Synthesis of hydroxymethyl side-chained α-aminoxy diamide

Article abstract of DOI:10.1080/00397910903243773

Unnatural polar α-aminoxy acid residue with proteingenous hydroxymethyl side chain, a building block of the peptidomimetic foldamer of -aminoxy peptide, was synthesized starting from natural amino acid L-serine. The starting material, L-serine, undergoes a reaction sequence to produce compound 1 in three steps: (1) the neighboring carboxyl group participates in diazotization/bromination to transform the amino group to a bromo group, (2) the C-terminal carboxyl group is protected, and (3) bromide is SN2-displaced by N-hydroxyl phthalimide to introduce a N-O bond. After several conventional deprotection/coupling reactions, compound 1 is easily transformed to an -aminoxy diamide, which can be widely used in peptidomimetics design.

Full text of DOI:10.1080/00397910903243773

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Synthesis of Hydroxymethyl Side-
Chained α-Aminoxy Diamide
Zheng Luo a , Hai-Feng Yang a , Xiao-Wei Chang a & Dan-Wei Zhang a
a Department of Chemistry, Fudan University, Shanghai, China
Published online: 25 Aug 2010.
To cite this article: Zheng Luo , Hai-Feng Yang , Xiao-Wei Chang & Dan-Wei Zhang (2010) Synthesis
of Hydroxymethyl Side-Chained α-Aminoxy Diamide, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:19, 2815-2821, DOI:
10.1080/00397910903243773
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Synthetic Communications1, 40: 2815–2821, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903243773
SYNTHESIS OF HYDROXYMETHYL SIDE-CHAINED
a-AMINOXY DIAMIDE
Zheng Luo, Hai-Feng Yang, Xiao-Wei Chang, and
Dan-Wei Zhang
Department of Chemistry, Fudan University, Shanghai, China
Unnatural polar a-aminoxy acid residue with proteingenous hydroxymethyl side chain, a
building block of the peptidomimetic foldamer of a-aminoxy peptide, was synthesized start-
ing from natural amino acid L-serine. The starting material, L-serine, undergoes a reaction
sequence to produce compound 1 in three steps: (1) the neighboring carboxyl group parti-
cipates in diazotization=bromination to transform the amino group to a bromo group, (2)
the C-terminal carboxyl group is protected, and (3) bromide is SN2-displaced by
N-hydroxyl phthalimide to introduce
a
NꢀO bond. After several conventional
deprotection=coupling reactions, compound 1 is easily transformed to an a-aminoxy
diamide, which can be widely used in peptidomimetics design.
Keywords: a-Aminoxy acid; diazotization=bromination; neighboring carboxyl group participation; pep-
tide synthesis; polar side chain
Since the first report of an unusual turn and helix structure (so-called a NꢀO turn
and a NꢀO helix) adopted by a-aminoxy peptides,[1] a kind of peptidomimetic
foldamer,[2] their conformational studies[3] and bioactivities[4] have widely attracted
researchers’ interest. Because of the importance of the natural amino acid side
chains’ function in biosystems, for example, participation in molecular recognition,
the synthesis of chiral a-aminoxy acid residues with various side chains have been
reported.[5] Herein, we report another synthetic strategy for hydroxymethyl side-
chained a-aminoxy acid residue, which can be incorporated into aminoxy peptide
backbones for peptidomimetic studies.
a-Aminoxy acid residues have an oxygen atom inserted between the amino
group and a-carbon of the natural a-amino acid backbone (Fig. 1). As shown in
Scheme 1, a retrosynthetic analysis of hydroxymethyl side-chained a-aminoxy acid
residue illustrates that the building block can be synthesized from a,b-dihydroxyl
propanoic acid (glyceric acid) or a-bromo-b-hydroxyl propanoic acid. Both inter-
mediates can be synthesized from the natural amino acid L-serine conveniently.
The literature reports usually adopted the strategy to transform L-serine to glyceric
Received March 27, 2009.
Address correspondence to Dan-Wei Zhang, Department of Chemistry, Fudan University,
Shanghai 200433, China. E-mail: zhangdw@fudan.edu.cn
2815

2816
Z. LUO ET AL.
Figure 1. Chiral a-aminoxy acid residue.
acid with protected primary hydroxyl group, selectively protect the C-terminal
carboxyl group, and introduce a NꢀO bond by the Mistunobu reaction.[5a,b]
As shown in Scheme 2, the strategy to transform the amino group to a bromo
group by diazotization=bromination provides a-bromo-b-hydroxyl propanoic acid,
which can displace via the SN2 mechanism without previously protecting the primary
hydroxyl group of glyceric acid. Moreover, starting from L-serine, its carboxyl group
as the neighboring group makes the retention of a-carbon’s configuration while
producing (S)-a-bromo-b-hydroxyl propanoic acid.[6]
Based on these two advantages, we prepared compound 1 in three sequential
steps: (1) diazotization=bromination of L-serine, (2) protection of C-terminal car-
boxyl group by methyl ester, and (3) displacement of bromide by N-hydroxyl
phthalimide via SN2 mechanism to introduce an NꢀO bond in 44% yield over three
steps (Scheme 3).
The primary hydroxyl group of compound 1 was then protected by tert-butyl-
dimethyl chlorosilane (TBDMSCl) to produce compound 2 in 82% yield (Scheme 4).
The protective groups of three functional groups of compound 2 can be removed
under different reaction conditions. That means this building block can be incorpo-
rated into aminoxy peptide backbone by a conventional peptide synthesis procedure.
To prove it, we synthesized the hydroxymethyl side-chained a-aminoxy acid
monomer 5 from building block 2 with the general deprotection=coupling methods.
As shown in Scheme 4, compound 2 was deprotected by hydrazine hydrate first to
provide N-terminal free amine, which coupled with pivalyl chloride to produce
compound 3. Then, the C-terminal of compound 3 was deprotected by LiOH ꢁ H2O
O followed by coupling with isobutylamine using 1-hydroxy-7-azabenzotriazole
(HOAt) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI)
as coupling reagent. At last, the TBDMS group bonded to the hydroxyl group was
removed by tetra-n-butylammonium fluoride (TBAF) in 90% yield.
Scheme 1. Retrosynthetic analysis of aminoxy acid residue with hydroxymethyl side chain.

HYDROXYMETHYL SIDE-CHAINED a-AMINOXY DIAMIDE
2817
Scheme 2. Mechanism for retention of configuration through neighboring carboxyl group participation
during the key diazotization=bromination sequence of L-serine.
Scheme 3. Three-step sequence to introduce NꢀO bond starting from L-serine, which reverses the
a-carbon’s configuration.
Scheme 4. Synthesis of a-aminoxy diamide 5 with hydroxymethyl side chain. Reagents and conditions: (a)
TBDMSCl, DMAP, DMF, rt, overnight; (b) (i) NH2NH2 ꢁ H2O, MeOH, rt, 2.5 h; (ii) pivalyl chloride,
K2CO3, CH2Cl2, 0 ꢂC, 4 h; (c) (i) LiOH ꢁ H2O, H2O=THF, rt, 2 h; (ii) isobutylamine, EDCI, HOAt,
CH2Cl2, rt, overnight; and (d) TBAF, THF, rt, 2 h.

2818
Z. LUO ET AL.
In conclusion, an a-aminoxy monomer with polar hydroxymethyl side chain
was synthesized from L-serine in 15% overall yield. The first strategy contains three
steps: neighboring carboxyl group participation in the diazotization=bromination of
L-serine, carboxyl group protection, and introduction of an NꢀO bond by SN2
displacement with N-hydroxyl phthalimide. This provides a convenient method to
prepare both N-terminal and C-terminal protected a-aminoxy residue with polar
hydroxymethyl side chains.
EXPERIMENTAL
All reagents and solvents for the reactions were of analytical grade and were
dried and distilled if necessary. Flash-column chromatography was performed on
Qing Dao Hai Yang silica gel 60 (230–400 mesh, ASTM) using ethyl acetate=n-hex-
ane as eluting solvents. Optical rotations were measured with a Perkin-Elmer 341MC
automatic polarimeter. NMR spectra were recorded on Jeol ECA-400 or Bruker
DMX-400 instruments. Mass spectra were recorded with a Finningan MAT 95 or
a Finnigan MAT 96 mass spectrometer for both low-resolution and high-resolution
mass spectra.
(R)-Methyl 2-(N-Phthalimidoxy)-3-hydroxypropanoate (1)
Aqueous sulfuric acid (220 ml, 2.5 N) was added to the mixture of 10.5 g of
L-serine (100 mmol) and 41.7 g of KBr (350 mmol) and cooled to 0 ꢂC. A solution
of NaNO2 (10.9 g, 158 mmol) in 50 ml of water was added to this mixture dropwise
while the reaction temperature was less than 5 ꢂC. Then the mixture was stirred at
0 ꢂC for 3 h. Upon completion, the reaction mixture was extracted with ethyl ether
(50 ml ꢃ 3), dried over anhydrous MgSO4, and concentrated. The crude product
was dissolved in 80 ml of dried methanol. Eleven ml of acetyl chloride (156 mmol)
were added dropwise to this mixture with stirring at room temperature. Then
it was refluxed for 4 h, the volatiles were removed under vacuum, and the residue
was dissolved in 100 ml of ethyl acetate. The organic solution was washed with satu-
rated NaHCO3 solution (30 ml) and brine (30 ml), dried over anhydrous MgSO4, and
concentrated to provide a colorless oil. This colorless oil was dissolved in 100 ml of
DMF, and 16.0 g of N-hydroxy phthalimide (100 mmol) and 14 ml of triethylamine
(100 mmol) were added to the solution. The mixture was then stirred at room tem-
perature overnight. Upon completion, the solution was concentrated and purified
by column chromatography to give 1 (11.62 g, 44%, over three steps) as colorless
20
oil. Rf ¼ 0.30 (EtOAc=hexane ¼ 1:2); ½aꢄD þ 55.5 ꢂ (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.90–7.80 (m, 4H), 4.76 (dd, J ¼ 4.8, 2.5 Hz, 1H), 4.08–3.92
(m, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.3, 164.3, 135.2, 128.7,
124.2, 85.9, 60.8, 52.9; EI-MS (20 eV) m=z 148 (100), 266 (Mþ þ 1, 1); HRMS-EI
m=z for C12H11NO6 (Mþ) calcd. 265.0586, found 265.0612.
(R)-Methyl 3-(tert-Butyldimethylsilyloxy)-2-(N-
phthalimidoxy)propanoate (2)
To a solution of 9.40 g of compound 1 (35.4 mmol) in 80 ml of DMF, 9.8 ml of
triethylamine (70.7 mmol), 0.31 g of DMAP (2.5 mmol), and 5.90 g of TBDMSCl

HYDROXYMETHYL SIDE-CHAINED a-AMINOXY DIAMIDE
2819
(39.2 mmol) were added. The mixture was stirred at room temperature overnight
and then concentrated. The residue was purified by column chromatography to give
2 (11.02 g, 82%) as yellow solid. Rf ¼ 0.30 (EtOAc=hexane ¼ 1:6); mp 100.5–103.5 ꢂC;
20
1
½aꢄD þ 15.2 ꢂ (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) d 7.85–7.74 (m, 4H), 4.85
(t, J ¼ 5.5 Hz, 1H), 4.15 (ABd, J ¼ 11.0, 5.5 Hz, 2H), 3.82 (s, 3H), 0.85 (s, 9H), 0.07
(s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) d 168.1, 163.1, 134.7, 128.9, 123.8,
85.9, 62.5, 52.6, 25.9, 25.6, 18.3, ꢀ5.4; ESI-MS m=z 274 (100); HRMS-ESI m=z for
C18H25NO6SiNa (Mþ þ Na) calcd. 402.1349, found 402.1368.
(R)-Methyl 3-(tert-Butyldimethylsilyloxy)-2-(N-
pivaloylamidoxy)propanoate (3)
Hydrazine hydrate (24.0 mmol, 1.5 g, 80%) was added to a solution of 3.0 g of
compound 2 (7.9 mmol) in 40 ml of methanol. The mixture was stirred at room tem-
perature for 2.5 h and then concentrated. The residue was dissolved in 20 ml of
CH2Cl2. The organic solution was washed with 3% NaHCO3 aqueous solution
(5 ml ꢃ 2), dried over anhydrous MgSO4, and concentrated to provide colorless
oil. This colorless oil was dissolved in 15 ml of CH2Cl2 and 8 ml of water. K2CO3
(2.51 g, 18.2 mmol) was added to the solution and cooled to 0 ꢂC. Pivalyl chloride
(1.25 ml, 10.2 mmol) was added to this mixture with vigorous stirring. The mixture
was stirred at room temperature for 4 h, and then 20 ml of CH2Cl2 was added.
The organic layer was separated, washed with brine, and dried over anhydrous
MgSO4. The mixture was concentrated and purified by column chromatography
to give 3 (2.0 g, 76% over two steps) as colorless oil. Rf ¼ 0.30 (EtOAc=hexane ¼
20
1:3); ½aꢄD þ 50.0 ꢂ (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 8.94 (s, 1H),
4.54 (t, J ¼ 3.2 Hz, 1H), 4.13–4.03 (m, 2H), 3.80 (s, 3H), 1.18 (s, 9H), 0.86 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) d 175.8, 170.3, 84.2,
62.7, 52.1, 38.0, 27.1, 25.7, 18.2, ꢀ5.4; ESI-MS m=z 356 (Mþ þ Na, 100), 274
(90); HRMS-ESI m=z for C15H31NO5SiNa (Mþ þ Na) calcd. 356.1869, found
356.1883.
(R)-3-(tert-Butyldimethylsilyloxy)-2-(N-pivaloylamidoxy)-
N-isobutylpropanamide (4)
LiOH ꢁ H2O (190 mg, 4.5 mmol) was added to a solution of 501 mg of 3
(1.5 mmol) in 8 ml of THF and 1 ml of water. The mixture was stirred at room tem-
perature over 2 h. Upon completion, the mixture was extracted by ethyl acetate
(15 ml ꢃ 2). The combined organic layer was dried over anhydrous MgSO4 and con-
centrated. The residue was dissolved in 10 ml of CH2Cl2. 1-Hydroxy-7-azobenzotria-
zole (HOAt, 264 mg, 1.9 mmol) and isobutyl amine (0.22 ml, 2.2 mmol) were added
to this solution at room temperature. After stirring the reaction mixture for 5 min,
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI, 431 mg,
2.2 mmol) was added and stirred overnight. Upon completion, the reaction mixture
was washed by 0.5 N hydrochloride aqueous solution (10 ml), water (10 ml), satu-
rated NaHCO3 aqueous solution (10 ml), water (10 ml), and brine (10 ml); dried over
anhydrous MgSO4; and then concentrated. The crude product was purified by flash
chromatography to give 4 (337 mg, 60% over two steps) as colorless oil. Rf ¼ 0.30

2820
Z. LUO ET AL.
20
1
(EtOAc=hexane ¼ 1:3); ½aꢄD þ 16.0 ꢂ (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) d
8.93 (s, 1H), 8.37 (s, br, 1H), 4.28–4.19 (m, 2H), 3.91 (dd, J ¼ 11.5, 4.0 Hz, 1H),
3.14–3.05 (m, 2H), 1.84–1.79 (m, 1H), 1.20 (s, 9H), 0.93 (d, J ¼ 6.4 Hz, 6H),
0.92 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H);13C NMR (100 MHz, CDCl3) d 178.6,
168.4, 86.5, 61.5, 46.4, 38.0, 28.2, 26.9, 19.9, ꢀ0.2; ESI-MS m=z 375 (Mþ þ 1,
100), 274 (50); HRMS-ESI m=z for C18H39N2O4Si (Mþ þ 1) calcd. 375.2679, found
375.2695.
(R)-3-Hydroxy-2-(N-pivaloylamidoxy)-N-isobutylpropanamide (5)
One ml of 1 M TBAF was added to a solution of 301 mg of compound 4
(0.8 mmol) in 5 ml of THF. The reaction mixture was stirred for 2 h. Upon com-
pletion, the mixture was concentrated and purified by flash chromatography to give
20
5 (187 mg, 90%) as colorless oil. Rf ¼ 0.30 (EtOAc=hexane ¼ 1:2); ½aꢄD þ 23.6 ꢂ (c 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) d 8.87 (s, 1H), 7.83 (s, br, 1H), 4.28 (t,
J ¼ 4.9 Hz, 1H), 3.98–3.89 (m, 2H), 3.47 (s, br, 1H), 3.14–3.10 (m, 2H), 1.86–1.79
(m, 1H), 1.23 (s, 9H), 0.93 (d, J ¼ 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3) d
179.0, 168.8, 86.9, 61.7, 46.7, 38.2, 28.5, 27.2, 20.1; ESI-MS m=z 242 (100), 283
(Mþ þ Na, 44); HRMS-ESI m=z for C12H24N2O4Na (Mþ þ Na) calcd. 283.1634,
found 283.1645.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of
China (Project No. 20202001), Fok Ying Tung Education Foundation (Project
No. 94023), and Fudan University. D.-W. Z. thanks Fudan University for the
Century Star Award.
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