2850, 2096, 1673, 1519, 1468, 1401, 1330, 1271, 1232, 1191, 1022
cm-1; HRMS (ESI): calculated for C6H6N3O2: [M+H]+ 152.0454;
found: 152.0451.
5-Aminolevulinic acid hydrochloride 9
A mixture of 8 (0.250 g, 1.65 mmol) and Rose Bengal (10 mg)
in dry methanol (20 mL) was irradiated with a halogen lamp
(Sylvania 250 W) for 6 h, during which a gentle stream of oxygen
was passed through the solution. The reaction mixture was kept
at 20 ◦C by use of an ice-water bath. Concentrated HCl (1.0
mL) and 10% Pd/C (60 mg) were then added and the mixture
was shaken under 2 atm H2 for 6 h. The reaction was filtered
to remove the catalyst and the resulting colorless solution was
evaporated to give a beige solid. The crude product was dissolved
in methanol (10 mL) and re-precipitated by the addition of ether
to gi◦ve the pure product (0.206 g, 74%), mp 143–146 ◦C (lit. 144–
147 C).20 1H NMR (D2O, 300 MHz) 4.01 (2H, s), 2.77 (2H, t,
J = 6.1 Hz), 2.59 (2H, t, J = 6.1 Hz); 13C NMR (D2O, 75 MHz)
204.0, 176.7, 47.2, 34.5, 27.8.
Scheme 3 Synthesis of ALA 9 from 1.
oxygen-mediated synthesis of ALA. Thus, 5-(azidomethyl) fur-
fural 8 was prepared in 92% yield from a neat mixture of 1
and NaN3 and then irradiated with oxygen in the presence
of Rose Bengal to give a mixture of 6 and 7 (R = CH2N3).
These products were not isolated but the mixture was directly
hydrogenated to give ALA 9 (as the stable hydrochloride salt) in
3 steps and an overall yield of 68% from 1 (Scheme 3).10 If this
result is superimposed on previously reported yields of 1 from
biomass sources1 the result would be 61, 57, and 55% isolated
chemical yield of ALA 9 from sucrose, cellulose, and corn stover,
respectively.
Acknowledgements
This research was supported by the US National Science
Foundation, grant CBET 0932391.
ALA 9 is an intermediate in the biosynthesis of tetrapyrrole,
which is the core structure of porphyrins and heme. It is a
compound of current interest as both a herbicide and insecticide
due to the fact that it is highly active, biodegradable, and
nontoxic to humans and animals.11 It has also been proposed as a
plant growth regulator,12 and increases salt and cold temperature
tolerance in crops.13 Presently, ALA is employed as a sensi-
tizer in photodynamic therapy for cancer and dermatological
disorders.14 The reason for the limited adoption of ALA in
agricultural practice has been its poor availability and therefore
high price. It can be produced microbially,13 but this is slow
and expensive, and generally not well suited to production on
an agrochemical scale. Other chemical routes via levulinic acid
itself have generally suffered from poor yields.15–19 We suggest
that the efficient, renewable approach to the synthesis of ALA 9
described here will enable broader applications of this valuable
natural product.
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1
was evaporated to give 8 (1.99 g, 92%) as a pale yellow oil. H
NMR (CDCl3, 300 MHz) 9.64 (1H, s), 7.23 (1H, d, J = 3.4
Hz), 6.56 (1H, d, J = 3.4 Hz), 4.42 (2H, s); 13C NMR (CDCl3, 75
MHz) 177.8, 155.5, 152.9, 122.3, 111.7, 47.0; IR (neat): nmax 2920,
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