Facile synthetic route to (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid and its derivatives, the key intermediates for HIV protease inhibitors

Article abstract of DOI:10.1081/SCC-200058003

A facile and efficient route to (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid and its derivative (4S,5S)-4-benzyl-5-hydroxymethyl oxazolidin-2-one is presented. N-phthaloyl protected L-phenylalanine 1 was treated with thionyl chloride followed by hydroge

Full text of DOI:10.1081/SCC-200058003

This article was downloaded by: [Boston University]
On: 04 October 2014, At: 19:10
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Facile Synthetic Route to
(2S,3S)‐3‐Amino‐2‐hydroxy‐4‐phen
Acid and Its Derivatives, the
Key Intermediates for HIV
Protease Inhibitors
Lijun Lei a , Xuchang He a & Donglu Bai a
a Shanghai Institute of Materia Medica, Shanghai
Institutes for Biological Sciences , Chinese Academy
of Sciences , Shanghai, China
Published online: 17 Dec 2010.
To cite this article: Lijun Lei , Xuchang He & Donglu Bai (2005) Facile Synthetic
Route to (2S,3S)‐3‐Amino‐2‐hydroxy‐4‐phenylbutyric Acid and Its Derivatives, the Key
Intermediates for HIV Protease Inhibitors, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:11, 1535-1540,
DOI: 10.1081/SCC-200058003
To link to this article: http://dx.doi.org/10.1081/SCC-200058003
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views

expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 1535–1540, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200058003
Facile Synthetic Route to (2S,3S)-3-Amino-
2-hydroxy-4-phenylbutyric Acid and Its
Derivatives, the Key Intermediates for
HIV Protease Inhibitors
Lijun Lei, Xuchang He, and Donglu Bai
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological
Sciences, Chinese Academy of Sciences, Shanghai, China
Abstract: A facile and efficient route to (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric
acid and its derivative (4S,5S)-4-benzyl-5-hydroxymethyl oxazolidin-2-one is
presented. N-phthaloyl protected L-phenylalanine 1 was treated with thionyl chloride
followed by hydrogenation of the acyl chloride 2 on Pd/C, giving (S)-2-
phthalimido-3-phenylpropionaldehyde 3. Aldehyde 3 reacted with Nagata’s reagent
to afford 3-phthalimido-2-hydroxy-4-phenylbutyronitrile 4 as a diastereomeric
mixture. After hydrolysis, protection, esterification, and reduction, 4 was transformed
into the optically pure compound 7 in good yield.
Keywords: AHPBA, HIV protease inhibitors, Nagata’s reagent, N-phthaloyl protect-
ing group
INTRODUCTION
(2S,3S)-3-Amino-2-hydroxy-4-phenylbutyric acid (AHPBA)[1] and its deriva-
tive, (4S,5S)-4-benzyl-5-hydroxymethyl oxazolidin-2-one, are the chiral
building blocks for the synthesis of HIV protease inhibitors such as saquina-
vir[2] and amprenavir.[3] To date, considerable efforts have been directed
Received in the UK October 27, 2004
Address correspondence to Lijun Lei, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555
Zuchongzhi Road, Shanghai 201203, China. Tel.: 86-21-50806600-3522; Fax: 86-
21-50806770; E-mail: qlijunlei@sina.com
1535

1536
L. Lei, X. He, and D. Bai
toward the synthesis of stereochemical pure (2S,3S)-AHPBA methyl ester and
its derivatives.[4–9] Kottenhahn et al.[10] first reported a practical synthetic route
suitable for the large-scale preparation of AHPBA. However, the synthetic
methods described in literature[4,11] all started from the boc or di-benzyl
protected 2-amino propionaldehyde, which underwent cyanohydrin reaction,
and followed by a sequence of reactions to obtain the target compound 7.
Herein, as part of our research work concerning the synthesis of novel HIV
protease inhibitors, we report a facile and efficient synthetic route to (4S,5S)-
4-benzyl-5-hydroxymethyl oxazolidin-2-one (7) in good yield and .99% e.e.
RESULTS AND DISCUSSION
Our synthesis started from phthaloyl protected L-phenylalanine 1, which was
treated with thionyl chloride instead of oxalyl chloride,[2] affording (S)-
phthaloyl phenylalanyl chloride 2. Aldehyde 3 was obtained in 55% yield
by catalytic hydrogenation of acyl chloride 2 on Pd/C (Scheme 1). It was
reported that 2 could be also reduced to 3 with lithium tris-(t-butoxy)-
aluminium hydride.[12]
With (S)-2-phthalimido-3-phenylpropionaldehyde 3 in hand, it was then
treated with diethylaluminum cyanide in toluene at 2788C, and the adduct
2-hydroxy-3-phthalimido-4-phenylbutyronitrile 4 was obtained in 80% yield
as a (2S,3S)-4 and (2R,3S)-4 mixture in a ratio of 2.6:1. The crude mixture
4 was used without purification. After hydrolysis of the cyanohydrins 4,
(2RS,3S)-AHPBA were afforded, which was protected once again with ethyl
Scheme 1. Reagents and conditions: (a) SOCl2, CH2Cl2, reflux, 12 h; (b) 10% Pd/C,
H2, 40–508C, 20 h; (c) Et2AlCN, toluene, 2788C; (d) i) 25% HCl, reflux, 24 h; ii) 40%
NaOH, ClCOOEt, pH ¼ 7–8; (e) 3M NaOH, rt, 4 h; (f) CH3 OH, Hþ, reflux, 4.5 h;
(g) NaBH4, CH3OH.

(2S,3S)-3-Amino-2-hydroxy-4-phenylbutyric Acid
1537
chloroformate to yield (2RS,3S)-3-ethoxycarbonylamino-2-hydroxy-4-phe-
nylbutyric acid. The diastereomeric enrichment was achieved by recrystalliza-
tion of the acids from toluene, giving (2S,3S)-3-ethoxycarbonylamino-2-
hydroxy-4-phenylbutyric acid 5 as a stereochemically pure compound in
54.5% yield in two steps. In comparison with other methods, our approach
to AHPBA and its derivatives features phthaloyl used as the protecting
group of a-amino aldehyde 3 in cyanidation with Nagata’s reagent, and
hydrolysis, deprotection, and reprotection of 4 could be processed in one
pot; thus, hydroxy acid 5 was obtained via a more convenient route.
(2S,3S)-3-Ethoxycarbonylamino-2-hydroxy-4-phenylbutyric acid 5 was
then treated with 3 M of NaOH for 8 h, affording (4S,5S)-4-benzyl-2-oxo-
oxazolidine-5-carboxylic acid 6 in 68.5% yield. After esterification of 6 and
reduction of the resulting ester with NaBH4 in methanol, the target
compound (4S,5S)-4-benzyl-5-hydroxymethyl oxazolidin-2-one
obtained in 74.5% yield and .99% e.e. value. The configuration of
compound was established by comparing the coupling constant
7 was
7
(J4,5 ¼ 8 Hz) and IR absorption of carbonyl group (1731 cm21).[6] To
determine the e.e. value of compound 7, we also prepared the enantiomer of
7, (4R,5R)-4-benzyl-5-hydroxymethyl oxazolidin-2-one from (R)-phthaloyl
phenylalanine via the same approach.
EXPERIMENTAL
General Procedures
Melting points were measured on a Buchi 510 apparatus and are uncorrected.
Elemental analyses were performed on a Carlo-Erba 1106 instrument. Infrared
spectra were obtained on a Nicolet Magna 750 spectrometer. NMR spectra
were measured on Bruker AMX-400 spectrometer with tetramethylsilane as
internal standard. Chemical shifts are reported in d (ppm) and coupling
constants in Hz. Specific rotations were measured on a Perkin-Elmer 241
MC. Mass spectra were determined on a Varian MAT-95 mass spectrometer.
(S)-Phthaloyl Phenylalanyl Chloride (2)
(S)-Phthaloyl phenylalanine 1 (5.9 g, 0.02 mol) was dissolved in dichloro-
methane (60 mL), and thionyl chloride (12 mL) was added to by one portion.
The solution was heated under mild reflux for 12 h. After cooling to rt, the
solution was concentrated in vacuum to dryness. The crude product was
dissolved in dichloromethane (6 mL), and petroleum ether (30 mL) was
added to the solution dropwise. The white solid was precipitated. The solid
was filtered and washed with petroleum ether (20 mL) and dried in vacuum,
giving 2 (5.0 g, 80%) as a white solid. Mp 79–828C, [a]2D0 ¼ 22318C (c 1.4,
benzene); lit.[13] Mp 82–838C, [a]2D0 ¼ 22008C (c1.4, benzene).

1538
L. Lei, X. He, and D. Bai
(S)-2-Phthalimido-3-phenylpropionaldehyde (3)
Chloride 2 (1.37 g, 4.36 mmol) was hydrogenated in toluene (40 mL) in the
presence of 1,2-butylene oxide (0.95 mL) and Pd/C (10%, 130 mg). The sus-
pension was stirred at 40–508C for 17 h until absorption of hydrogen was
stopped. The mixture was filtered and the filtrate was washed with saturated
sodium bicarbonate (2 mL ꢀ 3) and water (2 mL ꢀ 3). The organic layer
was concentrated in vacuum to provide the desired aldehyde 3 as a
yellowish solid, which was used without further purification. Recrystallization
from dichloromethane/petroleum ether afforded 3 as a white solid (662 mg,
55%). Mp 101–1048C, [a]D20 ¼ 22668C (c 0.5, benzene); lit.[13] Mp 110–
1138C, [a]2D0 ¼ 22078C (c 0.5, benzene). H NMR (CDCl3): d 9.8 (s, 1H),
1
7.10–7.20 (m, 5H), 7.70 (m, 2H), 7.80 (m, 2H), 5.0 (dd, J ¼ 5.5, 10.7 Hz,
1H), 3.60 (dd, J ¼ 5.5, 14.1 Hz, 2H), 3.30 (dd, J ¼ 10.7, 14.1 Hz, 2H); EI-
MS m/z (%): 279 (Mþ, 8), 251 (100), 91 (56).
2-Hydroxy-3-phthalimido-4-phenylbutyronitrile (4)
Aldehyde 3 (280 mg, 1.0 mmol) was dissolved in anhydrous toluene (30 mL)
and cooled to 2788C under argon. To the solution was added diethylalumi-
num cyanide (1.2 mL, 1 M in toluene, 1.2 mmol) dropwise over 10 min. The
mixture was stirred at this temperature for 20 h, and then saturated aqueous
ammonium chloride (10 mL) was added to quench the reaction. The organic
layer was separated and the aqueous phase was extracted with ethyl acetate
(10 mL ꢀ 3). The combined organic layers were washed with brine and
water and dried over anhydrous Na2SO4. The solid obtained after removal
of the solvent was recrystallized from dichloromethane/petroleum ether,
affording 4 as a white solid (245 mg, 80%). After separation with preparative
TLC, two diastereomeric isomers (2S,3S)-4 and (2R,3S)-4 were obtained,
respectively. The diastereoselection (2.6:1) of cyanohydrin 4 was measured
1
by H NMR.
(2S,3S)-2-Hydroxy-3-phthalimido-4-phenylbutyronitrile: Mp 133–1358C.
1H NMR (CDCl3): d 7.10–7.20 (m, 5H), 7.70 (m, 2H), 7.80 (m, 2H), 5.15 (dd,
J ¼ 5.2, 1.6 Hz, 1H), 4.80 (m, J ¼ 5.2, 1.6, 4.0 Hz, 1H), 4.10 (s, 1H), 3.40
(ABXsystem, J ¼ 4.0, 1.2Hz, 2H); EI-MS m/z(%): 306 (Mþ, 3), 279 (16),
251 (100), 250 (90), 232 (76), 91 (30); IR (KBr, cm21): 3494.4, 1774.2,
1390.4, 1365.4, 1107.0, 721.3.
(2R,3S) hyphen;2-Hydroxy-3-phthalimido -4-phenylbutyronitrile: Mp
1
155–1578C. H NMR (CDCl3): d 7.10–7.20 (m, 5H), 7.80 (m, 2H), 7.90
(m, 2H), 5.40 (d, J ¼ 11.2 Hz, 1H), 4.80 (m, J ¼ 4.8, 8.0 Hz, 1H), 4.75 (dd,
J ¼ 4.8 Hz, 1H), 3.30 (dd, J ¼ 8.0, 5.6 Hz, 1H), 3.10 (dd, J ¼ 8.0, 5.6 Hz,
1H); EI-MS m/z (%): 306 (Mþ, 3), 279 (16), 251 (100), 250 (90), 232 (76),
91 (30); IR(KBr, cm21): 3349.8, 1770.4, 1697.1, 1402.0, 1375.0, 1110.8, 721.3.

(2S,3S)-3-Amino-2-hydroxy-4-phenylbutyric Acid
1539
(2S,3S)-3-Ethoxycarbonylamino-2-hydroxy-4-phenylbutyric Acid (5)
Cyanohydrin 4 (2.0 g, 6.54 mmol) was suspended in 25% HCl (30 mL) and the
mixture was heated to reflux for 17 h. The reaction mixture was then cooled to
08C and stirred for 2 h. After filtration, the filtrate was adjusted to pH 7–8 with
40% aqueous solution of NaOH. To the solution was added ethyl chlorofor-
mate (0.9 mL, 9.41 mmol) and 40% aqueous solution of NaOH alternately
to maintain pH value of the reaction mixture at 7–8. The mixture was
stirred at rt for an additional 2 h, then adjusted to pH 1 with concentrated
hydrochloric acid. The mixture was extracted with ethyl acetate
(30 mL ꢀ 3). The organic layer was washed with water and dried over
anhydrous MgSO4. Removal of the solvent gave a yellow oil and which
was crystallized from toluene to afford 5 (0.95 g, 54.5%) as a white crystal.
Mp 137–1398C (Lit.[10] Mp 138–1408C), [a]2D0 ¼ 20.58 (c 0.56,
1
methanol); H NMR (DMSO): d 7.0–7.3 (m, 5H), 3.6–4.0 (m, 4H,), 2.65
(d, J ¼ 6.9 Hz, 2H), 1.0 (t, J ¼ 7.2 Hz, 3H); EI-MS m/z (%): 267 (Mþ, 8),
222 (10), 192 (100), 176 (80), 120 (68), 91 (100); IR(KBr, cm21): 307.4,
1737.6, 1687.4, 1552.4, 1274.7, 1049.1, 752.1, 702.0. Anal. calcd. for
C13H17NO5: C, 58.40; H, 6.37; N, 5.24. Found: C, 58.52; H, 6.40; N, 5.30.
(4S,5S)-4-Benzyl-2-oxo-oxazolidine-5-carboxylic Acid (6)
Acid 5 (1.2 g, 5.4 mmol) was added in one portion to 0.75 M of NaOH solution
(40 mL). After stirring at rt for 9 h, the solution was adjusted to pH 7 with con-
centrated hydrochloric acid and concentrated in vacuum to about 10 mL. The
pH of the residue was further adjusted to 1 with concentrated hydrochloric
acid, and the mixture was extracted with CH2Cl2 (20 mL ꢀ 3). The organic
layer was dried over anhydrous Na2SO4, and the solvent was removed in
vacuum. The residue was dissolved in ethyl acetate, and the product was pre-
cipitated by the addition of toluene. After stirring for 2 h, the solid was
collected by suction to afford 6 (0.68 g, 68.5%) as a white solid. Mp 174–
1768C, [a]2D0 ¼ 21108C (c 0.48, methanol). Lit.[10] Mp 172–1748C,
[a]2D0 ¼ 2106.28C (c 1.0, methanol). 1H NMR (CD3COCD3): d 7.2–7.4
(m, 5H), 5.2 (d, J ¼ 8.8 Hz, 1H), 4.5 (ddd, J ¼ 3.6, 8.8, 3.2 Hz, 1H), 3.0
(dd, J ¼ 3.6, 10.4 Hz, 1H), 2.6 (dd, J ¼ 10.4, 3.2 Hz, 1H); EI-MS m/z (%):
222 (M þ 1, 4), 203 (12), 130 (42), 92 (100). IR (KBr, cm21): 3330.5,
2843.9, 1758.8, 1670.1, 1392.4, 1278.6, 1081.9, 713.5; Anal. calcd. for
C11H11NO4: C, 59.70; H, 4.97; N, 6.33. Found: C, 59.95; H, 5.07; N, 6.36.
(4S,5S)-4-Benzyl-5-hydroxymethyl Oxazolidin-2-one (7)
To a solution of acid 6 (0.53 g, 2.40 mmol) in anhydrous methanol (20 mL)
was added sulfuric acid (0.5 mL), and the mixture was refluxed for 4 h.
After cooling to rt, the solution was adjusted to pH 7 with 40% NaOH
solution. The aqueous solution was concentrated under vacuum. To the

1540
L. Lei, X. He, and D. Bai
residue was added water (10 mL), and the mixture was extracted with CH2Cl2
(20 mL ꢀ 3). The combined organic layers were dried and evaporated in
vacuum to afford methyl ester of acid 6 as an oil. To the solution of the
methyl ester in anhydrous methanol (20 mL) was added sodium borohydride
(0.14 g, 3.6 mmol) portion wise under stirring at room temperature. The
reaction was monitored by TLC. At the end of the reaction, the mixture was
adjusted to pH 7 with 25% hydrochloric acid and concentrated to dryness in
vacuum. Water (10 mL) was added to the residue, and the mixture was
extracted with CH2Cl2 (20 mL ꢀ 3). The combined organic layers were
dried over anhydrous Na2SO4 and evaporated in vacuum to afford the crude
product as a white solid, which was recrystallized from ethyl acetate/
petroleum ether to afford the target compound 7 (0.37 g, 74.5%) with e.e.
value of more than 99% (chiral OD column, hexane/iPrOH ¼ 3/7, 215 nm,
0.9 mL/min). Mp 164–1668C, [a]2D0 ¼ 276.48C (c 0.36, methanol). Lit.[10]
1
Mp 166–1688C, [a]2D0 ¼ 279.48C (c 1.0, methanol). H NMR (CDCl3): d
7.2–7.4 (m, 5H), 4.95 (s, 1H), 4.80 (m, 1H), 4.2 (m, 1H), 4.0 (m, 2H), 3.0
(dd, J ¼ 13.5, 3.6 Hz, 1H), 2.8 (dd, J ¼ 13.5, 11.0 Hz, 1H); EI-MS m/z
(%): 208 (M þ 1, 6), 192 (42), 178 (44), 162 (36), 148 (44), 130 (45), 116
(88), 92 (100); IR(KBr, cm21): 3347.9, 3263.0, 2931.3, 1731.8, 1398.2,
1259.3, 1039.5, 738.6; Anal. calcd. for C11H13NO3: C, 63.76; H, 6.28; N,
6.76. Found: C, 63.90; H, 6.30; N, 6.86.
REFERENCES
1. Seigo, I.; Takeshi, N.; Tadao, I.; Takeshi, K. Nat. Prod. Lett. 1992, 1, 21–24.
2. Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis 2001, 15, 2203–2229.
3. Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Kishibata, N.; Izawa, K. Org.
Biomol. Chem. 2004, 2, 2061–2070.
4. Shibata, N.; Itoh, E.; Terashima, S. Chem. Pharm. Bull. 1998, 46, 733–735.
5. Manickam, G.; Nogami, H.; Kanai, M.; Groger, H.; Shibasaki, M. Synlett 2001,
617–620.
6. Melon, D.; Gravier-Pelletier, C.; Merrer, Y. L.; Depezay, J. C. Bull. Soc. Chim. Fr.
1992, 129, 585–593.
7. Yuan, W.; Munoz, B.; Wong, C.-H. J. Med. Chem. 1993, 36, 211–220.
8. Fassler, A.; Bold, G.; Steiner, H. Tetrahedron Lett. 1998, 39, 4925–4928.
9. Ambroise, L.; Dumez, E.; Szeki, A.; Jackson, R. F. W. Synthesis 2002, 15,
2296–2308.
10. Kottenhahn, M.; Drauz, K.; Hilpert, H. US Patent 5994555, 1999.
11. Andres, J. M.; Martinez, M. A.; Pedrosa, R.; Perez-Encabo, A. Tetrahedron:
Asymmetry 2001, 12, 347–353.
12. Zlatoidsky, P. Tetrahedron Lett. 1995, 36, 7281–7284.
13. Gacek, M.; Undheim, K. Tetrahedron. 1974, 30, 4233–4237.