Improved enantioselective synthesis of protected (3S,4S)-4-amino-3,5- dihydroxypentanoic acid (ADPA)

Article abstract of DOI:10.1080/00397910903029958

An improved enantioselective synthesis of protected (3S,4S)-4-amino-3,5- dihydroxypentanoic acid (ADPA) from L-serine has been developed. Enantioselectivity is improved by replacing the methyl ester with the tert-butyl ester and using neutral magnesium salt of esters to give β-keto ester.

Full text of DOI:10.1080/00397910903029958

Synthetic Communications1, 40: 1099–1105, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903029958
IMPROVED ENANTIOSELECTIVE SYNTHESIS
OF PROTECTED (3S,4S)-4-AMINO-3,5-
DIHYDROXYPENTANOIC ACID (ADPA)
Duo Mei, Wei Zhang, and Yingxia Li
School of Pharmacy, Fudan University, Shanghai, China
An improved enantioselective synthesis of protected (3S,4S)-4-amino-3,5-dihydroxypentanoic
acid (ADPA) from L-serine has been developed. Enantioselectivity is improved by replacing
the methyl ester with the tert-butyl ester and using neutral magnesium salt of esters to give
b-keto ester.
Keywords: ADPA; c-amino-b-hydroxy acids; enantioselective synthesis
INTRODUCTION
The stereoselective synthesis of c-amino-b-hydroxy acids has received increas-
ing attention because of their biological activity as peptide mimics.[1] Statine (1),
(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (Fig. 1), as the c-amino-b-
hydroxy acid[2] first discovered, is an important component of pepstatin, which is
a natural aspartate protease inhibitor. Its different c-side chain analogs have been
developed as potent inhibitors of pepsin, penicilloepsin, and rennin.
Other c-amino-b-hydroxy acids are also found in natural products. For
example, (3S,4S)-4-amino-3,5-dihydroxypentanoic acid (ADPA, 2), an important
member in this family, has been found in cyclic depsipeptide thalassosiramides A
and B,[3] which are the first secondary metabolites isolated from marine a-proteobac-
terium Thalassospira sp. The thalassosiramides bearing three c-amino acids have
novel structures and show immunosuppressive activity in an interleukin-5 inhibition
assay (IC50 ¼ 5 mM for thalassospiramide B). As a part of the total synthesis of
thalassosiramides, we herein report the efficient enantioselective synthesis of
(3S,4S)-4-amino-3,5-dihydroxypentanoic acid (ADPA).
RESULTS AND DISCUSSION
One of the simplest conceptual approaches to the statine family is the NaBH4
reduction of c-(N,N-dibenzylamino)-b-keto esters (Scheme 1), which are available
Received March 12, 2009.
Address correspondence to Yingxia Li, School of Pharmacy, Fudan University, Shanghai 201203,
China. E-mail: liyx417@hotmail.com
1099

1100
D. MEI, W. ZHANG, AND Y. LI
Figure 1. Structures of statine, ADPA, and thalassospiramides A and B.
Scheme 1. General synthetic route of c-amino-b-hydroxy acid.
from a-amino acids, to yield syn diastereoisomers in good diastereomeric ratios.[4]
The excellent diastereoselectivity is attributed to the Fekin–Ahn transition state
for the bulky N,N-dibenzyl-protected compounds. The carboxylate group is gener-
ally masked with methyl ester first to avoid benzylating before the amino group is
dibenzylated. After hydrolysis of methyl ester, the amino acid is converted to a more
reactive acylating agent to give b-keto ester via Claisen condensation. However,
Scheme 2. (a) AcOtBu, HClO4, rt, 65%; (b) BnBr, NaHCO3, THF, DMSO, reflux, 92%; (c) 50% TFA=
DCM, rt, quant.; (d) TBSCl, imidazole, DMAP, THF, rt, 84%; (e) CDI, THF, and then MgCl2, KO2CCH2
CO2Me, THF, 60%; (f) NaBH4, MeOH, ꢀ40 ꢁC, 89%, de 81%; and (g) TBAF, THF, 0 ꢁC, 75%. DMAP,
4-dimethylamino pyridine; TBAF, tetrabutyl ammonium fluoride; and CDI, carbonyldiimidazole.

SYNTHESIS OF PROTECTED ADPA
1101
different degrees of racemization may occur when cleaving the methyl ester.[4] For
the amino acid ADPA, it was reported that the saponification of methyl ester caused
significant racemization for Bn2-Ser(TBDPS)-OMe.[5] What is worse, the O-benzyl
derivative was racemized completely in this step.[5] We turned to another method
reported by Hoffman[4] to cleave the methyl ester. We treated the methyl ester
with LiI=NaCN in refluxed pyridine, however, the amino acid was also racemized
completely. It is necessary to develop a racemation-free route for (3S,4S)-4-amino-3,
5-dihydroxypentanoic acid.
Our improved synthetic route is displayed as Scheme 2. Treatment of L-serine
with tert-butyl acetate with the catalysis of 0.2 eq of HClO4 gave its tert-butyl ester 4
in 65% yield. The traditional methyl ester was replaced by tert-butyl ester to avoid
the strong basic conditions of hydrolysis, and the tert-butyl ester could be removed
by 50% trifluoroacetic acid=dichloromethane (TFA=DCM) that may not cause race-
mization. Notably, the quantity of catalyst must be controlled, or the hydroxyl
group and the tert-butyl ether will be protected simultaneously. The free amine
in Ser-OtBu was dibenzylated with BnBr and NaHCO3 in tetrahydrofuran=
dimethylsulfoxide (THF=DMSO) under reflux in 92% yield. The tert-butyl ester of
5 was removed by 50% TFA=DCM quantitatively. As expected, no significant race-
mization was detected by chiral high-performance liquid chromatography (HPLC) in
this step (>98% ee). Compound 6 was converted to serine by hydrogenolysis in
MeOH, and its enantiomeric excess was detected by chiral HPLC.
The primary hydroxyl group of 6 was protected as tert-butyldimethylsilyl
(TBS) ether 7 in 84% yield. Next was the Claisen condensation. Lithium diisopropyl-
amide (LDA), which is used to produce lithio tert-butyl acetate of Claisen conden-
sation, is a strong base that may lead to racemization. We adopted a milder
condition developed by Brooks et al.[6] to get c-(N,N-dibenzylamino)-b-keto esters.
MgCl2 and KO2CCH2CO2Me were refluxed in THF for 5 h to be activated as
K-Mg-enolate, and at the same time acid 7 was activated to the imidazolide. Then
the activated amino acid was added dropwise to the K-Mg-enolate suspension at
0 ꢁC, and the mixture was stirred for 16 h at rt, giving b-keto ester 8 in 60% yield.
Stereoselective reduction of 8 with NaBH4 in methanol at ꢀ40 ꢁC gave 9a and 9b
as a 9.5:1 diastereomeric mixture in 89% yield (81% de), but they were only separable
by flash chromatography after desilylation with TBAF in THF to give 10a and 10b
in the total yield of 75%. The physical data of pure 10a was matched excellently to
the literature. No detectable racemization was found in these steps.[7]
CONCLUSION
In conclusion, an improved enantioselective synthesis of protected ADPA
derivativing from L-serine has been developed. Enantiospectivity is improved by
replacing the methyl ester with the tert-butyl ester and using neutral magnesium salt
of esters to give b-keto ester. No detectable racemization was found in these steps.
EXPERIMENTAL
Solvents were purified in a conventional manner. Thin-layer chromatography
(TLC) was performed on precoated E. Merck silica-gel 60 F254 plates. Flash-column

1102
D. MEI, W. ZHANG, AND Y. LI
chromatography was performed on silica gel (200–300 mesh, Qingdao, China).
Optical rotations were determined with a Perkin-Elmer model 241 MC polarimeter.
1H NMR and 13C NMR spectra were taken on a Jeol JNM-ECP 600 spectrometer
with tetramethylsilane (TMS) as an internal standard, and chemical shifts are
recorded in parts per million (ppm).
L-Serine tert-Butyl Ester (4)
HClO4 (170 mL, 2.0 mmol) was added dropwise to a solution of L-serine
(1.05 g, 10.0 mmol) in tert-butyl acetate (20 mL) at 0 ꢁC. The reaction mixture was
stirred at room temperature for 12 h and then washed with H2O (2 ꢂ 10 mL) and 1
N HCl (2 ꢂ 10 mL). The resultant aqueous solution was adjusted to pH 9 by addition
of 10% K2CO3 solution and then extracted with DCM (3 ꢂ 100 mL). The combined
organic phases were dried over Na2SO4, filtered, and concentrated to give a yellow
oil (1.04 g, 65.0%), which was directly used in the next step without further
purification.
N,N-Dibenzylamino-L-serine tert-Butyl Ester (5)
Benzyl bromide (2.2 mL, 19.5 mmol) and NaHCO3 (2.73 g, 32.5 mmol) were
added to a solution of 4 (1.04 g, 6.5 mmol) in a mixture of THF (12 mL) and DMSO
(3 mL). The reaction mixture was heated to reflux for 15 h, cooled to room tem-
perature, and diluted with H2O (100 mL). The aqueous phase was extracted with
EtOAc (3 ꢂ 50 mL). The combined organic phase was washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. Flash chromatography on
silica gel (eluent: heptane=EtOAc ¼ 10=1 to 6=1) afforded 5 as a yellow oil (2.04 g,
20
92.0%). ½aꢃD ¼ ꢀ5.8 (c ¼ 0.2, CHCl3); IR (KBr): 3325, 1659, 1442, 1005, 745,
1
700 cmꢀ1; H NMR (CDCl3, 600 MHz) d: 7.21–7.41 (m, 5H, Ar-H), 3.96 (d, 2H,
J ¼ 13.7 Hz, NCH2Ph), 3.72 (dd, 1H, J ¼ 8.8, 7.1 Hz, CHaHbOH), 3.70 (d, 2H,
J ¼ 13.7 Hz, NCH2Ph), 3.57 (dd, 1H, J ¼ 8.8, 5.5 Hz, CHaHbOH), 3.44 (dd, 1H,
J ¼ 7.1, 6.0 Hz, CHNBn2), 1.53 [s, 9H, OC(CH3)3]; HR ESI-MS calcd. [M þ H]þ
342.2003; found 342.1999.
N,N-Dibenzylamino-L-serine (6)
TFA (5.0 mL, 67.3 mmol) was added dropwise to a solution of 5 (2.00 g,
5.9 mmol) in DCM (5 mL) at 0 ꢁC and stirred 2 h at 0 ꢁC. The reaction was moni-
tored by TLC, and after the starting material had disappeared, the reaction mixture
20
was concentrated twice to give 6 as white crystals (2.04 g, 92.0%). ½aꢃD ¼ ꢀ103.1
20
(c ¼ 1.0, CH3OH), lit.[8] ½aꢃD ¼ ꢀ79.0 (2% CH3OH); IR (KBr): 3421, 3196, 1617,
1
1355, 1050, 758, 700 cmꢀ1; H NMR (DMSO-d6, 600 MHz) d: 7.19–7.36 (m, 10H,
Ar-H), 4.18 (brs, 1H, OH), 3.80 (d, 2H, J ¼ 14.4 Hz, NCH2Ph), 3.77 (dd, 1H,
J ¼ 11.0, 7.7 Hz, CHaHbOTBS), 3.65 (d, 2H, J ¼ 14.3 Hz, NCH2Ph), 3.62 (dd,
1H, J ¼ 11.0, 6.6 Hz, CHaHbOTBS), 3.24 (dd, J ¼ 7.7, 6.6 Hz, CHNBn2); 13C
NMR (DMSO-d6, 150 MHz) d: 140.4, 128.9, 128.7, 127.3, 63.3, 61.0, 55.2; HR
ESI-MS calcd. [M ꢀ H]þ, 284.1366, found 284.1362.

SYNTHESIS OF PROTECTED ADPA
1103
(S)-2-(N,N-Dibenzylamino)-3-(tert-butyl-dimethylsiloxy)-propanoic
Acid (7)
Imidazole (506.7 mg, 7.5 mmol) was added to a solution of 6 (1.65 g, 5.8 mmol)
in THF (12 mL) under argon at 0 ꢁC and stirred 0.5 h. Then tert-butyldimethylsilyl
chloride (1.05 g, 7.0 mmol) was added. The reaction mixture was stirred at room tem-
perature for 3 h (100 mL) and quenched by addition of H2O (100 mL). The aqueous
phase was extracted with EtOAc (3 ꢂ 100 mL). The combined organic phases were
washed with 1 N HCl (2 ꢂ 20 mL) and brine (2 ꢂ 20 mL), dried over Na2SO4, and
concentrated under reduced pressure. Flash chromatography on silica gel (eluent:
chloroform=methanol ¼ 100=1 to 40=1) afforded 7 as a yellow oil (1.95 g, 84.0%).
20
20
½aꢃD ¼ ꢀ52.6 (c ¼ 0.2, CH3OH), lit.[9] ½aꢃD ¼ ꢀ50.85 (c ¼ 0.35, CHCl3); IR (KBr):
3328, 3149, 1563, 1066, 834, 662 cmꢀ1; H NMR (CDCl3, 600 MHz) d: 7.31–7.38
1
(m, 10H, Ar-H), 4.32 (dd, 1H, J ¼ 11.5, 5.0 Hz, CHaHbOTBS), 3.75 (dd, 1H,
J ¼ 11.5, 8.7 Hz, CHaHbOTBS), 4.11 (d, 2H, J ¼ 11.0 Hz, NCH2Ph), 3.98 (d, 2H,
J ¼ 11.0 Hz, NCH2Ph), 3.77 (dd, J ¼ 9.2, 5.5 Hz, CHNBn2), 0.96 [s, 9H, (CH3)3CSi],
0.14 (s, 3H, CH3Si), 0.13 (s, 3H, CH3Si); HR ESI-MS calcd. [M ꢀ H]þ; 398.2151;
found 398.2148.
(S)-4-(N,N-Dibenzylamino)-3-oxo-5-(tert-butyl-dimethylsiloxy)-
pentanoic Acid Methyl Ester (8)
MgCl2 (730.8 mg, 7.7 mmol) was suspended in THF (40 mL), KO2CCH2
CO2Me (1.39 g, 8.3 mmol) was added in one portion, and the resulting suspension
heated to reflux for 5 h. The suspension was then cooled with an ice bath. In the
meantime, 7 (1.90 g, 4.8 mmol) was dissolved in THF (10 mL). The solution was
cooled in an ice bath, and CDI (843.4 mg, 5.2 mmol) was added in portions. The
solution was stirred 1 h at 0 ꢁC and 1 h at rt. This solution containing the activated
amino acid was then added dropwise to the K-Mg-enolate suspension via addition
funnel at 0 ꢁC. The resulting suspension was stirred for 16 h at room temperature.
The solvent was evaporated, the residue was taken up in EtOAc (50 mL), and 1 N
HCl (50 mL) solution was added. The mixture was stirred for 10 min, resulting in a
yellowish solution. The layers were separated, and the aqueous layer was extracted
with EtOAc (3 ꢂ 100 mL). The combined organic layers were then washed with 1 N
HCl (2 ꢂ 20 mL), 10% NaHCO3 solution (2 ꢂ 20 mL), and brine (2 ꢂ 20 mL). The
organic layer was dried over Na2SO4 and filtered, and the solvent was evaporated.
Flash chromatography on silica gel (eluent: heptane=EtOAc ¼ 80=1 to 20=1)
20
afforded 8 as a yellow oil (1.95 g, 84.0%). ½aꢃD ¼ ꢀ10.3 (c ¼ 0.2, CHCl3); IR
(KBr): 2932, 1742, 1455, 1140, 837, 699 cmꢀ1 1H NMR (CDCl3, 600 MHz) d:
;
7.24–7.52 (m, 10H, Ar-H), 4.11 (dd, 1H, J ¼ 10.5, 3.2 Hz, CHaHbOTBS), 4.03
(dd, 1H, J ¼ 10.5, 5.1 Hz, CHaHbOTBS), 3.84 (d, 2H, J ¼ 13.5 Hz, NCH2Ph),
3.80 (d, 2H, J ¼ 13.5 Hz, NCH2Ph), 3.62 (s, 3H, OCH3), 3.58 (dd, 1H, J ¼ 5.5,
3.2 Hz, CHNBn2), 3.51 (d, 1H, J ¼ 16.0 Hz, CHaHbCO), 3.44 (d, 1H, J ¼ 16.0 Hz,
CHaHbCO), 0.92 [s, 9H, (CH3)3CSi], 0.10 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si);
13C NMR (CDCl3, 150 MHz) d: 203.6, 166.7, 129.1, 128.4, 127.2, 81.5, 66.9,
60.3, 55.2, 48.2, 25.8, ꢀ3.4, ꢀ4.4; HR ESI-MS calcd. [M þ H]þ, 456.2493; found
456.2491.

1104
D. MEI, W. ZHANG, AND Y. LI
(3S,4S)- and (3R,4S)-4-(N,N-Dibenzylamino)-3-hydroxy-5-(tert-
butyl-dimethyl siloxy)-pentanoic Acid Methyl Ester (9a and 9b)
Compound 8 (1.30 g, 2.9 mmol) in methanol (50 mL) was cooled to ꢀ40 ꢁC and
treated with NaBH4 (220.4 mg, 5.8 mmol). The reaction was monitored by TLC.
After 3 h, the solution was quenched with H2O (100 mL) at pH, 5–6 (adjusted by
1 N HCl solution), extracted with ethyl ether (3 ꢂ 100 mL), washed with brine
(3 ꢂ 20 mL), dried over MgSO4, and filtered, and the solvent was evaporated. Flash
chromatography on silica gel (eluent: heptane=EtOAc ¼ 80=1 to 15=1) afforded
1
compounds 9a and 9b (1.18 g, 89.0%, 81% de based on H NMR) as a yellow oil.
1H NMR (CDCl3, 600 MHz) d: 9a: 7.22–7.31 (m, 10H, Ar-H), 4.13–4.16 (m, 1H,
CHOH), 4.01 (d, 2H, J ¼ 13.2 Hz, NCH2Ph), 3.90 (dd, 1H, J ¼ 10.5, 5.0 Hz, CHaHb
OTBS), 3.88 (dd, 1H, J ¼ 10.5, 5.5 Hz, CHaHbOTBS), 3.65 (s, 3H, OCH3), 3.58 (d,
2H, J ¼ 13.2 Hz, NCH2Ph), 2.64–2.67 (m, 1H, Bn2NCH), 2.50 (dd, 1H, J ¼ 14.9,
2.8 Hz, CHaHbCO), 2.31 (dd, 1H, J ¼ 14.9, 8.8 Hz, CHaHbCO), 0.94 [s, 9H,
SiC(CH3)3], 0.12 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3); 9b: 7.22–7.32 (m, 10H, Ar-
H), 4.28–4.31 (m, 1H, CHOH), 4.10 (dd, 1H, J ¼ 10.5, 5.0 Hz, CHaHbOTBS), 4.03
(dd, 1H, J ¼ 10.5, 5.5 Hz, CHaHbOTBS), 3.88 (d, 2H, J ¼ 13.7 Hz, NCH2Ph), 3.66
(s, 3H, OCH3), 3.62 (d, 2H, J ¼ 13.2 Hz, NCH2Ph), 3.31 (d, 1H, J ¼ 4.4 Hz, CHOH),
2.95 (dd, 1H, J ¼ 16.0, 2.8 Hz, CHaHbCO), 2.64–2.67 (m, 1H, Bn2NCH), 2.26 (dd,
1H, J ¼ 16.0, 9.4 Hz, CHaHbCO), 0.94 [s, 9H, (CH3)3CSi], 0.13 (s, 3H, CH3Si),
0.12 (s, 3H, CH3Si); HR ESI-MS calcd. [M þ H]þ; 458.2650; found 458.2650.
(3S,4S)-4-(N,N-Dibenzylamino)-3,5-dihydroxypentanoic Acid
Methyl Ester (10a)
A solution of tetrabutylammonium fluoride (576.8 mg, 2.2 mmol) in THF
(10 mL) was slowly added to a solution of 9a and 9b (1.00 g, 2.2 mmol) in THF
(5 mL) at 0 ꢁC. The mixture was stirred for 2 h at 0 ꢁC and quenched by addition
of water (100 mL). The aqueous phase was extracted with ethyl ether (3 ꢂ 50 mL),
and the combined organic extracts were washed with brine (3 ꢂ 20 mL), dried over
MgSO4, concentrated, and chromatographed on silica gel (eluent: heptane=
EtOAc ¼ 6=1 to 1=1) to afford compound 10a (512.7 mg, 75%) as a colorless oil.
20
½aꢃD ¼ ꢀ5.9 (c ¼ 1.0, CHCl3); IR (KBr): 3265, 2983, 1684, 1368, 1125, 754,
1
700 cmꢀ1; H NMR (CDCl3, 600 MHz) d: 7.24–7.33 (m, 10H, Ar-H), 4.22–4.26
(m, 1H, CHOH), 4.12 (d, 2H, J ¼ 13.2 Hz, NCH2Ph), 3.80 (d, 2H, J ¼ 13.2 Hz,
NCH2Ph), 3.72 (dd, 1H, J ¼ 10.4, 4.8 Hz, CHaHbOH), 3.88 (dd, 1H, J ¼ 10.4,
6.8 Hz, CHaHbOH), 3.62 (s, 3H, OCH3), 2.71–2.76 (m, 1H, Bn2NCH), 2.41 (dd,
1H, J ¼ 15.4, 3.3 Hz, CHaHbCO), 2.36 (dd, 1H, J ¼ 15.4, 8.8 Hz, CHaHbCO); 13C
NMR (CDCl3, 150 MHz) d: 172.3, 129.3, 128.5, 127.4, 67.7, 66.8, 62.9, 58.3, 54.7,
40.1; HR ESI-MS calcd. [M þ H]þ, 344.1785; found 344.1784.
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SYNTHESIS OF PROTECTED ADPA
1105
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7. The methyl ester of 10a was converted to tert-butyl ester, ½aꢃD ¼ ꢀ4.4 (c ¼ 1.0, CDCl3), lit.
20
´
´
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Copyright of Synthetic Communications is the property of Taylor & Francis Ltd and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.