Synthesis of (S)-(+)-2-amino-6-(aminooxy)hexanoic acid

Article abstract of DOI:10.1081/SCC-100000585

(S)-(+)-2-Amino-6-(aminooxy)hexanoic acid (AAHA, 3), a non-proteinogenic amino acid, and its derivative, (S)-(-)-6{[(tert-butoxycarbonyl)amino]oxy}-2-{[(9H-fluoren-9-ylmethoxy) carbonyl]amino}hexanoic acid (4), were synthesized from (S)-(-)6-amino-2-{[(be

Full text of DOI:10.1081/SCC-100000585

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SYNTHESIS OF (S)-(+)-2-AMINO-6-(AMINOOXY)-
HEXANOIC ACID
Maciej Adamczyk a & Rajarathnam E. Reddy a
a Department of Chemistry (9NM, Bldg AP20-2), Diagnostics Division, Abbott
Laboratories, 100 Abbott Park Road, Abbott Park, IL, 60064-6016, U.S.A.
Version of record first published: 16 Aug 2006.
To cite this article: Maciej Adamczyk & Rajarathnam E. Reddy (2001): SYNTHESIS OF (S)-(+)-2-AMINO-6-(AMINOOXY)-
HEXANOIC ACID, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:4, 579-586
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SYNTHETIC COMMUNICATIONS, 31(4), 579–586 (2001)
SYNTHESIS OF
(S)-(+)-2-AMINO-6-(AMINOOXY)-
HEXANOIC ACID
Maciej Adamczyk∗ and Rajarathnam E. Reddy
Department of Chemistry (9NM, Bldg AP20-2),
Diagnostics Division, Abbott Laboratories, 100 Abbott
Park Road, Abbott Park, IL 60064-6016, USA
ABSTRACT
(S)-(+)-2-Amino-6-(aminooxy)hexanoic acid (AAHA, 3),
a non-proteinogenic amino acid, and its derivative, (S)-(−)-6-
{[(tert-butoxycarbonyl)amino]oxy}-2-{[(9H-fluoren-9-ylmethoxy)-
carbonyl]amino}hexanoic acid (4), were synthesized from (S)-(−)-
6-amino-2-{[(benzyloxy)carbonyl]amino}hexanoicacid(5)ingood
overall yield.
Synthesis of non-proteinogenic amino acids is of considerable interest
currentlybecauseoftheirimportanceinavarietyofmedicinalandbiotechnological
–
applications (1–5). The aminooxy group ( ONH2) exhibits greater nucleophilicity
than the corresponding primary amino group, and the resulting O-alkyl oximes,
which are formed by reaction of aminooxy group with carbonyl compounds, are
more stable than the imines (6,7). Thus, proteins (8,9), oligonucleotides (10,11),
and hapten-label conjugates (12,13) have been chemoselectively ligated through
∗Corresponding author. E-mail: maciej.adamczyk@abbott.com
579
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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580
ADAMCZYK AND REDDY
NH2
NHR1
NHR2
N
R
O
O
HO2C
HO2C
(+)-3: R1 = R2 = H
(−)-4: R1 = Fmoc, R2 = Boc
L-Canaline (1): R = H2
L-Canavanine (2): R = C(NH2)2
Figure.
the oxime bond from aminooxy and carbonyl functional groups, thereby avoiding
the activation of carboxylic acid and side-chain protection. The aminooxy group
is also present in natural products, e.g., L-canaline (1) (Figure), which was iso-
lated from leguminous plants as a degradation product of L-canavanine (2) ex-
hibiting insecticidal and antitumor activities (14,15). Recently, for our program
on the synthesis of novel peptidimemtics, we needed an amino acid building
block, L-lysine derivative with aminooxy functionality. In this paper, we de-
scribe the synthesis of (S)-(+)-2-amino-6-(aminooxy)hexanoic acid (AAHA, 3)
and its derivative, (S)-(−)-6-{[(tert-butoxycarbonyl)amino]oxy}-2-{[(9H-fluoren-
9-ylmethoxy)carbonyl]amino} hexanoic acid (4) from (S)-(−)-6-amino-2-
{[(benzyloxy)carbonyl]amino}hexanoic acid (5).
The strategy for the synthesis of (S)-(+)-AAHA (3), which is depicted in
Scheme 1, involves the utilization of a commercially available L-lysine derivative,
(S)-(−)-6-amino-2-[(benzyloxy)carbonyl]amino}hexanoic acid (5), in which the
ε-amine could be transformed to the desired aminooxy functional group. Thus,
(S)-(−)-5 was first heated with sodium nitroprusside (16) in water at pH 9.5 and
the resulting crude hydroxy acid [(S)-6a] was treated with ethereal-diazomethane
in ethyl acetate to form (S)-(−)-6b in an improved yield (43%) for two steps on
a 15-g scale. The hydroxy functionality in (S)-(+)-6b was then transformed to
the corresponding iodide (S)-(+)-7 in excellent yield (84%) by treatment with
iodine, triphenylphosphine, and imidazole in THF (17). The aminooxy function-
–
ality was introduced via alkylation of tert-butyl N-hydroxycarbamate (8) with
iodide (S)-(−)-7 using sodium hydride in THF. Purification of the crude product
by preparative HPLC afforded (S)-(+)-9 in 76% yield. The Cbz group in (S)-
(+)-9 was removed by hydrogenolysis and the crude amine (S)-10a was treated
with lithium hydroxide in THF-water to hydrolyze the methyl ester. The crude
compound was purified by preparative HPLC to give the acid (S)-(+)-10b in
86% yield. Finally, the Boc group in (S)-(+)-10b was hydrolyzed by treatment
with TFA-water and purified the crude product by preparative HPLC to afford

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NON-PROTEINOGENIC AMINO ACIDS
581
NHCbz
NHCbz
Na2Fe(CN)5NO
I2, PPh3
HO2C
NH2
MeO2C
OH
Imidazole,
THF, rt, 1.5 h
aq NaOH, 65 °C,
6 h, then CH2N2
(S) - (−)-
(−)
-
6
(S) -
5
NHCbz
NHCbz
NHBoc
BocHNOH (8)
MeO2C
NHBoc
O
MeO2C
I
NaH, THF,
0 °C-rt, 8 h
(S) - (+)-
(S) - (+)-
9
7
NH2
Pd/C, MeOH
TFA-water
(S) - (+)-
3
RO2C
O
H2, 2 h then
LiOH, THF-H2O
(9.5: 0.5 ratio), rt
1.5 h
(S) - 10a: R = Me
(S) - (+)-10b: R = H
Fmoc-Cl, aq Na2CO3
(S) - (−)-
4
THF, 0 °C, 1 h
Scheme 1.
(S)-(+)-2-amino-6-(aminooxy)hexanoic acid (AAHA, 3) in good (83%) yield as
its TFA salt. The Fmoc derivative, (S)-(−)-6-{[(tert-butoxycarbonyl)-amino]oxy}-
2-{[(9H-fluoren-9-ylmethoxy)carbonyl]-amino}hexanoicacid(4), whichisneeded
for the solid phase peptide synthesis, was also prepared from (S)-(+)-10b by treat-
ment with Fmoc-Cl in aq sodium carbonate-THF in 88% yield after purification
by HPLC.
In summary, (S)-(−)-amino-6-(aminooxy)hexanoic acid (AAHA, 3) and
its derivative, (S)-(−)-6-{[(tert-butoxycarbonyl)amino]oxy}-2-{[(9H-fluoren-9-yl
methoxy)carbonyl]amino}hexanoic acid (4), were synthesized from (S)-(−)-
6-amino-2-{[(benzyloxy)carbonyl]amino}hexanoic acid (5) in good overall
yield.
EXPERIMENTAL
General Methods and Materials
1H and 13C NMR spectra were recorded on a Varian Gemini spectrometer
(300 MHz) and the chemical shifts (δ) were reported in ppm relative to TMS
and coupling constants (J) were reported in Hz. Electrospray ionization mass
spectrometry (ESI-MS) was carried out on a Perkin-Elmer (Norwalk, CT) Sciex
API 100 Benchtop system employing Turbo Ionspray ion source, and HRMS were

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582
ADAMCZYK AND REDDY
obtained on a Nermang 3010 MS-50, JEOL SX102-A mass spectrometer. THF
was freshly distilled from a purple solution of sodium and benzophenone. (S)-
(−)-6-Amino-2-{[(benzyloxy)carbonyl]amino}-hexanoic acid (5) was purchased
from Novabiochem (San Diego, CA) and all other reagents were from Aldrich
Chemical Co. (Milwaukee, WI) or Sigma Chemical Co. (St. Louis, MO) and used
without purification. All the solvents employed were of HPLC grade purchased
from EM Science (Gibbstown, NJ) and used as received. Analytical reversed phase
(RP) HPLC was performed using a Waters, RCM, C18, Symmetry, 7.0 µm (8 ×
100 mm) (solvents ratio v/v reported). Preparative reversed phase (RP) HPLC was
performed using Waters RCM, C18, Symmetry, 7.0µm (40 × 100 mm), (solvents
ratio v/v reported). Optical rotations were measured on Autopol III polarimeter
from Rudolph Research (Flanders, NJ).
(S)-(−)-Methyl-2-{[(benzyloxy)carbonyl]amino}-6-hydroxyhexanoate (6b)
(S)-(−)-6-Amino-2-{[(benzyloxy)carbonyl]amino}-hexanoic acid (5,
15.75 g, 56.19 mmol) was dissolved in water (225 mL) and the pH adjusted to
9.5 using 4M aq. NaOH. The mixture was heated to 60–65◦C in an oil bath.
Sodium nitroprusside (30.0 g, 100.67 mmol, 1.8 equiv.) was added portionwise
over a 35-min period while maintaining the pH of the reaction mixture between
9–10 using 4N NaOH and a pH meter. The resulting brown mixture was heated for
an additional 6 h while maintaining the pH between 9–10 with occasional addi-
tion of 4M aq. NaOH. The reaction mixture was cooled to room temperature and
filtered through celite powder (5 mm bed). The pH of the filtrate was adjusted to
1.5 using 6M HCl and extracted with EtOAc (3 × 250 mL). The combined or-
ganic layers were washed with brine (100 mL), dried (Na2SO4), and concentrated
on a rotary evaporator. The resulting crude hydroxy-acid (S)-6a (11.8 g) was
dissolved in EtOAc (55 mL) and cooled with an ice bath. A freshly generated
ethereal-diazomethanesolution[100mL, generatedfrom N-nitroso-N-methylurea
(17.36 g, 168.59 mmol, 3.0 equiv.), KOH (18.87 g, 337.0 mmol, 6.0 equiv.),
ether (100 mL) and water (80 mL)] was added at 0–5◦C and allowed the mix-
ture to warm to room temperature. The mixture was then stirred for 18 h, and
carefully concentrated on a rotary evaporator below 30◦C bath temperature. The
crude product was purified by silica gel column chromatography (60% EtOAc
in hexanes) to afford 7.1 g of (S)-(−)-6b in 43% yield for two steps as a col-
orless viscous oil. Rf: 0.37 (60% EtOAc in hexanes); Analytical RP HPLC:
MeCN:0.1% aq trifluoroacetic acid/50:50, 2.0 mL/min at 225 nm, tR: 2.62 min,
97%; ESI-MS (m/z): 296 (M + H)+, 313 (M + NH4)+, 318 (M + Na)+, 613
(2 × M + Na)+ and identical in other physical properties to the reported values
(16).

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NON-PROTEINOGENIC AMINO ACIDS
583
(S)-(+)-Methyl-2-{[(benzyloxy)carbonyl]amino}-6-iodohexanoate (7)
Triphenylphosphine (5.895 g, 22.5 mmol, 1.5 equiv.), imidazole (1.63 g,
24.0 mmol, 1.6 equiv.) and iodine (5.69 g, 22.5 mmol, 1.5 equiv.) were added
sequentially to a solution of (S)-(−)-6b (4.44 g, 15.0 mmol) dissolved in THF
(150 mL) at room temperature under nitrogen. After stirring the mixture for 1.5 h,
the solvent was removed on a rotary evaporator to dryness and the crude product
was purified by silica gel column chromatography (20–25% EtOAc in hexanes)
to afford 5.08 g of iodide (S)-(+)-7 in 84% yield as colorless thick oil. Rf: 0.43
(25% EtOAc in hexanes); Analyticl RP HPLC: MeCN:0.1% aq trifluoroacetic
acid/50:50, 2.0 mL/min at 225 nm, tR: 16.34 min, >99%; [α]23 + 14.2 (c 1.31,
D
CHCl3); 1H NMR (CDCl3): δ 7.38–7.32 (m, 5 H), 5.29 (d, 1 H, J = 7.5 Hz), 5.12
(s, 2 H), 4.40 (q, 1 H, J = 12.6, 7.2 Hz), 3.76 (s, 3 H), 3.16 (t, 2 H, J = 6.9 Hz),
1.92–1.78 (m, 3 H), 1.75–1.60 (m, 1 H), 1.54–1.40 (m, 2 H); 13C NMR (CDCl3):
δ 172.7, 155.8, 136.2, 128.6, 128.2, 128.1, 67.1, 53.6, 52.5, 32.7, 31.6, 26.0, 6.1;
ESI-MS (m/z): 406 (M + H)+, 423 (M + NH4)+, 428 (M + Na)+, 833 (2 × M +
Na)+; HRMS (FAB, m/z): calcd. for C15H21NO4I, 406.0515 (M + H)+; observed,
406.0509.
(S)-(+)-Methyl-2-{[(benzyloxy)carbonyl]amino}-6-{[tert-butoxy carbonyl)-
amino]oxy}hexanoate (9)
NaH (dry 95%, 0.598 g, 24.94 mmol, 2.0 equiv.) was added in three portions
to a 0◦C cooled solution of tert-butyl-N-hydroxycarbamate (8, 4.14 g, 31.17 g, 2.5
equiv.) dissolved in THF (100 mL) under nitrogen. After stirring the mixture for
30 min, a solution of (S)-(+)-7 (5.02 g, 12.47 mmol) dissolved in THF (80 mL)
was added via double-ended needle at 0◦C over a 5-min period. After stirring
the mixture for 3 h, the cooling bath was removed and the mixture allowed to
warm to room temperature. Stirring was continued for an additional 12 h. The
mixture was diluted with EtOAc (1 L) and washed with brine (3 × 100 mL),
dried (MgSO4), and concentrated on a rotary evaporator. The crude compound was
dissolved in MeCH-0.1% aq trifluoroacetic acid (100 mL, 70:30 ratio) and purified
by preparative RP HPLC (MeCN:0.1% aq trifluoroacetic acid/50:50, 45.0 mL/min
at 225). The product was lyophilized to afford 3.71 g of (S)-(+)-9 in 73% yield as
a colorless viscous oil. Analytical RP HPLC: MeCN:aq trifluoroacetic acid/50:50,
2.0 mL/min at 225, tR: 9.61 min, >99%; [α]23 + 1.54 (c 0.78, CHCl3); 1H NMR
D
(CDCl3): δ 7.38–7.32 (m, 5 H), 5.41 (d, 1 H, J = 8.4 Hz), 5.11 (s, 2 H), 4.41–4.36
(m, 1 H), 3.83 (t, 2 H, J = 6.3 Hz), 3.75 (s, 3 H), 3.02 (br s, 1 H), 1.92–1.40
(m, 6 H), 1.47 (s, 9 H); 13C NMR (CDCl3): δ 172.9, 157.0, 156.0, 136.2, 128.5,
128.2, 128.1, 81.8, 76.1, 67.0, 53.5, 52.4, 32.3, 28.2, 27.3, 21.6; ESI-MS (m/z): 411

ORDER
REPRINTS
584
ADAMCZYK AND REDDY
(M + H)+; 428 (M + NH4)+, 433 (M + Na)+, 838 (2 × M + NH4)+, 843,
(2 × M + Na)+; HRMS (FAB, m/z): calcd. for C20H31N2O7, 411.2131 (M + H)+;
observed, 411.2142.
(S)-(+)-2-Amino-6-{[(tert-butoxycarbonyl)amino]oxy}hexanoic Acid (10b)
Ten percent Pd/C [(wet, Deguassa type E101 NE/W), 0.371 g] was added to
a solution of (S)-(+)-9 (3.71 g, 9.05 mmol) dissolved in methanol and stirred under
H2 atmosphere using a balloon at room temperature. after 1.25 h, the mixture was
filtered through celite powder (5 mm bed), washed with methanol (20 mL), and the
filtrate was concentrated on a rotary evaporator. The resulting crude amino-ester
(10a, 2.62 g) was dissolved in THF (82 mL). To this mixture, LiOH (monohydrate,
0.760 g, 18.1 mmol, 2.0 equiv.) and water (28 mL) were added sequentially at room
temperature and stirred for 1.25 h. Most of the THF from the reaction mixture was
removed on a rotary evaporator, diluted with water (25 mL), and adjusted the pH
to 4.0 using 6N HCl. The mixture was diluted with MeCN (25 mL) and purified by
preparative RP HPLC (MeCN:0.1% aq trifluoroacetic acid/20:80, 45.0 mL/min at
225). Lyophilization of the product gave 2.53 g of (S)-(+)-10b-TFA salt in 74%
yield as a colorless glassy material. Analytical RP HPLC: MeCN:aq trifluoroacetic
acid/20:80, 2.0 mL/min at 225 nm; tR: 3.4 min, 98%; [α]23D + 7.4 (c 1.12, MeOH);
1H NMR (CD3OD): δ 3.91 (dd, 1 H, J = 7.2, 6.0 Hz), 3.80 (t, 2 H, J = 6.0 Hz),
2.04–1.82 (m, 2 H), 1.72–1.50 (m, 4 H), 1.46 (s, 9 H); 13C NMR (CDCl3): δ 172.2,
159.2, 82.1, 76.8, 54.1, 31.3, 28.6, 28.5, 22.6; ESI-MS (m/z): 263 (M + H)+, 525
(2 × M + H)+; HRMS (FAB, m/z): calcd for C11H23N2O5, 263.1607 (M + H)+;
observed, 263.1604; Anal calcd. for C11H23F3N2O7: C, 41.49; H, 6.16; F, 15.15;
N, 7.44; Found: C, 41.39; H, 6.17; F, 15.36; N, 7.35.
(S)-(+)-2-Amino-6-(aminooxy)hexanoic Acid (3)
Trifluoroacetic acid (19 mL) and water (1.0 mL) were added to (S)-(+)-
10b-TFA salt (0.094 g, 0.25 mmol) at room temperature and stirred for 1.5 h. The
mixture was concentrated on a rotary evaporator, dissolved in 0.1% aq trifluo-
roacetic acid (10.0 mL), and purified by preparative RP HPLC (MeCN:0.1% aq
trifluoroacetic acid/5:95, 25.0 mL/min at 225 nm). Lyophilization of the product
gave 0.081 g of (S)-(+)-3 as its TFA salt in 83% yield as a colorless gummy
material. Analytical RP HPLC: MeCN:0.5 M triethylammonium acetate/5:95,
1
2.0 mL/min at 225 nm; tR: 2.42 min, 97%; [α]23 + 11.7 (c 0.58, MeOH); H
D
NMR (CD3OD): δ 4.05 (t, 3 H, J = 6.0 Hz), 4.00–3.93 (m, 1 H), 2.02–1.82
(m, 2 H), 1.81–1.44 (m, 4 H), 1H NMR (CD3CN + 5 drops of CF3CO2D): δ 4.05
(t, 2 H, J = 6.0 Hz), 3.98 (t, 1 H, J = 6.3 Hz), 1.96–1.80 (m, 2 H), 1.71–1.62

ORDER
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NON-PROTEINOGENIC AMINO ACIDS
585
(m, 2 H), 1.59–1.34 (m, 2 H); 13C NMR (CD3CN + 5 drops of (CF3CO2D).
δ 170.2, 76.2, 54.0, 30.0, 27.6, 21.8; ESI-MS (m/z): 163 (M + H)+, 185 (M +
Na)+, 325 (M + H)+ HRMS (FAB, m/z): calcd for C6H14N2O3, 163.1083 (M +
H)+; observed, 163.1086.
(S)-(−)-6-{[(tert-Butoxycarbonyl)amino]oxy}-2-{[(9H-fluoren-9-yl methoxy)-
carbonyl]amino}hexanoic Acid (4)
Aqueous Na2CO3 [(0.334 g, 3.15 mmol, 3.0 equiv., dissolved in water
(6 mL)] was added to a solution of (S)-(+)-10b-TFA salt (0.393 g, 1.05 mmol)
dissolved in THF (6 mL) and the mixture was cooled to 0◦C. 9-Fluorenylmethyl
chloroformate(Fmoc-Cl, 0.299g, 1.16g, 1.1equiv.)wasaddedintwoportionsover
a 5-min period and the mixture stirred for 1 h. The mixture was diluted with water
(15 mL), adjusted the pH to 4.0 using 0.1N HCl and purified by preparative HPLC
(MeCN:0.1% aq trifluoroacetic acid/65:35, 45.0 mL/min at 225 nm). Lyophiliza-
tion of the product gave 0.443 g of (S)-(−)-4 in 88% yield as white powder.
Analytical RP HPLC: MeCN:0.1% aq trifluoroacetic acid/65:35, 2.0 mL/min at
225 nm; tR: 4.02 min, >99%; [α]23 − 3.2 (c 0.66, MeOH); 1H NMR (CD3OD):
D
δ 7.78 (d, 2 H, J = 7.5 Hz), 7.67 (t, 2 H, J = 6.6 Hz), 7.41–7.27 (m, 4 H),
4.42–4.30 (m, 2 H), 4.20 (t, 1 H, J = 6.9 Hz), 4.15–4.11 (m, 1 H), 3.78
(t, 2 H, J = 6.3 Hz), 1.92–1.42 (m, 6 H), 1.45 (s, 9 H); 13C NMR (CD3OD):
δ 175.9, 159.1, 158.8, 145.4, 145.2, 142.6, 128.8, 128.2, 126.3, 120.9, 81.9, 77.3,
68.0, 55.3, 32.4, 28.6, 27.7, 23.5; ESI-MS (m/z): 485 (M + H)+, 502 (M + NH4)+,
986 (2 × M + NH4)+; HRMS (FAB, m/z): calcd for C26H32N2O7, 485.2288 (M +
H)+; observed, 485.2282; Anal calcd. for C26H34N2O8 (monohydrate): C, 62.14;
H, 6.82; 5.57; Found: C, 62.62; H, 6.10; N, 5.89.
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Received in the USA May 4, 2000

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