– 81
Me Me
–(CH2)5–
–(CH2)2–O–(CH2)2– 84
83
≥99: ≤1
≥99: ≤1
5:1
≥99: ≤1
3:1
79
87
a
The anti/syn ratio was determined from the NMR spectra of the
crude product.
Scheme 2
Scheme 3
Reduction of 6a with sodium borohydride in ethanol at
room temperature produces the trans,cis-γ−hydroxy-α-
aminolactone 12a and the diastereoisomeric cis,cis-γ−
hydroxy-α-aminolactone 12a' in a ratio of 3 to 1. This re-
sult encouraged us to investigate the reduction of 6a and
7a with different reducing agents.3, 6
Table 2. Reduction of Ethyl γ-Oxo-α-aminocarboxylates 6a and 7a
Entry
Substrate Reducing
Agent
Yield
(%)a
Ratiob
(trans,cis/cis,cis)
c
1
2
3
4
5
6
6a
7a
6a
7a
6a
7a
NaBH4c
NaBH4
70
75
51
55
60
65
3:1
1:1
d
Zn(BH4)2d
95:5e
3.7:1e
≤1: ≥99
≤1: ≥99
The reduction of 6a with zinc borohydride in diethyl ether
at room temperature results in the isolation of the anti,an-
ti-γ−hydroxy-α-aminocarboxylate 10a as a crude product
(Scheme 4).14 During the purification on silica gel lacton-
ization to the trans,cis-γ−hydroxy-α-aminolactone 12a
occurs,15 whereas the use of L-Selectride leads to the
cis,cis-lactone 12a' as the single diastereoisomer. The
product results from an equatorial attack of the reducing
agent (Scheme 4).
Zn(BH4)2
L-Selectridef
L-Selectridef
a
Combined yields of both diastereoisomers after column chromato-
graphy.
b
c
d
e
The ratio was determined by 1H NMR spectra of the crude product.
Solvent: EtOH.
Solvent: Et2O.
The ratio was determined by 1H NMR spectra of the crude α-hydro-
xy-γ-aminocarboxylate
Solvent: THF.
f
Using bulky reducing agents like L-Selectride, the reduc-
tion of 7a takes place with high diastereoselectivity (only
the cis,cis-lactone 13a' is isolated). Reduction with sodi-
um borohydride in ethanol at room temperature or zinc
borohydride in diethyl ether at room temperature produc-
es a diastereomeric ratio of the aminolactones 13a/13a' of
1:1 and 3.7:1, respectively. The reaction with zinc boro-
hydride results in the formation of the γ−hydroxy-α-amino-
carboxylic ester 11a, which reacts on silica gel in the
same way as described before. All results are shown in
Table 2.
In summary, two of the three stereogenic centers of the
γ−hydroxy-α-amino acid unit are generated in a highly
stereoselective manner by using a simple one-pot proce-
dure. The third stereogenic center is determined by the re-
ducing agent.
Our method only utilized inexpensive, readily available
starting materials. Furthermore, there are many notable
prospects. Based on the excellent results achieved in the

SYNTHESIS
November 1998
1611
the ketone 4 or 5 was added and the solution heated under reflux for
3 h. The solvent was removed in vacuo and the crude product was
diluted with Et2O or EtOAc and filtered. The white residue was re-
crystallized from EtOAc.
Preparation of the Ethyl anti-γ-Oxo-α-aminocarboxylates 6a
from Imines:
The iminium salt 3a was generated as described above. The solution
of the ternary iminium salt was cooled to –80°C and the imine 8a or
8b (2 mmol)17 added under stirring. Afterwards, the temperature was
allowed to rise to –50°C over 2–3 h. 6 N HCl was added and the
aqueous layer was washed with Et2O several times. The aqueous layer
was basified by addition of sat. NaHCO3 and extracted quickly with
CH2Cl2 (3 × 50 mL). The organic layer was dried (Na2SO4) and the
solvent was removed in vacuo. The residue contained the ethyl anti-
γ-oxo-α-aminocarboxylate 6a and the piperidine amide 9a.
Scheme 4
alkylation of chiral imines derived from 1-phenylethyl-
amine with Michael acceptors,16 we also expect our meth-
od to be suitable for the enantioselective synthesis of
γ−hydroxy-α-amino acids.
Reduction with NaBH4:
The anti-γ-oxo-α-aminocarboxylate hydrochloride 6a or 7a (1 mmol)
was dissolved in EtOH (10 mL), NaBH4 (0.10 g, 2.5 mmol18 was add-
ed and the mixture was stirred for 5 h. Afterwards, 6 N HCl was added
and the mixture was washed with Et2O several times. The aqueous
layer was basified by the addition of NH3 (25% NH3/H2O 1:1). The
product was extracted with CH2Cl2 (3 × 50 mL) and the organic layer
was dried (Na2SO4). The solvent was removed in vacuo and the resi-
due purified by column chromatography (silica gel, CH2Cl2/MeOH
98:2).
Anhyd THF was freshly distilled from potassium under argon.
Zn(BH4)2 was synthesized according to literature procedure.13 Col-
umn chromatography on silica gel was performed with Merck Kiesel-
gel 60 (0.040–0.063 mm). 1H and 13C NMR spectra were recorded on
a Bruker ARX 200 spectrometer, using TMS as internal standard. IR
spectra were recorded on a Nicolet 510 P FT-IR spectrophotometer.
GC/MS data were obtained from a Finnigan MAT Magnum System
240 and MS data from a VG Fisons Autospec. Mps were determined
on a Mettler FP61 apparatus and are uncorrected. Elemental analyses
were performed on a Perkin–Elmer Elemental Analyser. Satisfactory
microanalyses were obtained for the new compounds 2, 6, 7, 12 and
13: C ±0.34, H ±0.28, N ±0.19.
Reduction with Zn(BH4)2:13
To NaBH4 (1.95 g, 50 mol) in anhyd Et2O (50 ml) recently fused
ZnCl2 (3.4 g, 25 mmol) was added. The mixture was stirred overnight
at 0–5°C. After filtration under N2, the clear solution (ca. 0.5 M) was
used immediately. The β-amino ketone 6a or 7a (1 mmol) was dis-
solved in anhyd Et2O (10 mL). A solution of Zn(BH4)2 (2 mmol,
1 mL18) was added. The mixture was stirred at r.t. overnight. After
usual workup, the crude product was identified as the γ-hydroxy-α-
aminocarboxylate 10 or 11 which converted to the lactone 12 or 13
during column chromatography.
Ethyl Glyoxylate Aminals 2; General Procedure:
A solution of 50% ethyl glyoxylate in toluene (18.8 mL, 0.10 mol,
Fluka) in toluene (20 mL) was stirred at 60°C for 1 h. The secondary
amine (0.20 mol) was added slowly (preparation of 2c: dried Me2NH
was discharged into the solution over 3 h). The mixture was stirred for
2 h at this temperature. Afterwards, K2CO3 was added to remove the
water and the mixture was cooled to r.t. After removal of the solvent
in vacuo, the oily crude product was used without further purification.
Reduction with L-Selectride:
To the anti-γ-oxo-α-aminocarboxylate 6a or 7a (1 mmol) in anhyd
THF (10 mL) was added 1 M L-Selectride in hexane (2 mL,18
2 mmol) at –78°C. The solution was stirred at r.t. overnight. EtOH
was added and when the evolution of gas was complete, 2 N NaOH
(1 mL) and 30% H2O2 (2 mL) were poured into the mixture. The or-
ganic layer was extracted with Et2O (3 × 50 mL), dried and evaporat-
ed. The crude product was purified by column chromatography (silica
gel, CH2Cl2/MeOH 98: 2).
Ethyl anti-γ-Oxo-α-aminocarboxylates 6 and 7: General Proce-
dure:
The reactions were conducted under argon. A solution of ethyl glyox-
ylate aminal 2 (2 mmol) in anhyd CH2Cl2 was cooled to 0°C. Acetyl
chloride (0.14 mL, 2 mmol) was added in one portion under stirring
to generate the iminium salt. After stirring the mixture for 1 h at 0°C,
Table 3. Characterization of Compounds 2a–c
Product 1H NMR (CDCl3/TMS)
13C NMR (CDCl3/TMS)
δ
IR
Yield
(%)
δ, J (Hz)
ν (cm–1)
2a
2b
2c
1.33 (t, 3 H, J = 7.1, CH2CH3), 1.40–1.58 [m, 15.15 (q, CH2CH3), 25.53, 26.36 [t, 2975, 2932, 2851, 2805,
10 H, N(CH2)5], 2.42–2.58 (m, 8 H, (CH2)5], 50.54 (t, –CH2–N–CH2–), 60.27 2750, 1741, 1724, 1442,
–CH2–N–CH2–), 3.28 (s, 1 H, –N–CH–N–), (t, CH2CH3), 88.08 (d, –N–CH–N–), 1174, 1159, 1132, 1123,
4.25 (q, 2 H, J = 7.1, CH2CH3) 169.47 (s, CO) 1104, 1029
89
1.31 (t, 3 H, J = 7.1, CH2CH3), 2.48–2.80 (m, 15.07 (q, CH2CH3), 49.75 (t, –CH2–N–C– 2963, 2916, 2854, 1739, 83
8 H, –CH2–N–CH2–), 3.31 (s, 1 H,
–N–CH–N–), 3.66–3.79 (m, 8 H,
H2–), 60.84 (t, CH2CH3), 67.37
(t, –CH2–O–CH2–), 86.91
1453, 1269, 1182, 1155,
1115, 1071, 1029
–CH2–O–CH2–), 4.22 (q, 2 H, J = 7.1, CH2CH3) (d, –N–CH–N–), 168.13 (s, CO)
1.31 (t, 3 H, J = 7.0, CH2CH3), 2.29 [s, 12 H, 15.05 (q, CH2CH3), 41.11 [q, N(CH3)2], 2972, 2925, 2849, 1738, 80
N(CH3)2], 2.43 (s, 1 H, –N–CH–N–), 4.25 (t, 2 60.46 (t, CH2CH3), 87.72 (d, –N–CH–N–), 1450, 1119, 1099, 1029
H, J = 7.0, CH2CH3)
169.09 (s, CO)

SYNTHESIS
Papers
Table 4. Characterization of Compounds 6a–c and 7a,b
1612
Product
1H NMR (CDCl3/TMS)
δ, J (Hz)
13C NMR (CDCl3/TMS)
δ
IR
MS (70 eV)
m/z (%)
mp
(°C)
Yield
(%)
ν (cm-1)
6a
1.22 (t, 3 H, J = 7.1, CH2CH3),
1.26–1.36 (m, 2 H), 1.39–1.95
(m, 4 H), 2.03–2.18 (m, 2 H),
2.29–2.43 (m, 2 H), 2.60–2.64
(m, 1 H), 3.03–3.86 (m, 7 H),
4.09–4.29 (m, 2H, CH3CH2),
11.90 (br. s, 1 H, NH)
13.66 (q, CH2CH3), 21.16, 23.00,
24.91, 26.66, 34.81, 41.65,
47.52, 53.45 [t, N(CH2)5,
(CH2)4], 52.38 (d, COCHCH),
61.62 (t, CH2CH3), 66.43 (d,
COCHCH), 166.56 (s, CO),
209.08 (s, CO)
2632, 2529, 194 [M+– HCl–
2428, 1744, CO2Et] (100),
1713, 1456, 170 (15), 150
1447, 1227, (3), 124 (6), 84
204
83
81
79
1195
(11), 55 (8)
6b
6c
1.20 (t, 3 H, J = 7.1, CH2CH3),
1.29–2.58 [m, 10 H, (CH2)4,
–CH2–N–CH2–], 2.91–3.26 [m,
2 H, (CH2)4], 3.56–4.25 (m, 8 H,
–CH2–O–CH2–, COCHCH,
COCHCH, CH 2CH3), 12.40 (br.
s, 1 H, NH)
14.17 (q, CH2CH3), 25.34, 26.99,
34.01, 42.04, 47.42, 52.12 [t,
(CH2)4, –CH2–N–CH2–], 52.41
(d, COCHCH), 62.37, 64.33 (t,
–CH2–O–CH2–), 66.49 (d,
2945, 2852, 315 [M+ – HCl] 198
1735, 1678, (0.5), 242 (100),
1234, 1194
170 (28), 142
(7), 96 (4), 84
(10)
COCHCH), 66.66 (t, CH2CH3),
166.14 (s, CO), 219.60 (s, CO)
1.28 (t, 3 H, J = 7.1, CH2CH3),
3.95–4.30 (m, 2 H, CH2CH3),
8.71 (br. s, 1 H, NH)a
13.50 (q, CH2CH)3, 24.51, 26.52,
33.73, 41.38 [t, (CH2)4], 39.14
[q, N(CH3)2], 50.61 (d,
2964, 2820,
1742, 1660,
1212, 1196a
–
–
COCHCH), 61.70 (t, CH2CH3),
65.57 (d, COCHCH), 166.33 (s,
CO), 208.45 (s, CO)b
13.76 (q, CH2CH3), 24.02, 26.37,
34.48, 43.00 [t, (CH2)4], 39.14
[q, N(CH3)2], 48.52 (d,
COCHCH), 62.17 (t, CH2CH3),
63.73 (d, COCHCH), 165.75 (s,
CO), 206.33 (s, CO)c
7a
0.88 (t, 3 H, J = 7.1 Hz, CH3CH2),
1.24–1.45 [m, 1 H, N(CH2)5],
1.66–1.78 [m, 3 H, N(CH2)5],
1.96–2.16 [m, 1 H, N(CH2)5],
2.20–2.28 [m, 6 H, N(CH2)5],
2.33–2.38 (m, 1 H, PhCH2CHH),
2.58–2.94 (m, 1 H, PhCH2CHH),
3.08–3.33 (m, 3 H, –CHH–N–
CHH–, PhCHHCH2), 3.59–3.63
(m, 2 H, CHH–N–CHH), 3.82–
4.07 (m, 4 H, CH2CH3,
13.44 (q, CH2CH3), 21.57, 22.89,
23.14, 29.36, 31.41 [t, N(CH2)5,
PhCH2CH2, PhCH2CH2], 47.90,
53.31 (t, –CH2–N–CH2–), 50.19
(d, CHCHN), 61.46 (t, CH2CH3),
67.29 (d, CHCHN), 126.41,
126.92, 128.56, 131.19 (d,
2950, 2840,
1748, 1676, (0.5), 242 (100),
1224, 1196
315 [M+ – HCl]
198
87
170 (28), 142
(7), 96 (4), 84
(10)
CHarom), 133.98, 144.04 (s,
C
arom), 166.10 (s, CO), 196.33
(s, CO)
COCHCH, COCHCH), 7.06–
7.13 (m, 2 H, Ar–H), 7.27–7.34
(m, 1 H, Ar–H), 7.73–7.76 (m, 1
H, Ar–H), 11.72 (br. s, NH)
7b
1.08 (t, 3 H, J = 7.1, CH2CH3),
7.27–7.35 (m, 2 H, Ar–H), 7.51
(d, 1 H, J = 7.6, Ar–H), 7.96 (d, 1
H, J = 7.6, Ar–H), 9.85 (br. s, 1
H, NH)a
13.38 (q, CH2CH3) 29.30, 30.86
(t, PhCH2CH2, PhCH2CH2),
43.09 (t, –CH2–N–CH2–), 49.12
(d, COCHCH), 60.41 (t,
3025, 2869,
2775, 1708,
1595, 1562,
1228a
–
–
84
CH2CH3), 63.33 (t,
–CH2–N–CH2–), 63.85
(t, –CH2–N–CH2–), 66.91 (d,
COCHCH), 126.63, 126.96,
128.82, 131.36 (d, CHarom),
134.21, 144.13 (s, Carom), 166.07
(s, CO), 196.31 (s, CO)b
13.78 (q, CH2CH3), 26.79, 28.04
(t, PhCH2CH2, PhCH2CH2), 43.09
(t, –CH2–N–CH2–), 46.36 (d,
COCHCH), 60.41 (t, CH2CH3),
63.33(t, –CH2–N–CH2–), 63.85(t,
–CH2–N–CH2–), 66.32 (d,
COCHCH), 122.95, 127.78 (d,
C
arom), 133.89, 144.13 (s, Carom),
165.93 (s, CO), 196.31 (s, CO)c
a Both diastereoisomers.
b Major product.
c Minor product.

SYNTHESIS
November 1998
1613
Table 5. Characterization of Compounds 10, 11, 12 and 13
Product
1H NMR (CDCl3/TMS)
δ, J (Hz)
13C NMR (CDCl3/TMs)
δ
IR
MS (70 eV)
m/z (%)
Yield
(%)
ν (cm–1)
10a
–
14.72 (t, CH2CH3), 24.64, 24.77, 26.27,
26.40, 28.47, 35.33 [t, (CH2)4, N(CH2)5],
42.44 (d, CHCHCH), 52.97 (t,
–
–
55
–CH2–N–CH2–), 60.64 (t, CH2CH3),
73.24, 74.78 (d, O–CHCHCH,
N–CHCHCH), 171.47 (s, CO)
11a
1.33 (t, 3 H, J = 7.1, CH2CH3), 1.40–1.78
[m, 8 H, PhCH2CH2), N(CH2)5], 2.25–
3.06 (m, 6 H, PhCH2CH2,
15.13 (q, CH2CH3), 23.43, 24.92, 26.74,
27.16, 28.78 [t, PhCH2CH2, PhCH2CH2,
N(CH2)5], 39.97 (d, CHCHCH), 52.53 (t,
CH2–N–CH2), 60.74 (t, CH2CH3), 71.51
(d, N–CHCHCH), 72.32 (d, O–CHCH),
126.63, 127.43, 127.87, 128.94 (d,
3430, 3931, 317 [M+] (1), 55
2851, 1727, 271 (1), 244
1652, 1535, (100),
227
–CH2–N–CH2–), 3.14 (d, 1 H, J = 7.4,
N–CHCHCH), 4.24 (q, 2 H, J = 7.1,
CH2CH3), 4.87 (d, 1 H, J = 8.1,
1456, 1165a (24), 170 (33),
142 (34), 124
(35), 114 (13),
O–CHCHCH), 7.07–7.65 (m, 4 H, Ar–H)b CHarom), 136.22, 139.28 (s, Carom),
98 (33), 84
171.43 (s, CO)b
(25), 41 (10)a
1.33 (t, 3 H, J = 7.1, CH2CH 3), 1.40–1.78
[m, 8 H, PhCH2CH2, N(CH2)5],
2.25–3.06 (m, 6 H, PhCH2CH2,
15.13 (q, CH2CH3), 23.43, 24.92, 26.74,
27.16, 28.78 [t, PhCH2CH2, PhCH2CH2,
N(CH2)5], 37.34 (d, CHCHCH), 51.65 (t,
–CH2–N–CH2–), 60.74 (t, CH2CH3),
69.43 (d, N–CHCHCH), 127.21, 128.80,
128.95, 130.50 (d, CHarom), 132.50,
–CH2–N–CH2–), 3.29 (d, 1 H, J = 5.6,
N–CHCHCH), 4.24 (q, 2 H, J = 7.1,
CH2CH3), 5.52 (d, 1 H, J = 7.3,
O–CHCHCH), 7.07–7.65 (m, 4 H, Ar–H)c 137.58 (s, Carom), 175.76 (s, CO)c
12a
13a
1.20–2.26 [m, 15 H, (CH2)4, N(CH2)5,
CHCHCH], 2.53–2.88 (m, 4 H,
CH2–N–CH2), 3.28 (d, 1 H, J = 12.1,
N–CHCHCH), 3.70 (td, 1 H, J = 3.9, J =
10.5, O-CHCHCH)
24.27, 24.71, 25.59, 28.90, 30.70 [t,
CH2)4, N(CH2)5], 26.73 (t, CH2
CH2–N–CH2CH2), 45.86 (d, CHCHCH),
51.23 (t, –CH2–N–CH2–), 70.55 (d,
CHCHCH–N), 80.70 (O–CHCHCH),
175.38 (s, CO)
3415, 2935, 224 [M++1] 51
2856, 1781, (100),
179
1635, 1446, (23), 150 (19),
1169, 1126, 124 (52), 110
1115, 997
(13)d
1.22–2.10 [m, 8 H, N(CH2)5,
26.64, 26.61, 26.66, 27.81 [PhCH2CH2,
PhCH2CH2, N(CH2)5], 42.48
(CHHHCH), 51.33 (–CH2–N–CH2–),
71.16 (CHCHCH–N), 78.32 (O–
CHCHCH), 126.36, 128.15, 129.22,
130.48 (d, CHarom), 134.88, 135.69 (s,
3447, 1652, 271 [M+] (4), 52
1635, 1559, 227 (100), 142
1384, 1112, (40), 124 (60),
PhCH2CH2], 2.31–2.42 (m, 1 H,
CHCHCH), 2.58 –2.83 (m, 4 H,
–CH2–N–CH2–), 2.85–3.01 (m, 2 H,
PhCH2CH2), 3.51 (d, 1 H, J = 11.9,
N–CHCHCH), 4.84 (d, 1 H, J = 10.6,
O–CHCHCH), 7.14–7.46 (4 H, Ar–H)
1031
110 (43), 98
(45), 84 (37),
55 (20), 41
(55)
C
arom), 175.42 (s, CO)
12a'
13a'
1.18–1.98 [m, 12 H, (CH2)4, N(CH2)5],
2.36–3.00 (m, 4 H, –CH2–N–CH2–), 3.16
(d, 1 H, J = 7.3, N–CHCHCH), 4.60 (q, 1
H, J = 6.1, OCHCHCH)
21.44, 21.95, 24.65, 25.76, 29.17 [t,
CH2)4, N(CH2)5], 26.73 (t, CH2CH2–N–
CH2CH2), 37.38 (d, CHCCH), 51.86 (t, – 1635, 1450
CH2–N–CH2–), 68.94 (d, CHCHCHN),
77.34 (d, O-CHCHCH), 175.98 (s, CO)
3410, 2932,
2855, 1770,
48
1.22–2.10 [m, 8 H, N(CH2)5,
24.22, 24.45, 25.13, 26.61, 27.14
[PhCH2CH2, PhCH2CH2, N(CH2)5],
37.31 (CHCHCH), 51.64
(–CH2–N–CH2), 69.88 (CHCHCHN),
77.21 (OCHCHCH), 127.19, 127.62,
128.94, 130.48 (d, CHarom), 132.45,
137.52 (s, Carom), 175.35 (s, CO)
3447, 1652, 271 [M+] (4), 65
1635, 1559, 227 (100), 142
1384, 1112, (54), 124 (30),
PhCH2CH2], 2.58–2.83 (m, 7 H,
PhCH2CH2, CH2–N–CH2–, CHCHCH),
3.27 (d, 1 H, J = 5.6, N–CHCHCH), 5.49
(d, 1 H, J = 7.3, O–CHCHCH), 7.14–7.46
(4 H, Ar–H)
1031
110 (53), 98
(45), 84 (37),
55 (20), 41
(55)
a Both diastereoisomers.
b Major product.
c Minor product.
d Determined by GC-MS.
(c) Banks, B. J.; Barrett, A. G. M.; Russell, M. A.; Williams,
D. J. J. Chem. Soc., Chem. Commun. 1983, 873.
(d) Zimmermann, G.; Hass, W.; Faasch, H.; Schmalle, H.; Kö-
nig, W. A. Liebigs Ann. Chem. 1985, 2165.
(e) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1991, 56,
4875.
We would like to thank the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft for supporting this research.
(1) (a) Hass, W.; König, W.A. Liebigs Ann. Chem. 1980, 1615.
(b) Jäger, V.; Grund, H.; Buß, V.; Schwab, W.; Müller, I.; Scho-
he, R.; Franz, R.; Ehrler, R. Bull. Soc. Chim. Belg. 1983, 92,
1039.
(f) Barrett, A. G. M.; Dhanak, D.; Lebold, S. A.; Russell, M. A.
J. Org. Chem. 1991, 56, 1894.

SYNTHESIS
Papers
1614
(g) Melnick, M. J.; Weinreb, M. J. Org. Chem. 1988, 53, 850.
(h) Barluenga, J.; Viado, A. L.; Aguilar, E.; Fustero, S.; Olano,
B. J. Org. Chem. 1993, 58, 5972.
(i) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1990, 55,
5818.
(11) Arend, M.; Risch, N. Synlett 1997, 974.
(12) Münster, P.; Steglich, W. Synthesis 1987, 223.
Roos, E. C.; López, M. C.; Brook, M. A.; Hiemstra, H.;
Speckamp, W. N.; Kaptein, B.; Kamphuis, J.; Schoemaker H. E.
J. Org. Chem. 1993, 58, 3259.
(2) König, W. A.; Hass, W.; Dehler, W; Fiedler, H. P.; Zähner, H.
Liebigs Ann. Chem. 1980, 622.
Dyker, G. Angew. Chem. 1997, 109, 1777; Angew. Chem., Int.
Ed. Engl. 1997, 36, 1700.
(3) Thodo, K.; Hamada, Y.; Shioiri, T. Synlett 1994, 105.
(4) Helms, G. L.; Moore, R. E.; Niemczura, W. P.; Patterson, G. M.
L.; Tomer, K. B.; Gross, M. L. J. Org. Chem. 1988, 53, 1298.
(5) Raffauf, R. F.; Zennie, T. M.; Onan, K. D.; Le Quesne, P. W.
J. Org. Chem. 1984, 49, 2714.
(13) Crabbé, P.; García, G. A.; Ríus, C. J. Chem. Soc., Perkin Trans
1 1973, 810.
(14) Ashby, E. C.; Boone, J. R. J. Org. Chem. 1976, 41, 2890.
(15) Fisher, M. J.; Hehre, W. J.; Kahn, S. D.; Overman L.E. J. Am.
Chem. Soc. 1988, 110, 4625.
(6) Jackson, R. F. W.; Wood, A.; Wythes, M. J. Synlett 1990, 735.
(7) Gloede, J.; Freiberg, J.; Bürger, W; Ollmann, G; Groß, H. Arch.
Pharm. (Weinheim) 1969, 302, 354.
(8) Groß, H.; Freiberg, J. Chem. Ber. 1966, 99, 3260.
Groß, H,; Gloede, J.; Freiberg, J. Liebigs Ann. Chem. 1967, 702,
68.
(9) Risch, N; Arend, M. Angew. Chem. 1994, 106, 2531; Angew.
Chem., Int. Ed. Engl. 1994, 33, 2422.
(10) Arend, M.; Risch, N. Angew. Chem. 1995, 107, 2861; Angew.
Chem., Int. Ed. Engl. 1995, 34, 2639.
(16) d’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetra-
hedron: Asymmetry 1992, 3, 459.
(17) The imines 8a and 8b are prepared by stirring equimolar
amounts of 5, amine and MgSO4 (1 g) in CH2Cl2 overnight. Af-
ter evaporation, the imine was used without further purification.
(18) The hydrochlorides may also be deprotonated with sat.
NaHCO3 before reduction. However, the free bases are quite
unstable. Therefore, the deprotonation with the reducing agent
is useful for a small quantity of the γ-oxo-α-aminocarboxylate
hydrochloride.