Application of the Blaise reaction: Stereoselective synthesis of (4R)- tert-butyl 3-amino-4-trimethylsilyloxy-2-alkenoates from (R)-cyanohydrins

Article abstract of DOI:10.1016/S0957-4166(98)00039-1

O-Trimethylsilyl protected (R)-cyanohydrins 3 react with Reformatsky reagents from tert-butyl 2-bromoesters 4 and zinc dust (Blaise reaction) to give the corresponding addition products in high yields. Workup with an aqueous solution of NH₄Cl a

Full text of DOI:10.1016/S0957-4166(98)00039-1

Pergamon
Tetrahedron: Asymmetry 9 (1998) 805–815
Application of the Blaise reaction: stereoselective synthesis of
(4R)-tert-butyl 3-amino-4-trimethylsilyloxy-2-alkenoates from
(R)-cyanohydrins1
Jana Syed,† Siegfried Förster and Franz Effenberger ∗
Institut für Organische Chemie der Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 5 January 1998; accepted 26 January 1998
Abstract
O-Trimethylsilyl protected (R)-cyanohydrins 3 react with Reformatsky reagents from tert-butyl 2-bromoesters 4
and zinc dust (Blaise reaction) to give the corresponding addition products in high yields. Workup with an aqueous
solution of NH4Cl at low temperature gives (4R)-tert-butyl 3-amino-4-trimethylsilyloxy-2-alkenoates (R)-5 with-
out racemization. Hydrogenation of the alkenoates 5 to the corresponding tert-butyl β-amino-γ-hydroxyalkanoates
6, resulting in a mixture of two diastereoisomers, was only possible under special hydrogenation conditions. With
HCl in dichloromethane compounds 6 cyclize to the corresponding β-amino-γ-hydroxybutyrolactones 8. © 1998
Elsevier Science Ltd. All rights reserved.
The (1R,2S)- and (1S,2R)-2-amino alcohols are easily accessible by addition of Grignard reagents to
O-protected (R)- and (S)-cyanohydrins and subsequent hydrogenation.2 Since Grignard reagents derived
from α-halo ethers or silylmethyl chlorides for the preparation of an additional functional group in the 3-
position of the amino alcohols gave no addition products with O-protected cyanohydrins,3 the addition of
vinylmagnesium bromide was applied.3 Reductive ozonolysis of the primarily obtained 2-vinyl-2-amino
alcohols resulted in the formation of (1R,2S)-2-amino-1,3-diols starting from (R)-cyanohydrins.3
In the present paper the results of the reaction of Reformatsky reagents, derived from 2-bromo esters
and zinc, with O-protected (R)-cyanohydrins, a further example of the application of optically active
cyanohydrins in stereoselective synthesis, are described.
The reaction of Reformatsky reagents with nitriles, known as the Blaise reaction,4 has already been
applied to racemic5 as well as to optically active6 O-protected cyanohydrins. In all cases workup
under acidic conditions resulted in the formation of tetronic acids.5,6 Under special reaction conditions,
however, the intermediate β-amino-α,β-unsaturated esters could be isolated.4d,7 In the case of the Blaise
reaction with optically active cyanohydrins, this type of intermediate, not yet described in the literature,
∗
†
Corresponding author. E-mail: franz.effenberger@po.uni-stuttgart.de
Part of dissertation, Universität Stuttgart, 1997.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00039-1

806
J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
would be of interest for the stereoselective synthesis of β-amino-γ-hydroxy carboxylic acids and β-
amino-γ-butyrolactones, respectively.
β-Amino-γ-hydroxy acids are main components in macrocyclic peptides or glycopeptides with anti-
fungal, antibiotic8 and gastroprotective9 activity. β-Amino-γ-butyrolactones are key intermediates for
the synthesis of pharmacologically important β-amino alcohols,10 β-lactam antibiotics11 and polyene
macrolide antibiotics.12 They are also of interest as phosphodiesterase inhibitors13 and moreover they
potentiate the action of adrenaline on blood pressure.14 We therefore have investigated the Blaise reaction
with O-protected (R)-cyanohydrins in detail in a more general way.
1. Preparation of (4R)-tert-butyl 3-amino-4-trimethylsilyloxy-2-alkenoates (R)-5 from
(R)-cyanohydrins (R)-2
The Blaise reaction of racemic O-protected cyanohydrins, described by Krepski et al.,5b leads after
hydrolysis with diluted sulfuric acid directly to tetronic acids. According to this described procedure we
tried to synthesize (R)-tetronic acids starting from (R)-cyanohydrins. We did not, however, succeed in
the isolation of the desired products after hydrolysis, neither with diluted sulfuric acid nor with aqueous
HCl (10%). We therefore decided to optimize first the reaction conditions for this type of Reformatsky
reaction.
Parameters such as solvent, state and activation of the zinc applied as well as the hydrolysis conditions
were varied widely in the reaction of racemic 2-(trimethylsilyloxy)pentanenitrile 3b with tert-butyl α-
bromoacetate 4a. Ethyl α-bromoacetate commonly used in Reformatsky reactions was replaced by the
tert-butyl ester 4a in order to minimize side-reactions of the organozinc compound. THF was retained as
the most suitable solvent.
For hydrolysis, instead of mineral acid, we used a saturated solution of NH4Cl as a mildly acidic
medium at −30°C. Under these reaction conditions no lactonization occurred. We were able to isolate
tert-butyl 3-amino-4-trimethylsilyloxy-2-heptenoate 5b in 75% yield. By hydrolysis of the addition
product with glacial acetic acid at −30°C, 5b was isolated in 20% yield only. An interesting modification,
using THF/trimethyl borate15 as the solvent mixture instead of THF alone, gave 5b in 45% yield.
Both zinc dust and granulated zinc, which differ in their surfaces, were investigated. After identical
activations using 20% HCl and workup by hydrolysis with NH4Cl, 5b was obtained in comparable yields
of 75% (granulated zinc) and 79% (zinc dust). In all further reactions zinc dust was applied. Zinc dust
was activated not only by HCl but also by a solution of conc. HNO3 in conc. H2SO416 and by copper(II)
acetate solution.17 With the HCl and H2SO4/HNO3 activated zinc, respectively, 5b was obtained in 79%
yield. The yield by Zn–Cu activation was slightly less with 73%. We therefore used zinc activation with
HCl for further reactions.
The results described so far show a strong dependence of the yield of 5 on hydrolysis conditions and
workup. The influence of all other parameters we have varied, however, can be neglected.
Scheme 1 shows the Blaise reaction of optically active O-protected (R)-cyanohydrins (R)-3 with tert-
butyl 2-bromoalkanoates 4 under the optimized hydrolysis and workup conditions.
The (R)-cyanohydrins (R)-2a,b were already known,2b 2-hydroxydecanenitrile (R)-2c was prepared
in 82% yield and 96% ee ([α]23=+10.3 (c 0.5, CH2Cl2)) by (R)-oxynitrilase [EC 4.1.2.10] catalyzed
D
addition of HCN to aldehyde 1c. The trimethylsilyl protecting group in (R)-2a–c was introduced without
racemization according to a known procedure2a (see Experimental). The results of the addition of tert-
butyl α-bromoalkanoates 4a–c to racemic and to (R)-cyanohydrins 3a–c, respectively, are summarized
in Table 1.

J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
807
Scheme 1.
Table 1
tert-Butyl 3-amino-4-trimethylsilyloxy-2-alkenoates 5 by addition of Reformatsky reagents prepared
from α-bromoesters 4 to cyanohydrins 3 and subsequent hydrolysis
Table 1 shows that (4R)-tert-butyl 3-amino-4-phenyl-4-trimethylsilyloxy-2-butenoate 5a and (4R)-
tert-butyl 3-amino-4-trimethylsilyloxy-2-heptenoate 5b could be isolated without racemization. In the
reaction of (R)-3b with both tert-butyl α-bromopropionate 4b and -butyrate 4c, however, partial race-
mization was observed. Despite the bulky tert-butyl group, both esters 4b and 4c have the tendency
to yield the corresponding β-keto esters.18 It was therefore necessary to carry out the reactions at low
temperature (10–15°C) under ultrasound. The aromatic cyanohydrin (R)-3a reacts with the bromoesters
4b,c predominantly to give by-products which could not be separated from the corresponding α-alkylated
enaminoesters.
The Blaise reaction was also applied to the racemic trimethylsilylated ketone cyanohydrins 3d–f
(Scheme 2).
The ketone cyanohydrins 3d–f react with tert-butyl α-bromoacetate 4a to give the corresponding

808
J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
Scheme 2.
Fig. 1. ORTEP diagram of compound (R)-5a
enaminoesters 5f,g in 77% yield and the enaminoester 5h in 61% yield. We did not, however, succeed in
the reaction of 3d–f with tert-butyl α-bromopropionate 4b or ethyl α-bromopropionate. In these cases a
reaction to give the α-alkylated enaminoesters did not take place.
Our attempts to prepare (R)-3d by oxynitrilase catalyzed addition of HCN to (3E,5E)-octa-3,5-dien-
2-one failed. This ketone was not accepted as a substrate by (R)-oxynitrilase. 3,5-Octadien-2-one was
therefore reacted directly with cyanotrimethylsilane under ZnI2 catalysis to yield racemic 3d in 17%
yield.
In all cases the Blaise reaction to give compounds 5 proceeded stereoselectively resulting in only one
geometric isomer. The (Z)-configuration of 5a–d was determined by comparison of 13C–1H coupled
NMR spectra, and in the case of (R)-5a by X-ray crystallographic analysis19 (Fig. 1).
2. Preparation of tert-butyl β-amino-γ-hydroxyalkanoates 6 and β-amino-γ-butyrolactones 8 from
2-alkenoates 5
β-Amino-γ-hydroxycarboxylates should be accessible by simple hydrogenation of the double bond
in tert-butyl alkenoates 5. Pd/C or Rh/Al2O3 catalyzed hydrogenation with H2 at a higher temperature
and pressure, successfully used for non-alkylated enaminoesters,20 could not be applied due to the allyl–
and benzyl–oxygen bonds in 5, which are sensitive to hydrogenation. We therefore first studied suitable
methods for the hydrogenation using racemic 5a. We found that the application of NaBH4 or KBH4
in tert-butanol or ethanol as solvents did not lead to tert-butyl 3-amino-4-hydroxy-4-phenylbutanoate
6a (see Scheme 3). Also the hydrogenation with aluminium hydride complexes such as sodium bis[2-
methoxyethoxy]aluminium hydride or LiAlH4 failed.
From these results we concluded that the nonpolar enamino system in 5 requires a stronger activation
for the reaction with hydrides. One possibility for activation is the protonation of compounds 5 to

J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
809
Scheme 3.
Table 2
Hydrogenation of tert-butyl 3-amino-4-trimethylsilyloxyalkenoates 5 to tert-butyl 3-amino-4-
hydroxyalkanoates 6 and subsequent cyclization to γ-hydroxybutyrolactones 8
the more reactive iminium salts.21 Therefore a solution of 5a in absolute methanol was acidified with
methanolic HCl to pH ∼4 (indicator: bromocresol green), and after addition of the hydrogenating agent
NaBH3CN the pH value of the reaction mixture was fixed again at pH ∼4 with methanolic HCl. In this
way, the hydrogenated product 6a could be isolated in 88% yield with a diastereomeric ratio of 70:30
after 4 hours reaction time, basic workup and separation of the indicator by chromatography on silica gel
with CH2Cl2/NH3 sat. methanol. With NaBH4 in glacial acetic acid/THF22 the yield of 6a decreased to
20%.
Under the optimized reaction conditions described above, racemic 5b,e and the optically active
enaminoesters (R)-5a,b were hydrogenated (Scheme 3). The results are listed in Table 2.
As can be seen from Table 2, (R)-5a was hydrogenated without racemization to give 6a in a
diastereomeric ratio of 70:30. Since the use of the eluent CH2Cl2/NH3 sat. methanol led to partial
racemization in this case, the hydrogenation was carried out without the indicator bromocresol green. All
attempts to separate the diastereomers of 6a–c either by chromatographic methods or by recrystallization
failed so far. An unambiguous assignment of both diastereomers to the erythro or threo configuration by
X-ray analysis was therefore not possible. Also spectroscopic methods did not allow an assignment.
The selective introduction of an N-Boc or N-acetyl group in compounds 5 in order to activate
the ‘vinylogous amide’ was very difficult in the case of 5a. Besides the desired N-Boc substituted
derivative, the O-acylated compound was formed, and unreacted 5a was reisolated in 73% yield. The

810
J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
acetylation of 5a proceeded quantitatively but only undesired by-products were formed predominantly.
The enaminoester 5b, however, could be acetylated to the corresponding N,O-diacetyl derivative in 64%
yield. Unfortunately, hydrogenation of this compound with NaBH4 to 6b failed.
As outlined in Scheme 3, two pathways appeared to offer an approach to the β-amino-γ-butyrolactones
8. The enaminoesters 5a,b could be cyclized in dichloromethane to the hydrochlorides of the unsaturated
lactones 7a,b with ca 80% crude yield at −10°C by passing HCl through the reaction mixture. Unfortu-
nately both lactones 7a,b were extremely unstable and decomposed completely during the conversion to
N-acyl derivatives. Hydrogenation of 7 to give 8 was therefore not possible.
Under the same reaction conditions with HCl in dichloromethane, however, we succeeded in the
preparation of β-amino-γ-butyrolactone hydrochlorides 8a–c by cyclization of the racemic tert-butyl
β-amino-γ-hydroxycarboxylates 6a–c (Scheme 3, Table 2). The hydrochlorides 8 were obtained after
recrystallization with 39–49% yield (not optimized). The butyrolactone hydrochloride 8a10,14 could not
be isolated in an analytically pure form.
3. Experimental
3.1. Materials and methods
Avicel cellulose, cyanotrimethylsilane, ZnI2 and sodium cyanoborohydride were purchased from
Merck, nonanal and zinc dust from Fluka as well as granulated zinc (30 mesh) from Janssen Chimica.
Racemic cyanohydrins 1 were prepared according to the literature,23 tert-butyl 2-bromoesters 4 accord-
ing to Pavlov et al.,24 and 2-(trimethylsilyloxy)cyclohexanecarbonitrile 3f according to Rasmussen.25
Cyanohydrins 2 were silylated according to procedures described previously.2a All solvents were purified
and dried as described in the literature. Blaise reactions were performed under an argon atmosphere
(argon stream) in dried glassware. Melting points were determined on a Büchi SMP-20 and are uncor-
rected. 1H NMR spectra were recorded on a Bruker AC 250 F with TMS as an internal standard. Optical
rotations were determined on a Perkin–Elmer polarimeter 241 LC. Preparative column chromatography
was performed with glass columns of different sizes packed with silica gel S, grain size 0.032–0.063
mm (Riedel-de Haen). GC for determination of enantiomeric excess: (a) Carlo Erba HRGC 5300 Mega
Series with FID, Carlo Erba Mega Series integrator, 0.4–0.5 bar or 0.36 bar hydrogen, column 20 m,
phase OV 1701 or PS086 with 10% permethylated β-cyclodextrin or Bondex-unβ-5.5-Et-105 or pivaloyl
bornamide; (b) Hewlett–Packard 5890 Series II with HP 7673 injector and FID, Software HP 3365 Series
II ChemStation, Version A.03.21, hydrogen, column 30 m×0.32 mm, phase Chiraldex B-DA (ITC).
3.2. (R)-Oxynitrilase catalyzed preparation of (R)-cyanohydrins 2
Performed according to a literature method.2b,26 (R)-2-Hydroxydecanenitrile (R)-2c: colourless liquid,
bp 77–80°C/0.001 torr; 96% ee, [α]23=+10.3 (c 0.5, CH2Cl2); 1H NMR (CDCl3): δ=0.89 (broad t, J=6.6
D
Hz, 3H, CH3), 1.27–1.53 (m, 12H, (CH2)6), 1.80–1.90 (m, 2H, CH2), 2.33 (broad s, 1H, OH), 4.48 (t,
J=6.7 Hz, 1H, CHCN).
3.3. (R)-2-(Trimethylsilyloxy)decanenitrile (R)-3c
23
1
Colourless liquid, bp 137–138°C/14 torr; [α] =+39.4 (c 0.5, CH2Cl2); H NMR (CDCl3) δ=0.21
D
(s, 9H, Si(CH3)3), 0.88 (broad t, J=6.4 Hz, 3H, CH3), 1.20–1.50 (m, 12H, (CH2)6), 1.70–1.80 (m, 2H,

J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
811
CH2), 4.40 (t, J=6.6 Hz, 1H, CHCN). Anal. calcd for C13H27NOSi: C, 64.66; H, 11.27; N, 5.80. Found:
C, 64.73; H, 11.17; N, 5.85.
3.4. Preparation of (3E,5E)-2-methyl-2-(trimethylsilyloxy)octa-3,5-dienenitrile 3d
To a solution of cyanotrimethylsilane (10.6 g, 106.8 mmol) and ZnI2 (6 mg, 18.8 µmol) under an
argon atmosphere, (3E,5E)-octa-3,5-dien-2-one23b (12 g, 96.6 mmol) was added dropwise. After stirring
for 16 h at 50°C, the product was fractionally distilled three times in vacuo through a Spaltrohr® column
to yield 3.7 g (17%) of the pure product as a light yellow liquid, bp 85°C/0.35 torr; 1H NMR (CDCl3):
δ=0.21 (s, 9H, Si(CH3)3), 1.03 (t, J=7.4 Hz, 3H, CH3), 1.65 (s, 3H, CH3), 2.14 (dq, J=6.0, 7.4 Hz, 2H,
CH2), 5.51 (d, J=15.2 Hz, 1H, CH), 5.89 (dt, J=15.2, 5.9 Hz, 1H, CH), 6.02 (dd, J=9.6, 15.5 Hz, 1H,
CH), 6.47 (dd, J=15.2, 9.6 Hz, 1H, CH). Anal. calcd for C12H21NOSi: C, 64.52; H, 9.47; N, 6.27. Found:
C, 64.27; H, 9.49; N, 6.26.
3.5. Activation of zinc
Zinc dust was washed several times with 10% HCl followed by water (up to neutral pH), acetone and
dry diethyl ether, and dried at 100°C in vacuo. This activated zinc was stored under an argon atmosphere
in an exsiccator.
3.6. Blaise reaction of O-silylated cyanohydrins 3a–c with 2-bromoester 4a to enaminoesters 5a,b,e;
general procedure
To activated zinc dust (2 g, 30.6 mmol) in 7 ml THF under an argon atmosphere the respective
cyanohydrin 3 (16.6 mmol) was added via syringe. This reaction mixture was heated to reflux, the
heating was removed and a solution of 4a (5 g, 25.6 mmol) in 7 ml THF was slowly added dropwise,
so that the reaction mixture remained at reflux. After refluxing for a further 2 h followed by addition of
7 ml THF, the reaction mixture was cooled to −30°C, and a sat. solution of NH4Cl was slowly added
dropwise (temperature kept between −30 and −20°C). The reaction mixture was allowed to warm to
room temperature, treated with 14 ml water and extracted with ethyl acetate. The combined extracts were
dried (MgSO4), concentrated, and the residue either distilled in vacuo or recrystallized from ethyl acetate
(5a).
3.7. Blaise reaction of 3b with 2-bromoesters 4b,c to enaminoesters 5c,d; general procedure
To activated zinc dust (1 g, 15.3 mmol) in 3.5 ml THF under an argon atmosphere, 3b (1.4 g, 8.2 mmol)
was added via syringe. Under ultrasound at 10–15°C, a solution of 4b and 4c (12.9 mmol), respectively,
in 3.5 ml THF was slowly added dropwise. The reaction mixture was warmed to room temperature, and
stirred for a further 4 h. Workup was performed as described above.
3.8. Determination of enantiomeric excess
(a) A quantity of acetic anhydride (50 µl) and 10 µl pyridine were added to a solution of 5 µl crude
2 in 200 µl dichloromethane. After heating to 60°C for between 2 and 3 h, the reaction mixture was
filtered through a silica gel column (3×0.5 cm) with 3 ml dichloromethane. The enantiomeric excesses
were determined directly from the filtrate by gas chromatography.

812
J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
(b) A quantity of pivaloyl chloride (50 µl) was added to 6 (3 mg) in 300 µl pyridine. After standing at
room temperature for 16 h, the reaction mixture was filtered through a silica gel column (3×0.5 cm) with
4 ml dichloromethane. The ee value was determined directly from the filtrate by gas chromatography.

J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
813
3.9. Crystal structure analysis of (R)-5a
Crystal dimensions, 0.5×0.2×0.1 mm; formula, C17H27NO3Si; formula weight, 321.46; crystal
system, orthorhombic; space group, P212121; a=8.0301(36), b=12.0643(84), c=19.9056(109) Å;
α=β=γ=90°; V=1928.4(2) Å3; Z=4; ρ(calcd)=1.10 g cm−3; MoKα (λ=0.71073 Å); graphite
monochromator; temperature 293 K; θ–2θ scan; 2θ scan limits, 2–48°; independent reflections, 1745;
reflections observed I>3σ(I), 894. The crystal structure was solved by the direct method.19a Full matrix
least-squares refinement led to the final convergence with R=0.052 (Rw=0.050). The residual electron
density was 0.44 e Å−3. Complete data have been deposited at the Cambridge Crystallographic Data
Centre.
3.10. Hydrogenation of enaminoesters (R)-5 to tert-butyl β-amino-γ-hydroxyalkanoates (R)-6; general
procedure
A solution of 5 in dry methanol containing, with the exception of (R)-5a, bromocresol green as the
indicator was acidified to pH ∼4 with 2 N methanolic HCl. After addition of NaBH3CN, the reaction
mixture was again adjusted to pH ∼4 with methanolic HCl and stirred for a further 4 h (pH control). After
addition of sodium carbonate solution (10%), the aqueous phase was extracted several times with diethyl
ether. The combined extracts were washed with sat. NaCl solution (up to pH 7), dried (MgSO4) and
concentrated. The residue was chromatographed on silica gel with dichloromethane:NH3 sat. methanol
(10:1) (6a, (R)-6b), (7:1) (6c) and dichloromethane:methanol (5:1) ((R)-6a).
1
(R)-6a: White crystals, mp 88–106°C; dominant diastereomer: H NMR (CDCl3) δ=1.43 (s, 9H,
C(CH3)3), 2.17 (dd, J=16.0, 9.4 Hz, 1H, CH2), 3.37 (dd, J=16.0, 3.6 Hz, 1H, CH2), 3.44 (ddd, J=9.4,
3.6, 5.0 Hz, 1H, CH–N), 4.36 (d, J=5.0 Hz, 1H, CH–O), 7.30–7.40 (m, 5H, Ph). Minor diastereomer:
1.44 (s, 9H, C(CH3)3), 2.12–2.50 (2dd, 2H, CH2), 3.27 (ddd, J=9.0, 4.1, 6.3 Hz, 1H, CH–N), 4.40 (d,
J=6.3 Hz, 1H, CH–O), 7.30–7.40 (m, 5H, Ph). Anal. calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57.
Found: C, 66.76; H, 8.44; N, 5.47.
1
(R)-6b: Colourless oil and white crystals; diastereomeric mixture: H NMR (CDCl3) δ=0.94 (broad t,
6H, 2CH3), 1.30–1.60 (m, 8H, 2CH2CH2), 1.46 (s, 18H, 2C(CH3)3), 1.90 (broad s, 3H, OH, NH2), 2.24
(dd, J=9.5, 15.9 Hz, 1H, CH2), 2.26 (dd, J=8.9, 15.7 Hz, 1H, CH2), 2.44 (dd, J=15.8, 3.5 Hz, 1H, CH2),
2.48 (dd, J=15.6, 4.1 Hz, 1H, CH2), 2.96–3.04, 3.10–3.17 (2m, 2H, 2CH–N), 3.30–3.36, 3.49–3.55 (2m,
2H, 2CH–O). Anal. calcd for C11H23NO3: C, 60.80; H, 10.67; N, 6.44. Found: C, 60.57; H, 10.64; N,
6.54.
1
6c: Wax-like white solid; diastereomeric mixture: H NMR (CDCl3) δ=0.87 (broad t, 6H, 2CH3),
1.21–1.66 (m, 28H, 2(CH2)7), 1.46 (s, 18H, 2C(CH3)3), 2.10 (broad s, 3H, OH, NH2), 2.18–2.40 (2dd,
2H, 2CH2), 2.44 (dd, J=3.5, 16.0 Hz, 1H, CH2), 2.48 (dd, J=4.1, 15.7 Hz, 1H, CH2), 3.00 (ddd, J=4.1,
9.2, 5.3 Hz, 1H, CH–N), 3.18 (ddd, J=3.6, 9.6, 3.6 Hz, 1H, CH–N). Anal. calcd for C16H33NO3: C,
66.85; H, 11.57; N, 4.87. Found: C, 66.86; H, 11.66; N, 4.73.
3.11. Preparation of β-amino-γ-butyrolactones 8; general procedure
HCl was passed through a solution of 6 (7.8 mmol) in 25 ml dry ethanol at −10°C for 40 min, and
then the reaction mixture was stirred for a further 1 h without cooling. Ethanol was removed, and the
remaining solid was dried in vacuo and recrystallized from ethanol or ethanol/diethyl ether.
8a·HCl: first fraction: 27% yield, 68% de, mp 229°C (dec); second fraction: 25% yield, 60% de, mp
220°C;10,14 dominant trans-diastereomer: 1H NMR (DMSO) δ=2.76 (dd, J=3.6, 18.5 Hz, 1H, CH2), 3.25

814
J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
(dd, J=8.5, 18.5 Hz, 1H, CH2), 4.00–4.03 (m, 1H, CH–N), 5.75 (d, J=3.1 Hz, 1H, CH–O), 7.40–7.47 (m,
+
5H, Ph), 9.02 (broad s, 3H, NH3 ). Minor diastereomer: 4.69 (broad d, J=7.2 Hz, 1H, CH–O).
8b·HCl: 44% yield, 22% de, mp 184; diastereomeric mixture: 1H NMR (DMSO) δ=0.88–0.95 (2t, 6H,
2CH3), 1.20–1.80 (m, 8H, 2CH2CH2), 2.65 (2dd, J=3.6, 18.4 Hz, 2H, 2CH2), 3.05–3.20 (2dd, 2H, 2CH2
interfered), 3.74–3.77 (m, 1H, CH–N), 4.06–4.12 (m, 1H, CH–N), 4.54–4.67 (m, 2H, 2CH–O), 8.80
+
(broad s, 6H, 2NH3 ). Anal. calcd for C7H13NO2·HCl: C, 46.80; H, 7.85; N, 7.80; Cl, 19.73. Found: C,
46.90; H, 7.82; N, 8.01; Cl, 19.69.
8c·HCl: first fraction: 10% yield, 17% de, mp 190°C; second fraction: 29% yield, 43% de, mp 189°C;
1
diastereomeric mixture: H NMR (DMSO) δ=0.86 (broad t, 6H, 2CH3), 1.17–1.75 (m, 28H, 2(CH2)7),
2.64 (2dd, J=3.9, 18.4 Hz, 2H, 2CH2), 3.04–3.19 (2dd, 2H, 2CH2 interfered), 3.72–3.78, 4.03–4.14 (2m,
+
2H, 2CH–N), 4.52–4.65 (m, 2H, 2CH–O), 8.75 (broad s, 6H, 2NH3 ). Anal. calcd for C12H23NO2·HCl:
C, 57.70; H, 9.68; N, 5.61; Cl, 14.19. Found: C, 57.39; H, 9.66; N, 5.45; Cl, 14.24.
Acknowledgements
This work was generously supported by the Bundesministerium für Bildung und Forschung (Zentrales
Schwerpunktprogramm Bioverfahrenstechnik, Stuttgart). We would like to thank Sonja Henkel for the
X-ray crystallographic analysis.
References
1. Enzyme-catalyzed Reactions, Part 32. Part 31: Effenberger, F.; Graef, B. W. J. Biotechnol., in press.
2. (a) Effenberger, F.; Gutterer, B.; Ziegler, T. Liebigs Ann. Chem. 1991, 269–273. (b) Effenberger, F. Angew. Chem. 1994,
106, 1609–1619. Angew. Chem. Int. Ed. Engl. 1994, 33, 1555–1564. (c) Brussee, J.; Dofferhoff, F.; Kruse, C. G.; van der
Gen, A. Tetrahedron 1990, 46, 1653–1658. (d) Jackson, W. R.; Jacobs, H. A.; Matthews, B. R.; Jayatilake, G. S.; Watson,
K. G. Tetrahedron Lett. 1990, 31, 1447–1450.
3. Effenberger, F.; Gutterer, B.; Syed, J. Tetrahedron: Asymmetry 1995, 6, 2933–2943.
4. (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478 and 978. (b) Cason, J.; Rinehart Jr., K. L.; Thornton Jr., S.
D. J. Org. Chem. 1953, 18, 1594–1600. (c) Kagan, H. B.; Suen, Y.-H. Bull. Soc. Chim. Fr. 1966, 1819–1822. (d) Hannick,
S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833–3835.
5. (a) Anderson, J. R.; Edwards, R. L. J. Chem. Soc., Perkin Trans 1 1982, 215–221. (b) Krepski, L. R.; Lynch, L. E.; Heilmann,
S. M.; Rasmussen, J. K. Tetrahedron Lett. 1985, 26, 981–984.
6. (a) Kitazume, T. J. Fluorine Chem. 1987, 35, 287–294. (b) Duffield, J. J.; Regan, A. C. Tetrahedron: Asymmetry 1996, 7,
663–666.
7. Lee, A. S.-Y.; Cheng, R.-Y. Tetrahedron Lett. 1997, 38, 443–446.
8. (a) Bewley, C. A.; Faulkner, D. J. J. Org. Chem. 1994, 59, 4849–4852. (b) Matsunaga, S.; Fusetani, N.; Hashimoto, K.;
Wälchli, M. J. Am. Chem. Soc. 1989, 111, 2582–2588. (c) Wakamiya, T.; Shiba, T.; Kaneko, T. Bull. Chem. Soc. Jpn 1972,
45, 3668–3672.
9. (a) Shimojima, Y.; Hayashi, H.; Ooka, T.; Shibukawa, M. Tetrahedron 1984, 40, 2519–2527. (b) Shinozaki, K.; Mizuno,
K.; Masaki, Y. Heterocycles 1996, 43, 11–14.
10. Seki, M.; Moriya, T.; Matsumoto, K. Agric. Biol. Chem. 1987, 51, 3033–3038.
11. (a) Takahashi, Y.; Hasegawa, S.; Izawa, T.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1986, 34, 3020–3024. (b) Nitta,
H.; Hatanaka, M.; Ishimaru, T. J. Chem. Soc., Chem. Commun. 1987, 51–52.
12. McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J. Am. Chem. Soc. 1986, 108, 4943–4952.
13. Hoff, H.; Drautz, H.; Fiedler, H.-P.; Zähner, H.; Schultz, J. E.; Keller-Schierlein, W.; Philipps, S.; Ritzau, M.; Zeeck, A. J.
Antibiotics 1992, 45, 1096–1107.
14. Lawson, A. (National Research Development Corp.) Brit. 772,836, Apr. 17, 1957; Chem. Abstr. 1958, 52, 1242b.
15. Rathke, M. W.; Lindert, A. J. Org. Chem. 1970, 35, 3966–3967.
16. Vaughan, W. R.; Bernstein, S. C.; Lorber, M. E. J. Org. Chem. 1965, 30, 1790–1795.

J. Syed et al. / Tetrahedron: Asymmetry 9 (1998) 805–815
815
17. LeGoff, E. J. Org. Chem. 1964, 29, 2048–2050.
18. Cornforth, D. A.; Opara, A. E.; Read, G. J. Chem. Soc. C 1969, 2799–2805.
19. (a) Sheldrick, G. SHELXS-86, Institute of Inorganic Chemistry, University of Göttingen, 1986. (b) Stewart, J. M.; Dickinson,
P. A.; Ammon, H. L.; Flack, H.; Heck, H. XRAY-76, Tech. Rept. TR-446, University of Maryland, Computer Center, College
Park MD, 1976. (c) Johnson, C. K. A Fortran Thermal Ellipsoid Plot Program for Crystal Structure Illustrations, Tech. Rept.
ORNL-5138, Oak Ridge National Laboratory, Oak Ridge TN, 1971.
20. (a) Liska, K. J. J. Pharm. Sci. 1964, 53, 1427–1428. (b) Augustine, R. L.; Belling, R. F.; Gustavsen, A. J. J. Org. Chem.
1968, 33, 1287–1288.
21. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904.
22. Gribble, G. W.; Nutaitis, C. F. Org. Prep. Proced. Int. 1985, 17, 317–384.
23. (a) Brussee, J. Thesis, Universität Leiden, 1992. (b) Clemo, N. G.; Pattenden, G. J. Chem. Soc., Perkin Trans 1 1985,
2407–2411. (c) Ladenburg, K.; Folkers, K.; Major, R. T. J. Am. Chem. Soc. 1936, 58, 1292–1294.
24. Pavlov, S.; Bogavac, M.; Arsenijevic, V. Bull. Soc. Chim. Fr. 1974, 2985–2986.
25. Rasmussen, J. K.; Heilmann, S. M. Synthesis 1978, 219–221.
26. (a) Eichhorn, J. Dissertation, Universität Stuttgart, 1995. (b) Effenberger, F.; Jäger, J. J. Org. Chem. 1997, 62, 3867–3873.