3-Amino-1-hydroxyacetone

Article abstract of DOI:10.1139/v04-010

3-Amino-1-hydroxypropan-2-one (3-amino-1-hydroxyacetone) was prepared in an overall yield of 52% in 6 steps starting with N-phthaloylglycine. This synthesis is readily adaptable for the preparation of bond-labeled samples, i.e., samples that are labeled intramolecularly at contiguous sites.

Full text of DOI:10.1139/v04-010

579
3-Amino-1-hydroxyacetone
Nisar Ullah, Clara Nanfe Fali, and Ian D. Spenser
Abstract: 3-Amino-1-hydroxypropan-2-one (3-amino-1-hydroxyacetone) was prepared in an overall yield of 52% in 6
steps starting with N-phthaloylglycine. This synthesis is readily adaptable for the preparation of bond-labeled samples,
i.e., samples that are labeled intramolecularly at contiguous sites.
Key words: 3-amino-1-hydroxyacetone, 3-amino-1-hydroxypropan-2-one.
Résumé : On a préparé la 3-amino-1-hydroxypropan-2-one (3-amino-1-hydroxyacétone), avec un rendement global de
52 %, en six étapes à partir de la N-phtaloylglycine. La synthèse peut facilement être adaptée à la préparation
d’échantillons portant des marqueurs intramoléculaires sur des sites voisins.
Mots clés : 3-amino-1-hydroxyacétone, 3-amino-1-hydroxypropan-2-one.
[Traduit par la Rédaction] Ullah et al. 582
Introduction
In the present preparation of aminohydroxyacetone, an
acid-catalyzed decomposition of the diazo compound (6)
(18) gave 1-hydroxy-3-phthalimidopropan-2-one (7), the N-
phthaloyl derivative of the desired product. However, at-
tempts to obtain (10) by hydrolytic removal of the phthaloyl
group of (7) were unsuccessful.
The phthaloyl unit was removed by reaction with
hydrazine. Before doing so, the keto group of (7) had to be
protected. This was done by reaction with ethyleneglycol to
yield 2-hydroxymethyl-2-phthalimidomethyl-1,3-dioxolane (8).
This compound had been prepared previously by somewhat
different reaction sequences (19, 20). Treatment of the ketal
(8) with hydrazine, followed by dilute HCl, gave 2-hydroxy-
methyl-2-aminomethyl-1,3-dioxolane hydrochloride (9). For
hydrolysis, the ketal was suspended in aqueous acetonitrile,
and the mixture was refluxed in the presence of an ion-
exchange resin, from which the product, 3-amino-1-hy-
droxyacetone hydrochloride (10), was eluted with 2 mol L–1
HCl and obtained in high yield.
When acetone, in place of acetonitrile, was employed as
the solvent in the above procedure, the yield of product was
less than 40%. Other methods used to carry out the depro-
tection of 9 were entirely unsuccessful. Attempted hydroly-
sis of 9 with HCl, with HCl in THF solution, or with
CF3CO2H was unsuccessful, as was attempted hydrolysis
with pyridinium p-toluenesulfonate (0.33, 0.66, 1.0, 1.5, and
2.0 g equiv.) and with p-toluenesulfonic acid in acetone at
reflux temperature for 24 h. Hydrolysis with dilute sulfuric
acid and cerium ammonium nitrate was successful, but the
product could not be isolated since it could not be separated
from the other water-soluble solids.
3-Amino-1-hydroxyacetone 1-O-phosphate (2), derived by
oxidative decarboxylation of 4-hydroxy-L-threonine 4-O-
phosphate (1), serves as a precursor of the C3N unit, N-1,C-
6,5,5′ of vitamin B6 (3) in Escherichia coli (Scheme 1) (1).
In connection with our continuing investigations of the
biosynthesis of vitamin B6 in E. coli (2) and in yeast (3–5),
we required a sample of aminohydroxyacetone that was
intramolecularly contiguously 13C,13C or 15N,13C labeled,
i.e., bond labeled. None of the reported syntheses of the
compound (6–8) were readily adaptable to this purpose,
since the starting materials employed in these synthetic se-
quences are not available in labeled form. The synthetic se-
quence here described starts from N-phthaloylglycine (4).
Several syntheses of labeled samples of this compound, from
commercially available labeled starting materials in almost
quantitative yields, have been reported (see Scheme 2) in
connection with the preparation of labeled samples of δ-
aminolevulinic acid.
The preparation of the following singly and multiply la-
beled samples of N-phthaloylglycine (4) has been described:
1-14C- (9–11), 1-13C- (12–14), 2-13C- (13–15), 1,2-13C2-
(15), 15N- (13, 14), 1-13C,15N- (16), 2-13C,15N- (16), and 1,2-
13C2,15N- (17). The corresponding acyl chloride (5), which
was obtained quantitatively on treatment of the acid with
thionyl chloride (9–17), was then converted into δ-amino-
levulinic acid by several different routes.
In one of these routes, the labeled phthaloylglycyl chlo-
ride (5) was treated with diazomethane, an Arndt–Eistert re-
action that was originally described by Balenoviƒ (18),
yielding the correspondingly labeled 1-diazo-3-phthalimido-
propan-2-one (6) (9, 10, 17), which was then used in the
next step of the synthetic sequence, leading to labeled δ-
aminolevulinic acid.
The unlabeled aminohydroxyacetone (10) was employed
in two displacement experiments to test whether the com-
pound serves as an intermediate in the biosynthesis of vita-
min B6 from glucose in yeast, as it does in E. coli (1).
Received 15 September 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 7 April 2004.
N. Ullah, C.N. Fali, and I.D. Spenser.1 Department of Chemistry, McMaster University, Hamilton, ON L8S 4M1, Canada.
1Corresponding author (e-mail: spenser@mcmaster.ca).
Can. J. Chem. 82: 579–582 (2004)
doi: 10.1139/V04-010
© 2004 NRC Canada

580
Can. J. Chem. Vol. 82, 2004
Scheme 1. Biosynthetic origin, in E. coli, of the C3N unit N-1,C-6,5,5′ of pyridoxine phosphate.
Scheme 2. Synthesis of 3-amino-1-hydroxyacetone.
Incorporation of label from [13C6]glucose into pyridoxamine
was not displaced by aminohydroxyacetone (10), either in
Experimental
Saccharomyces cerevisiae or in Candida utilis (5). This re-
sult made it unlikely that incorporation of a label from a
sample of this compound into vitamin B6 would be observed
in these yeasts. The preparation of bond-labeled samples of
aminohydroxyacetone was therefore not pursued.
N-Phthaloylglycyl chloride (5) (18)
Phthaloylglycine (4) (15.4 g, 75 mmol) was suspended in
thionyl chloride (21 mL, 40.2 g, 336 mmol), and the mixture
was refluxed until a clear solution was obtained (ca.
35 min). Excess thionyl chloride was pumped off in vacuo,
© 2004 NRC Canada

Ullah et al.
581
and the residue solidified to yield the product (5) as a light
yellow crystalline mass. mp 85 to 86 °C (lit. (18) value mp
84 to 85 °C). Yield 16.7 g, 99%. 1H NMR (200 MHz,
CDCl3) δ: 7.93–7.89 (m, 2H), 7.80–7.76 (m, 2H), 4.82 (s,
2H). 13C NMR (75.5 MHz) δ: 169.0, 166.6, 134.6, 131.5,
123.9, 47.5.
filtered. The solid was washed with a little dilute HCl, and
the filtrate was evaporated at 40 °C under reduced pressure
to a thick syrup. Addition of methanol, followed by diethyl
ether gave the product (9) as a crystalline solid. mp. 175–
1
178 °C. Yield 4.2 g, 87%. H NMR (200 MHz, D2O) δ: 4.00
(s, 4H), 3.46 (s, 2H), 3.18 (s, 2H). 13C NMR (75.5 MHz,
D2O) δ: 106.4, 65.8, 61.9, 41.5.
1-Diazo-3-phthalimidopropan-2-one (6) (18)
Phthaloylglycyl chloride (5) (10.7 g, 48 mmol) in 500 mL
dry ether was treated with excess diazomethane (generated
from 49 g methylnitronitrosoguanidine in 500 mL dry ether,
adding 112 mL 40% KOH). The product crystallized from
the ether solution after being kept at room temperature over-
night. It was recrystallized from ethyl acetate. mp 163–
165 °C (with decomposition (decomp.)) after sintering from
158 °C (lit. (18) value mp 168 °C (decomp.)). Yield 11.0 g
(98%). IR (KBr pellet) (cm–1) ν: 2128, 1774, 1733, 1629. 1H
NMR (200 MHz, CDCl3) δ: 7.88–7.86 (m, 2H), 7.76–7.74
(m, 2H), 5.40 (s, 1H), 4.44 (s, 2H). 13C NMR (75.5 MHz,
CDCl3) δ: 186.5, 167.6, 134.2, 132.0, 123.6, 53.8, 44.1. MS
3-Amino-1-hydroxypropan-2-one (3-amino-1-
hydroxyacetone) hydrochloride (10)
The ketal (9) (2.0 g, 12 mmol) (MW 169.5) was sus-
pended in aqueous acetonitrile (5%, 100 mL). Dowex 50W-
X8, 20–50 mesh (20 g) was added, and the mixture was
refluxed for 5 h. The solvent was filtered off; the resin was
applied to a column, and the column was eluted with
2 mol L–1 HCl. The eluate was evaporated in vacuo at 40 °C,
and the residue was recrystallized from ethanol–ether to give
the product. Yield 1.38 g, 93%. The procedure was repeated
on a larger scale, when 3.3 g product (95%) was obtained
from 4.85 g (29.1 mmol) ketal (9). mp 136 to 137 °C. (lit.
(6) value mp 136 to 137 °C; lit. (8) value mp 134–136 °C;
+
(CI, NH3) m/z (%): 247 (70, [M + NH4 ]), 202 (100, [M –
+
N2 + H+]). MS (DEI) m/z (%): 201 (43, [M – N2 ], 160 (15,
1
lit. (7) value mp 139 °C). H NMR (200 MHz, D2O) δ: 4.37
+
(s, 2H), 4.04 (s, 2H). 13C NMR (75.5 MHz, D2O) δ: 206.6,
[M – COCHN2 ]).
65.7, 44.3.
1-Hydroxy-3-phthalimidopropan-2-one (7)
1-Diazo-3-phthalimidopropan-2-one (6) (10.9 g, 47.6 mmol)
was suspended in dilute sulfuric acid (20% volume fraction)
and stirred at 50 °C for 3 h until all the solid had gone into
solution. The mixture was then extracted with ethyl acetate,
and the solution was dried over CaCl2. The solvent was re-
moved, and the product was recrystallized from ethanol.
Yield 9.3 g (82%). mp 119–121 °C (lit. (18) value mp
121 °C, rising to 142 °C on recrystallization). 1H NMR
(200 MHz, CDCl3) δ: 7.91–7.87 (m, 2H), 7.78–7.76 (m, 2H),
4.59 (s, 2H), 4.45 (s, 2H), 2.50 (s, 1H). 13C NMR
(75.5 MHz, CDCl3) δ: 202.4, 167.5, 134.4, 131.9, 123.7,
66.8, 43.5.
Acknowledgments
This paper is dedicated to the memory of Dr. Clara Nanfe
Fali (born 26 October 1960) (M.Sc., University of Jos, Nige-
ria; Ph.D., University of Florida), who initiated this investi-
gation. Clara died unexpectedly and suddenly in May 2000
in Hamilton. She was a gifted organic chemist, a hard-
working research associate, and a delighful person. She is
sadly missed by the members of the McMaster Chemistry
Department.
A research grant from the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) is gratefully
acknowledged.
2-Hydroxymethyl-2-phthalimidomethyl-1,3-dioxolane (8)
To a soluton of (7) (8.5 g, 39 mmol) in 500 mL toluene
was added ethylene glycol (19.5 g, 310 mmol) and p-
toluenesulfonic acid monohydrate (0.28 g, 2 mmol). The
mixture was refluxed using a Dean–Stark trap to remove wa-
ter. After 5 h, the mixture was allowed to cool to room tem-
perature and was then concentrated. Purification by flash
column (diethyl ether, 100%) gave the product (8). Yield
7.9 g, 77%. mp 98–100 °C (lit. (20) value mp 114–117 °C).
1H NMR (200 MHz, CDCl3) δ: 7.84–7.80 (m, 2H), 7.72–
7.67 (m, 2H), 4.13–3.97 (m, 4H), 3.85 (s, 2H), 3.49 (s, 2H),
2.98 (s, 1H, OH). 13C NMR (75.5 MHz, CDCl3) δ: 168.4,
134.1, 131.6, 123.4, 108.0, 65.3, 63.6, 38.8.
References
1. D.E. Cane, Y. Hsiung, J.A. Cornish, J.K. Robinson, and I.D.
Spenser. J. Am. Chem. Soc. 120, 1936 (1998).
2. R.E. Hill, K. Himmeldirk, I.A. Kennedy, R.M. Pauloski, B.G.
Sayer, and I.D. Spenser. J. Biol. Chem. 271, 30 426 (1996).
3. R.N. Gupta, T. Hemscheidt, B.G. Sayer, and I.D. Spenser. J.
Am. Chem. Soc. 123, 11 353 (2001).
4. J. Zeidler, N. Ullah, R.N. Gupta, R.M. Pauloski, B.G. Sayer,
and I.D. Spenser. J. Am. Chem. Soc. 124, 4542 (2002).
5. J. Zeidler, R.N. Gupta, B.G. Sayer, and I.D. Spenser. J. Org.
Chem. 68, 3486 (2003).
6. A.O. Jackson and C.S. Marvel. J. Biol. Chem. 103, 191 (1933).
7. C. Tarnus, J.-M. Rémy, and H. d’Orchymont. Bioorg. Med.
Chem. 4, 1287 (1996).
2-Hydroxymethyl-2-aminomethyl-1,3-dioxolane
hydrochloride (9)
To a solution of the ketal (8) (7.5 g, 28.5 mmol) in
500 mL ethanol was added hydrazine monohydrate (3 mL)
in ethanol (350 mL), and the mixture was allowed to stand at
room temperature for 36 h. The mixture was then refluxed
for 7 h, and the solvent was evaporated in vacuo to dryness.
The residue was suspended in 1 mol L–1 HCl (300 mL), and
the mixture was cooled to 0 °C, allowed to stand for 1 h, and
8. E. Wolf, I.A. Kennedy, K. Himmeldirk, and I.D. Spenser. Can.
J. Chem. 75, 942 (1997).
9. L. Pichat and M. Herbert. Bull. Soc. Chim. Fr. 673 (1957).
10. A.E.A. Mitta, A.M. Ferramola, H.A. Sancovich, and M.
Grinstein. J. Labelled Compd. 3, 20 (1967).
11. J.B. Campbell and J.S. Johnston. J. Labelled Compd.
Radiopharm. 27, 1353 (1989).
© 2004 NRC Canada

582
Can. J. Chem. Vol. 82, 2004
12. K. Kurumaya, T. Okazaki, N. Seido, Y. Akasaka, Y. Kawajiri,
M. Kajiwara, and M. Kondo. J. Labelled Compd. Radiopharm.
27, 217 (1989).
16. K. Iida and M. Kajiwara. J. Labelled Compd. Rariopharm. 45,
139 (2002).
17. B. Nitsche, H.-P. Köst, E. Cmiel, and S. Schneider. J. Labelled
13. R.A. Aitken, H.R. Cooper, and A.P. Mehotra. J. Chem. Soc.
Compd. Radiopharm. 27, 623 (1987).
Perkin Trans 1, 475 (1996).
14. J. Wang and A.I. Scott. Tetrahedron Lett. 38, 739 (1997); 2587
(1997).
18. K. Balenoviƒ, N. Bregant, D. Cerar, and M. Tkalꢀiƒ. J. Org.
Chem. 16, 1308 (1951).
19. K. Kobayashi, H.S. Forrest, and M. El-Emary. Arch. Biochem.
15. K. Iida and M. Kajiwara. J. Labelled Compd. Radiopharm. 45,
569 (2002).
Biophys. 121, 220 (1967).
20. M. Gall and B.V. Kamdar. J. Org. Chem. 46, 1575 (1981).
© 2004 NRC Canada