An efficient synthesis of δ-amino[3-13C]levulinic acid

Article abstract of DOI:10.1016/S0040-4039(02)01970-6

A new convenient synthesis of [3-¹³C]ALA, using ¹³C-methyl phenyl sulfone, with 62% overall yield in six steps, is described. The overall yield of this synthesis exceeds that of previously reported methods.

Full text of DOI:10.1016/S0040-4039(02)01970-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8795–8796
An efficient synthesis of d-amino[3-13C]levulinic acid
Yasuhiro Kajiwara and A. Ian Scott*
Center for Biological NMR, Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA
Received 26 July 2002; accepted 12 September 2002
Abstract—A new convenient synthesis of [3-13C]ALA, using 13C-methyl phenyl sulfone, with 62% overall yield in six steps, is
described. The overall yield of this synthesis exceeds that of previously reported methods. © 2002 Elsevier Science Ltd. All rights
reserved.
d-Aminolevulinic acid (ALA, 1a) which is known as an
insecticide and herbicide,1 is an intermediate in the
biosynthesis of tetrapyrrolic compounds such as vita-
min B12, chlorophyll and heme.2a,b As shown in Fig. 1,
vitamin B12 and other tetrapyrrolic compounds are
biosynthesized from uroporphyrinogen III (uro’gen III,
3), which is derived in turn from eight molecules of
ALA via ‘tetramerization’ of the monopyrrolic precur-
sor porphobilinogen (PBG, 2).3a,b
C-2, C-7, C-12 and C-18 of the porphyrinoid ring.4a,b
There have been several reports concerning the synthe-
sis of ALA5a–l including two regioselective synthesis of
[3-13C]ALA (1b).5a,b However, the synthetic methods
for 1b, which is now commercially available (but
extremely expensive), suffer from low yields resulting in
high costs. Therefore more efficient synthetic methods
for 1b were required and we now report on a new
synthetic method which is of lower cost, easy handling
and convenient for large scale preparations, as illus-
trated in Scheme 1.
Isotopomers of ALA regioselectively labeled with 13C
have been systematically used for the structural elucida-
tion of the intermediates in the biosynthesis and
metabolism of these tetrapyrrolic compounds in combi-
nation with the widely available high-field FT NMR
technique. Especially for the vitamin B12 biosynthetic
pathways, the availability of not only [4-13C]ALA and
[5-13C]ALA but also [3-13C]ALA (1b) has proved
extremely useful as 1b leads to the labeling of positions
The target product 1b was synthesized starting from
13C-methyl phenyl sulfone 4, which is easily made from
13C-iodomethane.6 Sulfone 4 was treated with nBuLi
and to the resulting yellow solution, ethyl tert-
butyldimethylsiloxy-acetate was added to give ketone 5
in 86% yield.7 Coupling of ketone 5 with ethyl bro-
moacetate using NaH in THF, gave sulfone 6 in 83%
Figure 1. Overview of the early stages in the biosynthesis of some porphyrinoids.
* Corresponding author. Fax: +1-979-845-5992; e-mail: scott@mail.chem.tamu.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01970-6

8796
Y. Kajiwara, A. I. Scott / Tetrahedron Letters 43 (2002) 8795–8796
n
Scheme 1. Reagents and conditions: (A) BuLi, THF, 0°C then TBSOCH2CO2Et, 86%; (B) NaH, THF, 0°C then BrCH2CO2Et,
83 and 15% recovered 5; (C) (i) Al(Hg), THF–H2O, rt, 97%, (ii) AcOH, THF–H2O, rt, 99%; (D) phthalimide, DEAD, Ph3P, PhH,
rt, 81%; (E) 6N HCl, reflux, 95%.
yield and recovered 5 (which can be recycled; 15%).
Removal of the benzensulfonyl group of 6 with Al(Hg)8
in 97% yield followed by removal of TBS group with
excess AcOH in THF–H2O provided alcohol 7 (99%).
Compound 7 was converted to phthalimido 8 via the
Mitsunobu reaction9 using phthalimide, DEAD and
Ph3P in 81% yield. Hydrolysis of the phthalyl and ethyl
ester groups with 6N HCl of phthalimido 8 followed by
recrystallization from H2O–iPrOH–Et2O yielded the
desired product 1b in 95% yield. The spectral data (mp,
Okazaki, T.; Seido, N.; Akasaka, Y.; Kawajiri, Y.; Kaji-
wara, M. J. Label. Compd. Radiopharm. 1989, 27, 217–
235; (c) Battersby, A. R.; Hunt, E.; McDonald, E.;
Moron, J. J. Chem. Soc., Perkin Trans. 1 1973, 2917–
2922; (d) Herdeis, C.; Dimnerling, A. Arch. Pharm. 1984,
317, 304–306; (e) Benedikt, E.; Kost, H.-P. Z. Natur-
forsch. 1986, 41b, 1593–1594; (f) Pfaltz, A.; Anwar, S.
Tetrahedron Lett. 1984, 25, 2977–2980; (g) Cambell, J. B.;
Johnston, J. S. J. Label. Compd. Radiopharm. 1989, 27,
1353–1358; (h) Kawakami, H.; Ebata, T.; Matsushita, H.
Agric. Biol. Chem. 1991, 55, 1687–1688; (i) Vishwakarma,
R. A.; Balachandran, S.; Alanine, A. I. D.; Stamford, N.
P. J.; Kiuchi, F.; Leeper, F. J.; Battersby, A. R. J. Chem.
Soc., Perkin Trans. 1 1993, 2893–2899; (j) Ha, H.-J.; Lee,
S.-K.; Ha, Y.-J.; Park, J.-W. Synth. Commun. 1994, 24,
2557–2562; (k) Wang, J.; Scott, A. I. Tetrahedron Lett.
1997, 38, 739–740; (l) Iida, K.; Tokiwa, S.; Ishii, T.;
Kajiwara, M. J. Label. Compd. Radiopharm. 2002, 45,
569–576.
1
IR, H, 13C NMR) for synthetic 1b10 are in full agree-
ment with those reported previously.5a,b
The above methodology was achieved in six steps and
62% overall yield (from 4). The overall yield of the
present synthesis and the better costs exceed that of any
other method reported to date.
Acknowledgements
6. Choudhry, S. C.; Serico, L.; Cupano, J. J. Org. Chem.
1989, 54, 3755–3757.
7. Initially we considered protection in the nitrogen form 10
instead of the oxygen form 5. However, this approach led
to a complex mixture of products, which did not include
sulfone 10.
We would like to thank the NIH and the Robert A.
Welch Foundation for financial support of this work.
References
1. Duke, S. O.; Rebeiz, C. A. Porphyric Pesticides: Chem-
istry, Toxicology, and Pharmaceutical Applications. ACS
Symposium Series 559, 1994.
2. (a) Bogorad, L. The Porphyrins; Dolphin, D., Ed.; Aca-
demic Press: New York, 1979; Vol. VI, Part A, pp.
125–178; (b) Leeper, F. J. Nat. Prod. Rep. 1985, 2,
561–580.
3. (a) Battersby, A. R.; Fookes, C. J. R.; Matcham, G. W.
J.; McDonald, E. Nature 1980, 285, 17–21; (b) Roessner,
C. A.; Santander, P. J.; Scott, A. I. Vitamins Hormones
2001, 61, 267–297.
4. (a) Scott, A. I. Angew. Chem., Int. Ed. Engl. 1993, 32,
1223–1243; (b) Blanche, F.; Cameron, B.; Crozet, J.;
Debussche, L.; Thibaut, D.; Vuilhorgne, M.; Leeper, F.
J.; Battersby, A. R. Angew. Chem., Int. Ed. Engl. 1995,
34, 383–411.
8. Corey, E. J.; Chavkovsky, M. J. Am. Chem. Soc. 1964,
86, 1639–1640.
9. Mitsunobu, O. Synthesis 1981, 1–28.
10. d-Amino[3-13C]levulinic acid hydrochloride (1b). Mp 144–
147°C. IR (KBr): 3461, 3042, 1725, 1692, 1419, 1403,
1
1178, 1146 cm−1. H NMR (500 MHz, D2O) l: 2.57–2.60
(2H, m), 2.64 (1H, t, J=6.2 Hz), 2.90 (1H, t, J=6.2 Hz),
4.00 (2H, s). 13C NMR (125 MHz, D2O) l: 27.5 (d,
J=37.8 Hz), 34.4 (13C, m), 47.1 (d, J=17.0 Hz), 176.9,
204.2 (d, J=41.9 Hz). ESIMS m/z: 133 (M+−Cl, 71), 115
(100).
5. (a) Pfaltz, A.; Jaun, B.; Fassler, A.; Eschenmoser, A.;
Jaenchen, R.; Gilles, H. H.; Diekert, G.; Thauer, R. K.
Helv. Chim. Acta 1982, 65, 828–865; (b) Kurumaya, K.;