A practical stereoselective synthesis of (2R,3S)-alloisoleucine

Article abstract of DOI:10.1016/S0957-4166(99)00118-4

An efficient asymmetric Strecker synthesis of the unnatural α-amino acid, D-alloisoleucine (3), from commercially available and inexpensive (S)- 2-methyl-1-butanol (4) was accomplished in four steps.

Full text of DOI:10.1016/S0957-4166(99)00118-4

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1451–1455
A practical stereoselective synthesis of (2R,3S)-alloisoleucine
Padma Portonovo, Bo Liang and Madeleine M. Joullié∗
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
Received 5 January 1999; accepted 15 March 1999
Abstract
An efficient asymmetric Strecker synthesis of the unnatural α-amino acid, D-alloisoleucine (3), from com-
mercially available and inexpensive (S)-2-methyl-1-butanol (4) was accomplished in four steps. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
The didemnins cyclic depsipeptides, isolated from a Carribean tunicate, exhibit antiviral and immu-
nosuppressive properties. Didemnin B was the first congener to enter clinical trials (phases I and II)
as a cytotoxic agent.1–4 The didemnins share a common macrocycle, and differ only in the side chain
attachment. The β-hydroxy-γ-amino acid, isostatine (1), is a subunit of the didemnin macrocycle and
is closely related to statine (2) which is found in the protease inhibitor pepstatine.5,6 Isostatine 1 differs
structurally from statine (2), having a sec-butyl in place of the isobutyl terminus.
Rinehart and co-workers reported that 1 is an essential unit for the bioactivity of didemnins.7,8 An
analog in which the isostatine residue (1) was replaced with statine (2) exhibited lower potency compared
with naturally occurring didemnin A. Based on this observation, and that of the spectral data presented
by Castro, the identity of 1 versus 2 was confirmed.9 The structure and configuration of 1 were later
obtained by X-ray crystallography.10
A convenient approach to 1 utilizes the unnatural α-amino acid, D-alloisoleucine [(2R,3S)-
alloisoleucine] (3), which is commercially available, yet expensive.11 Syntheses of 3 from the
more affordable isomer, L-isoleucine [(2S,3S)-isoleucine], either by inversion of stereochemistry
∗
Corresponding author. E-mail: mjoullie@sas.upenn.edu
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00118-4

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at C-2,12,13 or by epimerization at the same carbon, followed by enzymatic resolution are rather
lengthy.14 Other approaches include an asymmetric aza-Claisen rearrangement of N-2-butenyl-10-
phenylethylcarboximides15 or SN20-alkylation of bromoallenes using organocuprates.16 Both approaches
provided good selectivity. A stereoselective synthesis starting from 4 afforded the protected derivative of
1 in 11 steps.17
2. Synthesis
We report on an efficient asymmetric Strecker synthesis of 3 from commercially available and afford-
able (S)-2-methyl-1-butanol (4) (Scheme 1). This auxiliary controlled synthesis utilizes the enantiopure
sulfinimine 8 as a chiral building block. TEMPO-catalyzed oxidation of 4 to the corresponding aldehyde
5,18 followed by condensation with the silylsulfinamide anion 7, gave the enantiomerically pure 8.19 The
anion 7 was generated in situ by treating (R)-(+)-menthyl p-toluenesulfinate (Andersen reagent, 6) with
LiHMDS. Imine 8 was used, without further purification, in the next step.
Scheme 1. (i) TEMPO, KBr, NaOCl, CH2Cl2 (ii) LiHMDS, −78°C−rt/3 h, THF (iii) 5, −78°C/1 h, THF (iv) Et(i-PrO)AlCN,
−78°C−rt/1 h, THF (v) 6 N HCl, reflux
Stereoselective hydrocyanation of 8 using Et(i-PrO)AlCN afforded the major α-amino nitrile 9
(de=90%).20 Recrystallization from a mixture of ether and hexane gave the diastereomerically pure 9.
The stereochemistry of 9 was determined by X-ray crystallography.
Hydrolysis of 9, under acidic conditions, afforded the enantiomerically pure D-alloisoleucine (3)
(de=>95%).21 Compound 3 was transformed to the isostatine unit 1 by sequential activation, β-ketoester
formation and reduction.22 In summary, we have described a highly stereoselective approach to the
unnatural α-amino acid, D-alloisoleucine (3). The key step in this synthesis is the isolation of the
diastereomerically pure α-amino nitrile 9 by recrystallization.
3. Experimental
3.1. General
All solvents were reagent grade and were distilled before use. Diethyl ether and tetrahydrofuran (THF)
were distilled from sodium benzophenone. Isopropanol was distilled from calcium hydride and stirred

P. Portonovo et al. / Tetrahedron: Asymmetry 10 (1999) 1451–1455
1453
over 4 Å molecular sieves. Reagent Et2AlCN was purchased from Aldrich. The Et(i-PrO)AlCN complex
was formed by treating Et2AlCN (1.0 equiv.) with i-PrOH (1.0 equiv.) in THF at room temperature.
Proton magnetic resonance spectra (1H NMR) and carbon magnetic resonance spectra (13C NMR) were
recorded on a Bruker AMX-500 spectrometer operating at 500 MHz and 125.7 MHz, respectively.
Chemical shifts are in parts per million (ppm) relative to the solvent as the internal reference. Infrared
spectra were obtained on a Perkin–Elmer Model 281-B spectrometer. Absorptions are reported in
wavenumber (cm−1). Optical rotations (in degrees) were measured with a Perkin–Elmer Model 241
polarimeter. Elemental analyses were performed on a Perkin–Elmer 2400 Series II CHNS/O analyzer
at the University of Pennsylvania. Flash column chromatography was carried out on E. Merck silica gel
60 (240–400 mesh) using the solvent systems listed under the individual experiments.
3.2. (S)-(+)-2-Methylbutanal 518
Potassium bromide (0.62 g, 5.19 mmol) in water (2 mL) was added dropwise to a solution containing
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (0.081 g, 0.52 mmol) and (S)-(−)-2-methyl-1-butanol (4)
(4.57 g, 51.9 mmol) in CH2Cl2 (100 mL), at 0°C. During the addition, the reaction mixture was stirred
vigorously, and the temperature was maintained below 0°C. After 10 min, sodium hypochlorite (156 mL,
156 mmol, 1 M soln) adjusted to pH 9.5 using saturated NaHCO3, was added dropwise to the reaction
mixture over a period of 15–20 min. The reaction was allowed to warm to room temperature for an
additional 5 min. The organic phase was separated and the aqueous phase was extracted with CH2Cl2
(3×25 mL). The combined organic layer was washed with 20% HCl (50 mL) containing KI (0.16 g, 1.0
mmol), 10% Na2S2O3 (50 mL) and water (50 mL), and dried over Mg2SO4. Concentration under reduced
1
pressure provided 5 as a yellow oil, which was used without further purification. H NMR (250 MHz;
CDCl3) δ 0.92 (3H, t, J=7.2 Hz), 1.06 (3H, d, J=7.5 Hz), 1.33 (1H, m), 1.62 (1H, m), 2.2 (1H, m), 9.60
(1H, d, J=2Hz); νmax (CHCl3) 2970, 2940, 2890, 2820, 2710, 1725, 1460.
3.3. (R)-(−)-N-[(3S)-Methyl-butylidene]-p-toluenesulfinamide 8
LiHMDS (24.2 mL, 24.2 mmol, 1 M) was added dropwise to a solution of (R)-(+) menthyl p-
toluenesulfinate (6) (5.08 g, 17.3 mmol) in THF (50 mL), cooled to −78°C. After stirring for 10 min,
the reaction mixture was warmed to room temperature. After 3.5 h the reaction was again cooled to
−78°C and (S)-(+)-2-methylbutanal (5) was added. The reaction mixture was stirred for 1.5 h and then
quenched with saturated NH4Cl (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL).
The organic layers were combined, washed with saturated NaCl (50 mL), dried over MgSO4, filtered and
concentrated under reduced pressure to provide 8 as a yellow oil, which was used in the next step without
20
1
further purification. Rf 0.5 (ethyl acetate:hexane, 25:75); [α]D −343.1 (c 7.9; CHCl3); H NMR (500
MHz, CDCl3) δ 0.85 (3H, t, J=7.0 Hz), 1.1 (3H, d, J=7.0 Hz), 1.40 (1H, m), 1.55 (1H, m), 2.40 (1H,
s), 2.41 (1H, m), 7.27 (2H, d, J=8 Hz), 7.53 (2H, d, J=8.2 Hz), 8.09 (1H, d, J=5.3 Hz); 13C NMR (500
MHz, CDCl3) δ 11.4, 16.3, 21.4, 26.6, 41.3, 124.6, 129.8, 170.9; νmax (CHCl3) 2963, 2874, 1618, 1096,
1073, 1016. Found C, 64.50; H, 7.7; C12H17NSO requires C, 64.37; H, 7.68%.
3.4. (R)-(−)-[N-p-Tolylsulfinyl]-(2R)-amino-(3S)-methyl-butyronitrile 9
The Et(i-PrO)AlCN complex was cannulated into a solution of 8 dissolved in THF (30 mL), and
cooled to −78°C. After 20 min the reaction mixture was slowly warmed to room temperature with
stirring. After 40 min the reaction was again cooled to −78°C and quenched with 0.2 N HCl (5 mL).

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The reaction mixture was filtered through Celite and the filtrate eluted with EtOAc (80 mL). The organic
phase was washed with saturated NaCl (25 mL), dried over MgSO4, filtered and concentrated under
reduced pressure to provide a crude white solid 9. The solid was crystallized with ether/hexane to afford
20
white crystals (2.3 g, 53%, two steps). Rf 0.5 (ethyl acetate:hexane, 25:75); [α]D −55 (c 7.6; CHCl3);
1H NMR (500 MHz; CDCl3) δ 0.96 (3H, t, J=7.4 Hz); 1.04 (3H, d, J=7.0 Hz), 1.21 (1H, m), 1.62 (1H,
m), 1.76 (1H, m), 2.40 (1H, s), 4.01 (1H, q, J=5.2 Hz) 4.71 (1H, d, J=8.0 Hz), 7.34 (2H, d, J=8.2 Hz),
7.59 (2H, d, J=8.0 Hz); 13C NMR (500 MHz; CDCl3) δ 11.3, 15.4, 21.4, 24.8, 39.2, 47.0, 118.2, 125.8,
129.8, 139.7, 142.4; νmax (KBr) 3238, 3056, 2973, 2876, 1465, 1088, 1064, 1007, 950. Found C, 62.64;
H, 7.38; C13H18N2SO requires C, 62.36; H, 7.19%.
3.5. (2R,3S)-Alloisoleucine 3
Compound 9 (0.43 g, 1.72 mmol) was added to 6 N HCl (4 mL, 24 mmol) and refluxed for 3.5 h. The
reaction mixture was then washed with ether (2×10 mL) and the separated aqueous layer was loaded on
an ion-exchange resin (Dowex X 50 W X 8-400), eluted with 1.4 N NH4OH (500 mL) to afford a white
20
25
solid 3. (0.22 g, 98%). [α]D −17 (c 6.4; H2O), lit.21 [α]D −15.6 (c 2.0; H2O); 1H NMR (500 MHz;
D2O) δ 0.75 (3H, d, J=7.0 Hz), 0.85 (3H, t, J=7.0 Hz), 1.15 (1H, m), 1.20 (1H, m), 1.70 (1H, m), 3.77
(1H, d, J=4.0 Hz); 13C NMR (500 MHz; D2O) δ 11.4, 13.7, 25.9, 36.0, 58.9, 175.1; νmax (KBr) 3238,
3056, 2973, 2876, 1465, 1088, 1064, 1007, 950.
Acknowledgements
We gratefully acknowledge the National Institute of Health (CA 40081) and the University of
Pennsylvania for financial support.
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