Reaction of aspartic acid derivatives with Grignard reagents - Synthesis of γ,γ-disubstituted α- and β-amino-butyrolactones

Article abstract of DOI:10.1016/S0957-4166(00)00344-X

A series of γ,γ-dimethyl and γ,γ-diphenyl substituted α- and β-amino-butyrolactones have been prepared in enantiomerically pure form using L-aspartic acid as a chiral building block. For the final Grignard reaction the difference in chemical reactivity between the carboxyl groups of aspartic acid was increased or inverted by preparing the corresponding semiesters, diesters and anhydrides. The resulting hydroxyacids and hydroxyesters lactonised in most cases during work up. Thus, (2S)-2-ethoxycarbonylamino-succinic acid-4-methylester 1 reacted with methylmagnesium iodide to form (3S)-3-ethoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 2b. Two interesting side products were obtained and were found to result from attack at the C-1 carboxylic acid rather than the C-4 carboxylic ester group leading to (3S)-3-ethoxycarbonylamino-4-oxo-pentanoic acid methylester 3 and (4S)-4-ethoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 5a. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00344-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3827–3836
Reaction of aspartic acid derivatives with Grignard
reagents—synthesis of g,g-disubstituted a- and
b-amino-butyrolactones
Thomas Brinkmann, Alfred Gilg, Andreas Hamm, Hendrik Lu¨sch, Guido Morbach and
Horst C. Uzar*
Institut fu¨r Organische Chemie, Universita¨t–Gesamthochschule Siegen, Adolf-Reichwein-Straße,
D-57068 Siegen, Germany
Received 8 August 2000; accepted 29 August 2000
Abstract
A series of g,g-dimethyl and g,g-diphenyl substituted a- and b-amino-butyrolactones have been
prepared in enantiomerically pure form using L-aspartic acid as a chiral building block. For the final
Grignard reaction the difference in chemical reactivity between the carboxyl groups of aspartic acid was
increased or inverted by preparing the corresponding semiesters, diesters and anhydrides. The resulting
hydroxyacids and hydroxyesters lactonised in most cases during work up. Thus, (2S)-2-ethoxycarbonyl-
amino-succinic acid-4-methylester 1 reacted with methylmagnesium iodide to form (3S)-3-ethoxycarbonyl-
amino-5,5-dimethyl-tetrahydrofuran-2-one 2b. Two interesting side products were obtained and were
found to result from attack at the C-1 carboxylic acid rather than the C-4 carboxylic ester group leading
to (3S)-3-ethoxycarbonylamino-4-oxo-pentanoic acid methylester 3 and (4S)-4-ethoxycarbonylamino-5,5-
dimethyl-tetrahydrofuran-2-one 5a. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Non-proteinogenic a-amino acids are interesting target molecules in their own right due to the
biological and toxicological properties displayed by many of these compounds.1,2 Furthermore,
they are often used as chiral starting materials for the synthesis of natural products and chiral
auxiliaries.3 For example,
the synthesis of substituted
only been rarely explored. A potential preparation starts from the inexpensive
L
-homoserine lactone can be synthesised from
-homoserine lactones, which are a-amino-g-butyrolactones, has
-aspartic acid.
L
-a-amino acids,4 but
L
L
The tert-alcohol function can be introduced by addition of a Grignard reagent. However, one
has to direct the reaction to the 4- rather than to the 1-carboxyl group, which can be achieved
* Corresponding author. Tel: +49-271-740-4244; fax: +49-271-740-2780; e-mail: uzar@chemie.uni-siegen.de
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00344-X

3828
T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
by selective monoesterification of the acid functionality in the 4-position. Having established a
highly efficient route to N-protected aspartic acid semiesters 1,4 we now describe a straightforward
synthesis of substituted -homoserine lactones by their reaction with Grignard reagents.
L
2. Results and discussion
In a first attempt, methyl magnesium iodide was allowed to react with the semiesters 1a–c. At
least a fourfold excess of the methyl Grignard reagent is necessary: two equivalents for the acidic
protons and two more for the addition to the ester group. However, in the course of our attempts
to improve the synthesis, a 10-fold excess proved to be most useful giving the desired lactones
2a–c in moderate yields (14–24%). The reaction of the semiester 2b with a fivefold excess of
phenylmagnesium bromide led to the corresponding diphenyl-substituted product 2d. The free
hydroxyacids could not be isolated because of their tendency to undergo ring closure during work
up (Scheme 1).
Scheme 1.
The lactones 2a–c are derivatives of
L
-g-hydroxyleucines, which represent an important class
of non-proteinogenic amino acids occurring naturally as constituents of the phallotoxines, toxic
compounds from Amanita phalloides, the death cap mushroom.5 N-Protected
-g-hydroxyleucine
L
lactones had formerly been prepared by the photochlorination of leucine6 followed by derivatisation
of the amino group,7 by oxidation of N-benzyloxycarbonyl-leucine-1-methylester with 3,3-
dimethyldioxirane,8 and by Grignard reaction of an N-protected aspartic acid derivative, in which
the 1-carboxy group had been transformed to an orthoester.9 In comparison to the last preparation,
our method involves fewer steps leading to nearly the same yields.
While we tried to optimise the reaction conditions for the synthesis of the ethoxycarbonyl-
amino substituted lactone 2b, we always observed the formation of constant amounts of two minor
by-products, irrespective of the mode of addition, the excess of organometallic reagent, the solvents,
concentrations and the reaction temperatures. Since the main product 2b could be crystallised,
the by-products were accumulated in the mother liquors, which we studied by NMR spectroscopy.
1
A singlet at l 2.21 in the H NMR and a signal at l 205.8 in the 13C NMR pointed to a methyl
ketone. This was temporarily thought to be the presumable intermediate (2S)-2-ethoxycarbonyl-
amino-4-oxo-pentanoic acid, formed after the first Grignard addition to the methylester group.
However, after the compounds had been separated by silica gel chromatography, the structure
1
was unambiguously assigned as the ketoester 3 by an INADEQUATE experiment. The H and
13C NMR spectra of the second by-product closely resembld the ones of the lactone 2b. After
further NMR experiments (C,H long range correlation, NOE) we identified the product as the

T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
3829
regioisomeric inverse lactone 5a, which is a b-amino-g-butyrolactone. In the reaction of the
semiester 2b with phenylmagnesium bromide we found the corresponding by-product, that is the
inverse lactone 5b (Scheme 2).
Scheme 2.
Obviously, the by-products originate from an addition to the less reactive C-1 acid function-
ality which should be even more inactivated by deprotonation to the carboxylate anion.
However, the electron-withdrawing effect of the carbamate group might be counteracting and
favouring the nucleophilic attack at C-1. Examples for the addition of Grignard reagents to the
carboxylic acid group of amino acids can be found in the literature.10 On the other hand, we did
not find any formation of products derived from attack at the carbamate protecting group,
indicating that this is at least sufficiently deactivated during the reaction.
The b-amino-g-butyrolactones 5 could be synthesised by shifting the regioselectivity of the
Grignard addition, which was achieved by employing the aspartic acid anhydride 4 as starting
material. The electron-withdrawing carbamate group activated the C-1 carbon, which was
therefore preferentially attacked. Under optimised conditions we were able to synthesise the
b-amino substituted lactones 5 in 14–17% overall yield. While the dimethyl substituted product
lactonised during work up, the diphenyl substituted hydroxyacid 6 had to be heated to reflux
with a strong acid resin to close the lactone ring (Scheme 3).
Scheme 3.
The same reactivity was found in the reaction of the diester 7. As in the case of the anhydride,
the dimethyl-substituted hydroxyester lactonised during work up giving the lactone 5a, while the
corresponding diphenyl-substituted hydroxyester 8 could be isolated. The diols 9a and 9b which
result from the attack of the Grignard reagent to both carbonyl groups were found as
by-products of the reaction (Schemes 4 and 5).

3830
T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
Scheme 4.
Scheme 5.
The strongly basic reaction conditions necessitate a check of the enantiomeric purity of the
products which might well be lost due to deprotonation of the a-H. Nevertheless, all isolated
products were optically active and the observed molar rotation of the a-amino-g-butyrolac-
tone 2c is in good agreement with literature data.7
3. Conclusion
In the reaction of N-protected aspartic acid semiesters 1 with Grignard reagents moderate
yields of g,g-disubstituted a-amino-g-butyrolactones 2 were obtained. The carboxylic acid
functional group of 1 appeared to be not as inert as expected, giving rise to two minor
by-products, a methyl ketone 3 and the inverse lactone 5a, a product of a subsequent
reaction. It can be reasoned that these unexpected side reactions might be induced by the
activating neighbouring carbamate group. Employing the N-protected aspartic acid anhydride
4 and diester 7, the regioselectivitiy of the reaction could be inverted giving g,g-disubstituted
b-amino-g-butyrolactones 5 in moderate yields. The carbamate N-protecting group was found
to be stable under the reaction conditions, as was the configuration at the C-2 stereogenic
centre.

T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
3831
4. Experimental
4.1. General information
The reactions involving Grignard reagents were carried out under argon in anhydrous solvent.
Silica gel from Merck (0.2–0.5 mm; 0.040–0.063 mm) was used for column and flash chromatog-
raphy, respectively. TLC was performed on Polygram Sil G/UV254 plates (Macherey–Nagel,
40×80 mm; 0.25 mm layer thickness). Melting points were determined on a Bu¨chi 510 apparatus
and are uncorrected. Optical rotations were measured with a Technolab AA 1000 instrument.
1
IR spectra were recorded on a Perkin–Elmer FTIR 1750. H and 13C NMR spectra were
obtained on a Bruker AC 200 spectrometer at 200 and 50 MHz, respectively. Mass spectra were
measured in the EI mode at 70 eV with a Quadrupol-MS (HP59824a) instrument. Combustion
analyses were performed by Beller Mikroanalytisches Laboratorium, Go¨ttingen (Germany).
HRMS were obtained on a Finnigan MAT 8400 instrument with chemical ionisation.
4.2. Starting materials
4.2.1. (2S)-2-Alkoxycarbonylamino-succinic acid-4-methylesters 1
Previously, we have described the preparation of (2S)-2-alkoxycarbonylamino-succinic acid-4-
methylester dicyclohexylammonium salts.4 After selective monoesterification of
-aspartic acid
L
in acidic methanol followed by N-protection, we separated the monoester from the diester by
precipitation of the dicyclohexylammonium salts. The salt (20.0 g, 51.7 mmol methoxy deriva-
tive, 49.9 mmol ethoxy derivative, and 46.7 mmol tert-butoxy derivative) and NaHCO3 (20.0 g)
were then dissolved in water (200 mL). The resulting solutions were adjusted to pH 10 with
NaOH and extracted with diethyl ether (100 mL) to remove the dicyclohexylamine. The aqueous
phases were then acidified with 50% H2SO4 to pH 2.5 and extracted with diethyl ether (3×100
mL). After washing the ethereal phases with water (10 mL) the solvent was removed under
reduced pressure to give the semiesters 1 as thick colourless oils.
1
1a (4.24 g, 20.7 mmol, 40%). H NMR (CDCl3) l 2.84 (dd, J=17.3, 4.7 Hz, 1H), 3.02 (dd,
J=17.3, 4.6 Hz, 1H), 3.67 (s, 6H), 4.52–4.70 (m, 1H), 5.87 (d, J=8.6 Hz, 1H), 9.88 (s, 1H); 13C
NMR (CDCl3) l 36.2, 50.1, 52.1, 52.6, 156.8, 171.5, 174.8.
1
1b (5.91 g, 27.0 mmol, 54%). H NMR (CDCl3) l 1.24 (t, J=7.1 Hz, 3H), 2.85 (dd, J=17.4,
4.8 Hz, 1H), 3.05 (dd, J=17.4, 4.5 Hz, 1H), 3.69 (s, 3H), 4.12 (q, J=7.1 Hz, 2H), 4.55–4.73 (m,
1H), 5.74 (d, J=8.4 Hz, 1H), 7.99 (s, 1H); 13C NMR (CDCl3) l 14.4, 36.3, 50.0, 52.2, 61.6,
156.4, 171.5, 175.1.
1c (9.12 g, 36.9 mmol, 79%). 1H NMR (CDCl3) l 1.41 (s, 9H), 2.81 (dd, J=17.2, 4.9 Hz, 1H),
3.01 (dd, J=17.2, 4.4 Hz, 1H), 3.68 (s, 3H), 4.50–4.68 (m, 1H), 5.61 (d, J=8.6 Hz, 1H), 10.23
(s, 1H); 13C NMR (CDCl3) l 28.2, 36.4, 49.7, 52.1, 80.5, 155.6, 171.6, 175.6.
4.2.2. (2S)-2-Ethoxycarbonylamino-succinic acid anhydride 4
A solution of 88.0 g (429 mmol) of (2S)-2-ethoxycarbonylamino-succinic acid (synthesised
from
L
-aspartic acid according to Vernsten and Moore11) in acetic anhydride (500 mL) was
heated to reflux and stirred for 1 h at room temperature following a procedure of Lutz et al.12
for the preparation of (2S)-2-benzoxycarbonylamino-succinic acid anhydride. After removal of
the solvent under reduced pressure, the crude product crystallised overnight. It was washed with
diethyl ether:hexane (1:1) (2×100 mL), and the crystals were dried in vacuo over KOH to give

3832
T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
44.4 g (237 mmol, 55%) of 4. Mp 73°C; [h]2D0=−3.0 (c 2.6, THF); IR wmax/cm−1 (KBr) 3359, 1871,
1
1801, 1681, 1536, 1302, 1280, 1219, 1081, 1051, 1022, 980, 914; H NMR (CDCl3) l 1.22 (t,
J=7.1 Hz, 3H), 3.00–3.33 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 4.44–4.62 (m, 1H), 5.91 (d, J=7.1
Hz, 1H); 13C NMR (CDCl3) l 14.3, 34.8, 50.8, 62.3, 156.2, 168.1, 170.8.
4.2.3. (2S)-2-Ethoxycarbonylamino-succinic acid dimethylester 7
L
-Aspartic acid (20.0 g, 150 mmol) was dissolved in a mixture of methanol (200 mL),
trimethyl orthoformate (50 mL) and sulfuric acid (10 mL). After 20 h at room temperature the
1
diester was derivatised with ethylchloroformate4 to give 20.6 g (88.5 mmol, 59%) of 7. H NMR
(CDCl3) l 1.08 (t, J=7.1 Hz, 3H), 2.64–2.90 (m, 2H), 3.53 (s, 3H), 3.60 (s, 3H), 3.96 (q, J=7.1
Hz, 2H), 4.38–4.56 (m, 1H), 5.73 (d, J=8.2 Hz, 1H); 13C NMR (CDCl3) l 14.1, 36.1, 49.9, 51.6,
52.3, 60.9, 155.8, 170.9, 171.0.
4.3. Reactions of aspartic acid derivatives with Grignard reagents
4.3.1. Reactions of (2S)-2-alkoxycarbonylamino-succinic acid-4-methylesters 1
4.3.1.1. (3S)-3-Alkoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 2. The Grignard reagent
was prepared from 5.00 g (206 mmol) of magnesium suspended in 25 mL diethyl ether by dropwise
addition within 1 h of 26.3 g (185 mmol) of methyl iodide dissolved in 50 mL diethyl ether. To
complete the reaction, the mixture was heated to reflux and stirred for an additional 0.5 h.
Under vigorous stirring and cooling with an ice bath, the semiester 1 (18.5 mmol; a: 3.80 g; b:
4.06 g; c: 4.58 g) dissolved in 100 mL diethyl ether was then added within 1.5 h to the suspension.
Afterwards, stirring of the mixture was continued for 2 h. The remaining Grignard reagent was
hydrolysed by cautious addition of 50 g ice and 100 mL water, and the aqueous phase was acidified
to pH 2.5 with H2SO4 (50%). The ethereal phase was separated and the aqueous one was extracted
with diethyl ether (3×100 mL). The combined ethereal solutions were washed with 20 mL of water
and dried with MgSO4. The solvent was evaporated under reduced pressure and the residue was
recrystallised from diethyl ether to give white crystals of the lactone 2.
2a (0.554 g, 2.96 mmol, 16%). Mp 112°C; [h]2D0=−36.9 (c 1.0, MeOH); IR wmax/cm−1 (KBr) 3332,
1
2986, 1761, 1721, 1535, 1380, 1258, 1160; H NMR l 1.44 (s, 3H), 1.51 (s, 3H), 2.02 (t, J=12.4
Hz, 1H), 2.63 (dd, J=12.4, 9.0 Hz, 1H), 3.71 (s, 3H), 4.50–4.72 (m, 1H), 5.46 (d, J=5.1 Hz, 1H);
13C NMR l 26.9, 28.9, 42.1, 51.6, 52.5, 82.8, 157.1, 174.4. Anal. calcd for C8H13NO4: C, 51.33;
H, 7.00; N, 7.48; O, 34.19. Found: C, 51.04; H, 7.00.
2b (0.893 g, 4.44 mmol, 24%). Mp 115–116°C [lit. 112–114°C for racemate13]; [h]D20=−33.8 (c
1.0, MeOH); IR wmax/cm−1 (KBr) 3329, 2980, 1760, 1713, 1537, 1377, 1258, 1106; 1H NMR (CDCl3)
l 1.21 (t, J=7.1 Hz, 3H), 1.39 (s, 3H), 1.46 (s, 3H), 1.99 (t, J=12.4 Hz, 1H), 2.57 (dd, J=12.4,
8.9 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 4.45–4.67 (m, 1H), 5.44 (d, J=5.4 Hz, 1H); 13C NMR (CDCl3)
l 14.4, 26.9, 28.9, 42.0, 51.4, 61.4, 82.3, 156.2, 174.4. Anal. calcd for C9H15NO4: C, 53.72; H, 7.51;
N, 6.96; O, 31.80. Found: C, 53.49; H, 7.75.
2c (0.594 g, 2.59 mmol, 14%). Mp 145–146°C [lit. 145°C7]; [h]D20=−24.5 (c 0.99, MeOH) [lit.
−28.0 (c 1, MeOH),7 +13.0 (c 1.0, CHCl3)8]; IR wmax/cm−1 (KBr) 3321, 2981, 1756, 1707, 1529,
1376, 1272, 1158, 1109; 1H NMR (CDCl3) l 1.39 (s, 3H), 1.42 (s, 9H), 1.46 (s, 3H), 1.94 (t, J=12.0
Hz, 1H), 2.61 (dd, J=12.0, 9.3 Hz, 1H), 4.44–4.62 (m, 1H), 5.12 (d, J=4.4 Hz, 1H); 13C NMR
(CDCl3) l 26.8, 28.2, 28.9, 42.4, 51.2, 80.4, 82.3, 155.4, 174.5. Anal. calcd for C11H19NO4: C, 57.63;
H, 8.35; N, 6.11; O, 27.91. Found: C, 57.52; H, 8.25.

T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
3833
The combined mother liquors of different experiments for the synthesis of the ethoxycarbony-
lamino substituted lactone 2b were evaporated under reduced pressure. The residue (600 mg)
was purified under ambient pressure on a silica gel column using a step gradient of diethyl
ether:n-pentane (start 1:1, end 2:1). Three fractions were obtained and evaporated in vacuo to
give 50 mg of the ketoester 3 as a yellowish oil, 40 mg of the lactone 2b as colourless needles
and 40 mg of the inverse lactone 5a as a colourless oil.
(3S)-3-Ethoxycarbonylamino-4-oxo-pentanoic acid methylester 3. 1H NMR (CDCl3) l 1.20 (t,
J=7.1 Hz, 3H), 2.21 (s, 3H), 2.74 (dd, J=17.2, 4.9 Hz, 1H), 2.93 (dd, J=17.2, 4.7 Hz, 1H), 3.62
(s, 3H), 4.09 (q, J=7.1 Hz, 2H), 4.35–4.50 (m, 1H), 5.85 (d, J=8.1 Hz, 1H); 13C NMR (CDCl3)
l 14.2, 26.4, 35.1, 51.7, 56.4, 61.1, 156.0, 171.5, 205.8. HRMS (CI) calcd for C9H15NO5:
217.09502. Found: 217.09555.
Data for 5a: see Section 4.3.2.1.
4.3.1.2. (3S)-3-Ethoxycarbonylamino-5,5-diphenyl-tetrahydrofuran-2-one 2d. Bromobenzene
(70.7 g, 450 mmol) dissolved in 50 mL diethyl ether was added within 15 min to 10.9 g (448
mmol) of magnesium suspended in 60 mL diethyl ether. After refluxing for 30 min the reaction
mixture was transferred into a dropping funnel and added at 0°C within 1 h to a solution of 19.5
g (89.0 mmol) of the semiester 1 in 140 mL diethyl ether. The suspension was refluxed for 3 h,
hydrolysed with 30 mL water and acidified with sulfuric acid (50%) to pH 2.5. The organic layer
was separated and the residual aqueous layer was extracted with diethyl ether (3×30 mL) and
ethyl acetate (4×30 mL). The combined organic phases were washed with water (2×20 mL),
dried over Na2SO4, and the solvent was removed in vacuo to yield 23.9 g of a reddish oil. 5 was
purified by flash chromatography using toluene:ethyl acetate:acetic acid (100:11:0.1; Rf=0.22).
The resulting colourless crystals were washed with diethyl ether and dried in vacuo to give 4.62
g of 2d (14.2 mmol, 16%). Mp 139°C; [h]2D0=+25.7 (c 0.86, CHCl3); IR wmax/cm−1 (KBr) 3351,
1
1793, 1703, 1544, 1450, 1298, 1265, 1228, 1188, 1057, 963, 764, 708; H NMR (CDCl3) l 1.06
(t, J=7.1 Hz, 3H), 2.57 (t, J=12.3 Hz, 1H), 3.44 (dd, J=12.3, 7.9 Hz, 1H), 3.95 (q, J=7.1 Hz,
2H), 4.17–4.35 (m, 1H), 5.20 (d, J=5.7 Hz, 1H), 7.09–7.31 (m, 10H); 13C NMR (CDCl3) l 14.4,
42.6, 51.3, 61.6, 87.3, 125.2, 125.4, 128.0, 128.2, 128.5, 128.8, 141.2, 143.1, 156.1, 173.8; MS (EI),
m/z 193 (16.8), 192 (100.0), 191 (29.8), 165 (10.7), 105 (17.6), 103 (14.0), 90 (17.4), 77 (23.2), 29
(14.9). Anal. calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.30; O, 19.67. Found: C, 70.48; H,
5.88; N, 4.28.
4.3.2. Reactions of (2S)-2-ethoxycarbonylamino-succinic acid anhydride 4
4.3.2.1. (4S)-4-Ethoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 5a. The Grignard reac-
tion was performed as described in Section 4.3.1.2 using a solution of 42.5 g (299 mmol) methyl
iodide in 45 mL of diethyl ether, a suspension of 7.28 g (299 mmol) magnesium in 45 mL diethyl
ether, and a solution of 15.9 g (85.0 mmol) anhydride 4 in 100 mL diethyl ether. After
hydrolysis, extraction and evaporation of the solvent, a black oil was obtained that was purified
by flash chromatography with ethyl acetate:hexane (50:40; Rf=0.45) to give 2.91 g (14.5 mmol,
17%) of the inverse lactone 5a as a colourless oil that crystallised after 2 weeks. Mp 63°C;
[h]2D0=+11.3 (c 4.2, CH3CO2C2H5); IR wmax/cm−1 (KBr) 3359, 2977, 1764, 1709, 1682, 1532, 1259,
1
1123, 1048; H NMR (CDCl3) l 1.13 (t, J=7.1 Hz, 3H), 1.26 (s, 3H), 1.36 (s, 3H), 2.39 (dd,
J=18.1, 5.4 Hz, 1H), 2.89 (dd, J=18.1, 8.4 Hz, 1H), 4.01 (q, J=7.1 Hz, 2H), 4.16–4.30 (m, 1H),
5.71 (d, J=8.9 Hz, 1H); 13C NMR (CDCl3) l 14.3, 21.6, 26.8, 35.2, 54.8, 61.1, 87.2, 156.2, 174.3;

3834
T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
MS (EI), m/z (%) 115 (79.3), 56 (36.6), 43 (100), 42 (25.5), 41 (15.9), 29 (27.7), 28 (13.5), 27
(18.3). Anal. calcd for C9H15NO4: C, 53.72; H, 7.51; N, 6.96; O, 31.80. Found: C, 54.25; H, 7.23;
N, 6.75.
4.3.2.2. (4S)-4-Ethoxycarbonylamino-5,5-diphenyl-tetrahydrofuran-2-one 5b. The Grignard reac-
tion was performed as described in Section 4.3.1.2 using a solution of 10.4 g (66.2 mmol) of
bromobenzene in 20 mL of diethyl ether, a suspension of 1.60 g (65.8 mmol) magnesium in 15
mL diethyl ether, and a solution of 3.74 g (20.0 mmol) anhydride 4 in 80 mL diethyl ether. After
hydrolysis, extraction, and evaporation of the solvent, the yellowish, oily product was allowed
to crystallise overnight. The colourless crystals were filtrated, washed with diethyl ether and
dried in vacuo to give 1.17 g (3.41 mmol, 17%) of (3S)-3-ethoxycarbonylamino-4-hydroxy-4,4-
diphenylbutanoic acid 6. Mp 139°C; [h]2D0=−33.9 (c 3.5, CH3CO2C2H5); IR wmax/cm−1 (KBr)
1
3500–3300, 1726, 1707, 1537, 1448, 1241, 1062; H NMR (acetone-d6) l 1.10 (t, J=7.0 Hz, 3H),
2.46–2.83 (m, 2H), 3.97 (q, J=7.0 Hz, 2H), 5.15–5.33 (m, 1H), 5.64 (s, 1H), 6.34 (d, J=9.1 Hz,
1H), 7.19–7.80 (m, 10H), 10.83 (s, 1H); 13C NMR (acetone-d6) l 15.7, 36.8, 56.9, 61.9, 82.2,
127.3, 127.8, 128.2, 128.4, 129.5, 129.9, 147.3, 147.8, 158.3, 174.2; MS (EI), m/z (%) 208 (17.4),
183 (25.2), 115 (100.0), 105 (38.4), 77 (22.7). Anal. calcd for C19H21NO5: C, 66.46; H, 6.16; N,
4.08; O, 23.30. Found: C, 66.62; H, 5.79; N 3.88.
Lewatit S 100 (1.00 g, strong acidic ion-exchange resin) was added to 1.00 g (2.91 mmol)
(3S)-3-ethoxycarbonylamino-4-hydroxy-4,4-diphenylbutanoic acid 6 dissolved in 60 mL toluene
and heated to reflux for 1 h, the formed water being removed by aceotropic distillation.
Afterwards, the hot suspension was filtered and the solvent was removed under reduced pressure
to a residual volume of 15 mL. Overnight crystallisation gave 0.780 g (2.40 mmol, 82%) of
(4S)-4-ethoxycarbonylamino-5,5-diphenyl-tetrahydrofuran-2-one 5b as colourless crystals. Mp
170°C; [h]2D0=+0.7 (c 4.9, CHCl3); IR wmax/cm−1 (KBr) 3379, 1775, 1713, 1528, 1246, 1207, 1058,
1
976, 703; H NMR (CDCl3) l 0.94 (t, J=7.0 Hz, 3H), 2.43 (dd, J=17.7, 3.7 Hz, 1H), 2.72 (dd,
J=17.7, 7.0 Hz, 1H), 3.84 (q, J=7.0 Hz, 2H), 4.88 (d, J=9.0 Hz, 1H), 5.13–5.31 (m, 1H),
7.09–7.45 (m, 10H); 13C NMR (50 MHz, CDCl3) l 14.4, 36.4, 54.8, 61.3, 92.0, 125.7, 125.8,
128.0, 128.0, 128.4, 128.7, 138.5, 141.1, 155.6, 173.9; MS (EI), m/z (%) 208 (13.8), 183 (22.4), 115
(100.0), 105 (49.5), 77 (42.2), 56 (14.7), 43 (31.2), 29 (44.2). Anal. calcd for C19H19NO4: C, 70.14;
H, 5.89; N, 4.30; O, 19.67. Found: C, 70.17; H, 5.55; N, 4.20.
4.3.3. Reactions of (2S)-2-ethoxycarbonylamino-succinic acid dimethylester 7
4.3.3.1. (4S)-4-Ethoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 5a. The Grignard reac-
tion was performed as described in Section 4.3.1.2 using 19.9 g (140 mmol) methyl iodide
dissolved in 30 mL diethyl ether, a suspension of 3.40 g (140 mmol) magnesium in 20 mL of
diethyl ether, and a solution of 9.30 g (39.9 mmol) of the diester 7 in 60 mL diethyl ether gave
10.1 g of a brown oil. The NMR signals could be fully attributed to the diester 7 (39%) and the
lactone 5a (61%). No efforts were made to purify the product.
For data for 5a: see section Section 4.3.2.1.
4.3.3.2. (3S)-3-Ethoxycarbonylamino-2,4-dimethylhexane-2,4-diol 9a. The Grignard reaction was
performed as described in Section 4.3.1.1 using 15.7 g (111 mmol) methyl iodide dissolved in 15
mL diethyl ether, a suspension of 2.70 g (111 mmol) magnesium in 10 mL diethyl ether, and a
solution of 4.70 g (202 mmol) of the diester 7 in 25 mL diethyl ether. After hydrolysis,

T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
3835
extraction, and evaporation of the solvent, a crude black oil was obtained which was purified by
flash chromatography with ethyl acetate:hexane (50:40; Rf=0.43) to give 0.250 g (1.07 mmol,
1
0.5%) of (3S)-3-ethoxycarbonylamino-2,4-dimethylhexane-2,4-diol 9a. H NMR (CDCl3) l 1.10
(t, J=7.1 Hz, 3H), 1.15 (s, 12H), 1.35 (dd, J=19.5, 3.3 Hz, 1H), 1.80 (dd, J=19.5, 3.3 Hz, 1H),
3.54–3.74 (m, 1H), 4.05 (q, J=7.1 Hz, 2H), 4.45 (s, 2H), 5.38 (d, J=9.5 Hz, 1H); 13C NMR
(CDCl3) l 14.6, 26.3, 29.6, 29.8, 43.0, 56.5, 61.1, 70.4, 73.3, 157.6.
4.3.3.3. (3S)-3-Ethoxycarbonylamino-4-hydroxy-4,4-diphenylbutanoic acid methylester 8. The
Grignard reaction was performed as described in Section 4.3.1.2 using 10.4 g (66.2 mmol)
bromobenzene dissolved in 20 mL diethyl ether, a suspension of 1.60 g (65.8 mmol) of
magnesium in 15 mL diethyl ether, and a solution of 4.70 g (20.2 mmol) diester 7 in 80 mL
diethyl ether. After hydrolysis, extraction and evaporation of the solvent, the product crys-
tallised overnight to give 4.55 g (12.7 mmol, 63%) of (3S)-3-ethoxycarbonylamino-4-hydroxy-
4,4-diphenylbutanoic acid methylester 8, which was recrystallised from toluene. Mp 156–157°C;
[h]2D0=−46.6 (c 7.2, CHCl3); IR wmax/cm−1 (KBr) 3491, 3436, 3388, 3340, 1727, 1693, 1544, 1450,
1
1258, 1052, 762, 750, 708; H NMR (acetone-d6) l 1.12 (t, J=7.1 Hz, 3H), 2.47 (dd, J=14.9,
9.9 Hz, 1H), 2.72 (dd, J=14.9, 3.2 Hz, 1H), 3.63 (s, 3H), 3.98 (q, J=7.1 Hz, 2H), 5.18–5.29 (m,
1H), 5.49 (s, 1H), 6.27 (d, J=9.5 Hz, 1H), 7.20–7.73 (m, 10H); 13C NMR (acetone-d6) l 15.7,
37.2, 52.6, 56.9, 61.9, 82.1, 127.2, 127.7, 128.3, 128.4, 129.5, 129.9, 147.0, 147.7, 158.1, 173.4; MS
(EI), m/z (%) 208 (15.0), 183 (23.4), 115 (100.0), 105 (39.8), 77 (25.5). Anal. calcd for
C20H23NO5: C, 67.21; H, 6.49; N, 3.92; O, 22.38. Found: C, 67.72; H, 6.11; N, 3.79.
4.3.3.4. (2S)-2-Ethoxycarbonylamino-1,1,4,4-tetraphenylbutane-1,4-diol 9b. The Grignard reac-
tion was performed as described in Section 4.3.1.2 using 21.9 g (139 mmol) of bromobenzene
dissolved in 20 mL diethyl ether, a suspension of 3.40 g (140 mmol) magnesium in 15 mL diethyl
ether, and a solution of 4.70 g (20.2 mmol) diester 7 in 20 mL diethyl ether. After hydrolysis,
extraction and evaporation of the solvent, the product crystallised overnight to give 3.54 g (7.35
mmol, 36%) of (2S)-2-ethoxycarbonylamino-1,1,4,4-tetraphenylbutane-1,4-diol 9b, which was
recrystallised from toluene. Mp 175°C; [h]2D0=−100.8 (c 0.32, ethyl acetate); IR wmax/cm−1 (KBr)
1
3426, 1681, 1527, 1448, 1239, 1156, 1056, 696; H NMR (acetone-d6) l 0.94 (t, J=7.1 Hz, 3H),
2.31 (dd, J=14.7, 1.5 Hz, 1H), 2.97 (s, 1H), 3.19 (dd, J=14.7, 10.8 Hz, 1H), 3.70 (q, J=7.1 Hz,
2H), 5.05–5.25 (m, 1H), 5.42 (s, 1H), 5.77 (d, J=9.5 Hz, 1H), 7.15–7.64 (m, 20H); 13C NMR
(acetone-d6) l 15.4, 42.1, 55.6, 62.2, 77.9, 82.8, 127.0, 127.2, 127.4, 127.4, 127.6, 128.1, 128.1,
129.3, 129.5, 129.6, 129.9, 147.2, 148.3, 150.0, 150.7, 159.0; MS (EI), m/z (%) 192 (26.4), 184
(15.1), 183 (100.0), 116 (14.6), 105 (92.5), 77 (41.7). Anal. calcd for C31H31NO4: C, 77.32; H,
6.49; N, 2.91; O, 13.29. Found: C, 77.37; H, 6.32; N, 2.88.
References
1. Jakubke, H.-D.; Jeschkeit, H. Aminosa¨uren, Peptide, Proteine; Verlag Chemie: Weinheim, 1982; 3rd ed., pp.
26–29.
2. Chemistry and Biochemistry of the Amino Acids; Barett, G. C., Ed.; Chapman and Hall: London, 1985.
3. Drauz, K.; Kleemann, A.; Martens, J. Angew. Chem. 1982, 94, 590–613.
4. Uzar, H. C. Synthesis 1991, 526–528.
5. Wieland, T. Science 1968, 159, 946–952.
6. Faulstich, H.; Do¨lling, J.; Michl, K.; Wieland, T. Liebigs Ann. Chem. 1973, 560–565.

3836
T. Brinkmann et al. / Tetrahedron: Asymmetry 11 (2000) 3827–3836
7. Michl, K. Liebigs Ann. Chem. 1981, 1, 33–39.
8. Saladino, R.; Mezzetti, M.; Mincione, E.; Torrini, I.; Paradisi, M. P.; Mastropietro, G. J. Org. Chem. 1999, 64,
8468–8474.
9. Wipf, P.; Xu, W.; Kim, H.; Takahashi, H. Tetrahedron 1997, 53, 16575–16596.
10. Deng, W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241–11250.
11. Vernsten, M. R.; Moore, M. B. J. Am. Chem. Soc. 1953, 75, 1320–1321.
12. Lutz, W. B.; Ressler, C.; Nettleton, D. E., Jr.; du Vigneaud, V. J. Am. Chem. Soc. 1959, 81, 167–173.
13. Chakrabarti, J. K.; Cashin, C. H.; Sutton, S. Eur. J. Med. Chem.-Chim. Ther. 1981, 16, 188–190.
.