Total synthesis of L-biopterin from L-tartaric acid via 5-deoxy-L-arabinose

Full text of DOI:10.1021/jo961426s

8698
J . Org. Chem. 1996, 61, 8698-8700
Sch em e 1
Tota l Syn th esis of L-Biop ter in fr om
L-Ta r ta r ic Acid via 5-Deoxy-L-a r a bin ose
Anne-Marie Fernandez and Lucette Duhamel*
Universite´ de Rouen, URA 464 CNRS et IRCOF,
F-76821 Mont-Saint-Aignan Cedex, France
Received J uly 26, 1996
L-Biopterin (1), one of the most ubiquitous compounds
in the class of the naturally occurring pterins, was
isolated from human urine as a growth factor of Crithidia
fasciculata by Patterson et al.1 Through its 5,6,7,8-
tetrahydro form, 1 functions as an essential enzyme
cofactor in the conversion of phenylalanine to tyrosine2
and tyrosine to DOPA,3 in melanine synthesis,4 and in
tryptophan hydroxylation.5 As a consequence, tetrahy-
drobiopterin has been developed as a remedy for central
nervous system diseases such as phenylketonuria, Par-
kinson’s and Alzheimer’s diseases, and depression.6
Since the first synthesis of L-biopterin (1) by Patterson
et al.,7 several syntheses have been reported,8-13 espe-
cially by Viscontini’s group.8 In most of those,8,9 L-
rhamnose and L-arabinose are the starting materials to
the key intermediate, 5-deoxy-L-arabinose (2).10 More
recently, novel attractive syntheses of L-biopterin were
described, employing less expensive ethyl (S)-lactate11 or
D-ribose12 as starting materials; the key intermediate is
then 5-deoxy-L-ribose (epimer in C2 of 5-deoxy-L-arabi-
nose (2)). L-Biopterin (1) was also prepared by conden-
sation of triaminobutoxypyrimidine with 2-formylox-
iranes.13
pyrimidinol with 5-deoxy-L-arabinose phenylhydrazone,
which is directly prepared from 5-deoxy-L-arabinose (2).
Compound 2 could be obtained by reduction of the lactone
4 which presents the necessary asymmetric centers.
Starting from L-tartaric acid (3) in which the configura-
tion of two carbons is already determined we could
achieve the stereospecific construction of the third con-
tiguous asymmetric center by a stereoselective Grignard
reaction on aldo ester 5.
The first phase of our work was the functional trans-
formation of L-tartaric acid (3) to give the desired aldo
ester 5 (Scheme 2). After simultaneous protection of the
2,3-diol system and transformation into an intermediate
anhydride,14 the acid chloride 6 was directly provided by
the action of methanol15 followed by thionyl chloride.15
Reduction of 6 with bis(triphenylphosphine)copper(I)
borohydride in acetone gave the aldo ester 5 in 90% yield.
Compound 5 was then submitted to a Grignard reaction
using methylmagnesium bromide and to deprotection
under acidic conditions to afford (2R,3S,4S)-2,3-dihy-
droxy-4-methylbutyrolactone (4) in 78% yield. The Grig-
nard addition appears critical because of the possibility
of obtaining a mixture of epimeric lactones 7 transformed
into 4 in which the newly created asymmetric center
could be either (4R) or (4S). It is noteworthy that under
conditions reported in Scheme 2, only the (4S)-lactone 4
(de > 98%) is recovered.16 This high stereoselectivity in
the Grignard reaction can be rationalized by steric
hindrance due to the pivalate groups and will be dis-
cussed elsewhere.17 Moreover, optical rotations of
(2R,3S,4S)-lactone 4 and of its enantiomer (2S,3R,4R) are
described in the literature18,19 and are in total agreement
with our own results (Table 1).
In this paper, we describe a new synthetic access to
5-deoxy-L-arabinose (2) that employs L-tartaric acid (3)
as starting material and thus improves both efficiency
and economy. We thought that 2,3-dihydroxy-4-methyl-
butyrolactone (4) could be an excellent precursor of 2.
The retrosynthesis is presented in Scheme 1. This
strategy relies on the condensation of 2,5,6-triamino-4-
(1) Patterson, E. L.; Broquist, H. P.; Albrecht, A. M.; Von Saltza,
M. H.; Stokstad, E. L. R. J . Am. Chem. Soc. 1955, 77, 3167.
(2) Rembold, H.; Gyure, W. L. Angew. Chem., Int. Ed. Engl. 1972,
11, 1061.
(3) (a) Nagatsu, T.; Levitt, M.; Undenfriend, S. J . Biol. Chem. 1964,
239, 2910. (b) Lloyd, T.; Weiner, N. Mol. Pharm. 1971, 7, 569.
(4) (a) Ziegler, I. Z. Naturforsch. 1963, 18b, 551. (b) Kokolis, N.;
Ziegler, I. Z. Naturforsch. 1968, 23b, 860.
(5) (a) Gal, E. M.; Armstrong, J . C.; Ginsberg, B. J . Neurochem.
1966, 13, 643. (b) Hosoda, S.; Glick, D. J . Biol. Chem. 1966, 241, 192.
(c) Noguchi, T.; Nishino, M.; Kido, R. Biochem. J . 1973, 131, 375.
(6) Nagatsu, T.; Matsuura, S.; Sugimoto, T. Med. Res. Rev. 1989, 9,
25.
(7) Patterson, E. L.; Milstrey, R.; Stokstad, E. L. R. J . Am. Chem.
Soc. 1956, 78, 5868.
(8) (a) Viscontini, M.; Raschig, H. Helv. Chim. Acta 1958, 41, 108.
(b) Viscontini, M.; Provenzale, R. Helv. Chim. Acta 1969, 52, 1225. (c)
Viscontini, M.; Provenzale, R.; Frei, W. F. Helv. Chim. Acta 1972, 55,
570. (d) Viscontini, M.; Frei, W. F. Helv. Chim. Acta 1972, 55, 574.
(e) Schircks, B.; Bieri, J . H.; Viscontini, M. Helv. Chim. Acta 1977, 60,
211. (f) Schircks, B.; Bieri, J . H.; Viscontini, M. Helv. Chim. Acta 1985,
68, 1639.
The lactone 4 was then reduced to lactol 2 (5-deoxy-
L-arabinose) using DIBALH. The lactol 2 was trans-
formed into L-biopterin (1) according to known proce-
dures.8f,12 The treatment of the crude lactol 220 with
phenylhydrazine in methanol gave phenylhydrazone 8
(72% yield), which is identical to that derived from
(14) Duhamel, L.; Plaquevent, J . C. Org. Prep. Proced. Int. 1982,
14, 347.
(9) (a) Andrews, K. J . M.; Barber, W. E.; Tong, B. P. J . Chem. Soc.,
Chem. Commun. 1968, 120. (b) Andrews, K. J . M.; Barber, W. E.; Tong,
B. P. J . Chem. Soc. C 1969, 928. (c) Taylor, E. C.; J acobi, P. A. J . Am.
Chem. Soc. 1974, 96, 6781. (d) Sugimoto, T.; Matsuura, S. Bull. Chem.
Soc. J pn. 1979, 52, 181. (e) Sugimoto, T.; Matsuura, S.; Nagatsu, T.
Bull. Chem. Soc. J pn. 1980, 53, 2344. (f) Armarego, W. L. F.; Waring,
P.; Paal, B. Aust. J . Chem. 1982, 35, 785.
(15) Duhamel, L.; Herman, T.; Angibaud, P. Synth. Commun. 1992,
22, 735.
(16) The epimeric (2R,3S,4R) lactone was prepared independently:
Fernandez, A. M.; J acob, M.; Gralak, J .; Al-Bayati, Y.; Ple´, G.;
Duhamel, L. Synlett 1995, 5, 431.
(17) Fernandez, A. M.; Duhamel, L.; Plaquevent, J . C., to be
published.
(10) Viscontini, M. Biochem. Clin. Aspects Pteridines 1984, 3, 19.
(11) (a) Kikuchi, H.; Mori, K. Agric. Biol. Chem. 1989, 53, 2095. (b)
Mori, K.; Kikuchi, H. Liebigs Ann. Chem. 1989, 963.
(12) Mori, K.; Kikuchi, H. Liebigs Ann. Chem. 1989, 1267.
(13) Murata, S.; Sugimoto, T.; Ogiwara, S.; Mogi, K.; Wasada, H.
Synthesis 1992, 303.
(18) Andrews, P.; Hough, L.; J ones, J . K. N. J . Am. Chem. Soc. 1955,
77, 125.
(19) Torii, S.; Inokuchi, T.; Masatsugu, Y. Bull. Chem. Soc. J pn.
1985, 58, 3629.
(20) The product is contaminated by starting material 4 and tetrol
(total reduction). These products do not interfere with the next step.
S0022-3263(96)01426-0 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 24, 1996 8699
Sch em e 2
Ta ble 1. Op tica l Rota tion s. Com p a r ison to Liter a tu r e
(2R,3R)-Meth yl 4-Ch lor o-4-oxo-2,3-d ip iva loxybu ta n oa te
(6). Acid chloride 6 was obtained following the literature
procedures14,15 in 87% yield (oil) from 3: IR (neat) 1812, 1774,
1748 cm-1; 1H NMR (CDCl3) 1.16 (s, 9H), 1.17 (s, 9H), 3.69 (s,
3H); 5.71 (d, 1H, J ) 2.6), 5.75 (d, 1H, J ) 2.7); 13C NMR (CDCl3)
26.58, 26.63, 38.65, 52.9, 69.4, 76.6, 165.3, 167.9, 176.3, 176.6;
compd
[R]22 this work
[R]20 lit. (ref)
D
D
4
10
1
-38a,b
-109.8d
-65e
+37.3b,c (19)
-108d (12, 21)
-66e (8f, 12)
MS (CI/NH3) m/ z 352 [M + H]+; [R]26 -35.4 (c 1.3, CHCl3).
D
a
d
(2R,3S,4S). b c 1.1, EtOH. c (2S,3R,4R). c 1.08, CHCl3. e c 0.2,
Anal. Calcd for C15H23O7Cl: C, 51.36; H, 6.61. Found: C, 51.42;
H, 6.73.
0.1 N HCl.
(2R,3R)-Meth yl 4-Oxo-2,3-d ip iva loxybu ta n oa te (5). To
acid chloride 614,15 (5.0 g, 14.26 mmol) in acetone (80 mL, dried
30 min over 4 Å sieves) was added triphenylphosphine (7.6 g,
29 mmol). To the resulting solution was added bis(triphen-
ylphosphine)copper(I) borohydride (8.8 g, 14.6 mmol) at rt, and
the reaction mixture was stirred for 1.5 h. The white precipitate
(Ph3PCuCl) was removed by filtration, and the filtrate was
evaporated to dryness. The residue was extracted with ether
(the ether insoluble residue was triphenylphosphine-borane).
The ether was removed, the residue was dissolved again in
CHCl3 (80 mL), and the resulting solution was stirred for 1 h
with copper(I) chloride (2.87 g, 29 mmol) to remove the remain-
ing triphenylphosphine. The reaction mixture was filtered, the
CHCl3 was evaporated, and the residue was extracted with ether
(a 1/1 Ph3P/CuCl complex was formed which was soluble in
CHCl3 but insoluble in ether). After 30 min without stirring,
the mixture was filtered, the ether was evaporated, and the
residue was chromatographed on silica gel (PE/Et2O 90/10 to
50/50 to remove the resulting Ph3P) to give aldehyde 5 (4 g, 90%,
L-rhamnose.8f Phenylhydrazone 8 was acetylated to 9,
which after a reaction with 2,5,6-triamino-4-pyrimidinol
and oxidation with I2 and acetylation, gave triacetylbiop-
terin (10).12 This compound was purified by preparative
TLC and obtained in 36% yield. Physical data of tri-
acetylbiopterin (10) are in total agreement with the
literature12,21 (Table 1). Compound 10 underwent a
deprotection step leading to L-biopterin (1) which, with-
out further purification, was exactly the same as the
compound previously prepared by Viscontini.8f
In conclusion, this work describes the synthesis of
L-biopterin (1) starting from L-tartaric acid (3). This
synthesis improves the preparation of lactone 4 by highly
stereoselective addition of Grignard reagent on aldo ester
5. This excellent result prompted us to condense suc-
cessfully several Grignard reagents on compound 5.
These studies will be reported in due course.17
1
oil): IR (neat) 1740 cm-1; H NMR (CDCl3) 1.19 (s, 9H), 1.23
(s, 9H), 3.73 (s, 3H), 5.50 (d, 1H, J ) 2.6), 5.59 (d, 1H, J ) 2.6),
9.45 (s, 1H); 13C NMR (CDCl3) 26.6, 26.7, 38.6, 52.6, 69.3, 75.9,
166.5, 176.8, 177.1, 194; MS (CI/CH4) m/ z 317 [M + H]+; [R]21
D
Exp er im en ta l Section
-2.8 (c 7.83, CHCl3). Anal. Calcd for C15H24O7: C, 56.95; H,
7.65. Found: C, 56.80; H, 7.60.
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded on 200 and 50 MHz spectrometers, respectively.
Chemical shifts are reported in ppm and, J values are quoted
(2R,3S,4S)-2,3-Dih yd r oxy-4-m eth ylbu tyr ola cton e (4) via
P r otected La cton e 7. Methylmagnesium bromide (9.5 mmol,
3.2 mL, 3 M in Et2O) was added, at -70 °C, to a solution of
aldehyde 5 (2.0 g, 6.3 mmol) in THF (45 mL). After the mixture
was stirred at -70 °C for 12 h, the mixture was warmed to rt
during 2 h for lactonization step (TLC control). The mixture
was cooled to 0 °C and hydrolyzed with a saturated NH4Cl
solution. THF was removed, and the residue was extracted with
in Hz. Preparative TLC were run on silica gel (SDS) 60, 17
F254, 1 mm.
m
(21) Furrer, H. J .; Bieri, J . H.; Viscontini, M. Helv. Chim. Acta 1979,
62, 2577.

8700 J . Org. Chem., Vol. 61, No. 24, 1996
Notes
ether. The organic layer was dried (MgSO4) and evaporated.
The lactone 7 could be isolated by chromatography on silica gel
(PE/Et2O 90/10) (90% yield, oil): IR (neat) 1804, 1742 cm-1; 1H
NMR (CDCl3) 1.17 (s, 9H), 1.21 (s, 9H), 1.49 (d, 3H, J ) 6.4),
4.42 (qd, 1H, J ) 6.5, 6.5), 5.18 (dd, 1H, J ) 7.1, 7.1), 5.48 (d,
1H, J ) 7.3); irradiation of the protons of the methyl on C4 led
to the unambigous observation of a selective Overhauser effect
(5%) on H2 (Scheme 2); 13C NMR (CDCl3) 18.6, 26.8, 38.6, 72.4,
76.3, 77.1, 168.8, 176.9, 177.3; MS (CI/tBuH) m/ z 301 [M + H]+;
[R]23D -21.9 (c 1.22, CHCl3). Anal. Calcd for C15H24O6: C, 59.98;
H, 8.05. Found: C, 60.08; H, 7.97.
5-Deoxy-2,3,4-O-tr ia cetyl-L-a r a bin ose P h en ylh yd r a zon e
(9).8f To hydrazone 8 (0.3 g, 1.34 mmol) dissolved in Ac2O (3
mL) was added, under N2, pyridine (3 mL). After 4 h at rt, the
solution was evaporated under vacuum and the residue dried
to give protected hydrazone 9 (0.46 g, 98%, oil): IR (neat) 3300,
1
1741, 1600 cm-1; H NMR (CDCl3) 1.25 (d, 3H, J ) 6.5), 2.01
(s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 5.07 (qd, 1H, J ) 6.2, 5.8),
5.43 (dd, 1H, J ) 5.8, 5.7), 5.65 (dd, 1H, J ) 5.7, 5.5), 6.80-7.26
(m, 6H), 8.62 (s, 1H); MS (EI) m/ z 290 [M - CH3CO2H]+•, 321
[M - N2H], 350 [M]+•
.
2-N-Acetyl-1′,2′-d i-O-a cetyl-L-biop ter in (10).12,21 Acety-
A solution of crude protected lactone 7 (6.3 mmol) in dioxane
(60 mL) and 3 M HCl (120 mL) was stirred at reflux during 18
h. After being cooled, the reaction mixture was concentrated.
The remaining solids were washed twice with hot AcOEt, and
the washings were filtered, dried, and concentrated by azeotropic
distillation with toluene. Purification on silica gel (PE/AcOEt
70/30) gave lactone 4 (0.65 g, 78% from 5): mp 124-125 °C (lit.18
125 °C); IR (neat) 3366, 1748 cm-1; 1H NMR (CD3OD) 1.41 (d,
3H, J ) 6.2), 3.78 (dd, 1H, J ) 8.8, 8.7), 4.17 (qd, 1H, J ) 6.2,
8.3), 4.32 (d, 1H, J ) 9.0), 4.82 (s, 2H); 13C NMR (CD3OD)
18.1, 75.4, 78.4, 80.5, 176.4; MS (CI/tBuH) m/ z 115 [M + H -
lated hydrazone 9 (120 mg, 0.34 mmol) was dissolved in a
methanol (2.5 mL)/pyridine (0.5 mL) mixture, and then
a
solution of sodium dithionite (9 mg, 0.051 mmol) and sodium
acetate (64 mg, 0.782 mmol) in water (2.4 mL) and a suspension
of 2,5,6-triamino-4-pyrimidinol sulfate (96 mg, 0.374 mmol) in
water (3.2 mL) were successively added. The mixture was
heated at 40-45 °C under argon for 24 h. To the resulting clear
brown solution was added, at rt, iodine (203 mg, 0.8 mmol) in
methanol (2.4 mL) within 15 min. The reaction mixture was
then concentrated in vacuo to ca. 3 mL, and the brown suspen-
sion was cooled at 0 °C for 1 h. Then the precipitate was
collected on a filter and washed with cold water, cold ethanol,
and ether. The brown solid was dissolved in hot water (50 °C,
10 mL) and treated with active charcoal to give diacetylbiopterin.
Without further purification, the crude diacetate was treated
with Ac2O (0.2 mL) in pyridine (0.3 mL) at 100 °C for 4 h. After
concentration in vacuo, the residue was extracted with AcOEt.
The extract was washed with saturated copper(II) sulfate
solution, water, and brine and was dried (MgSO4) and concen-
trated in vacuo. Preparative TLC using AcOEt as eluant gave
triacetylbiopterin 10 (45 mg, 36%, pale yellow foam); IR (neat)
H2O]+, 133 [M + H]+; [R]21 -37.0 (c 1.1, EtOH) (lit.19 enanti-
D
omer (2S,3R,4R) [R]13 +37.3 (c 1.01, EtOH). Anal. Calcd for
D
C5H8O4: C, 45.46; H, 6.10. Found: C, 45.64; H, 6.26.
5-Deoxy-L-a r a bin ose (2). To a solution of lactone 4 (0.65 g,
4.9 mmol) in THF (250 mL) at -60 °C was added, in 1 h, a
solution of DIBALH (12.25 mmol, 7.7 mL, 1.6 M in toluene).
After being stirred vigorously during 30 min, the mixture was
hydrolyzed with water (7.5 mL) at -60 °C. A saturated NaHCO3
solution was added until pH ) 9-10, then the reaction mixture
was warmed up to 32-35 °C (to precipitate aluminum salts) and
filtered through Celite 545. Solids were washed with methanol
(30 mL) and then ether (75 mL). Solvents were removed by
evaporation. A mixture of starting material (0.13 g, 20%), lactol
2 (0.4 g, 60%), and tetrol (0.13 g, 20%, total reduction) was
obtained. Lactol 2 was obtained in 74% yield taking into account
recovered starting material 4. This was used as such for the
next step. La ctol 2: 1H NMR (CD3OD) 1.27 (d, 3H, J ) 6.2),
3.54 (dd, 1H, J ) 4.7, 7.7), 3.90 (dd, 1 H, J ) 4.7, 2.6), 3.99-
4.10 (m, 1H), 4.85 (large s, 3H), 5.08 (d, 0.7H, J ) 2.2), 5.13 (d,
0.3H, J ) 4.4). Tetr ol: 1H NMR (CD3OD) 1.23 (d, 3H, J ) 6),
3.61 (d, 2H, J ) 7.0), 3.71-3.87 (m, 2H), 4.85 (large s, 4H); MS
(CI/tBuH) m/ z 117 [M(lactol 2) + H - H2O]+, 137 [M(tetrol) +
H]+.
1
3161, 1742, 1677, 1627 cm-1; H NMR (CDCl3) 1.26 (d, 3H, J
) 6.6), 1.99 (s, 3H), 2.16 (s, 3H), 2.46 (s, 3H), 5.46 (qd, 1H, J )
6.7, 4.4), 6.04 (d, 1H, J ) 4.4), 8.94 (s, 1H), 11.21 (large s, 1H),
12.77 (large s, 1H); 13C NMR (CDCl3) 15.6, 20.8, 20.9, 24.9,
70.4, 75.7, 130.1, 149.1, 149.9, 150.3, 154.3, 159.6, 169.6, 169.8,
173.7; MS (CI/tBuH) m/ z 364 [M + H]+; [R]23 -109.8 (c 1.09,
D
CHCl3) (lit.12 [R]24 -108 (c 1.08, CHCl3)).
D
L-Biop ter in (1).12 A solution of triacetylbiopterin 10 (40 mg,
0.11 mmol) in 3 M HCl (0.7 mL) was heated at 100 °C for 30
min. The resulting pale yellow solution was concentrated in
vacuo to give a yellow foam. The residue was then extracted
with 3% aqueous NH4OH solution and the extract was concen-
trated at ca. 1 mL and cooled in an ice bath. After obtention of
a precipitate, the liquid was pumped off and the solid was dried
under P2O5 to give L-biopterin (1) as a yellow amorphous solid
5-Deoxy-L-a r a bin ose P h en ylh yd r a zon e (8).8f To the crude
lactol 2 (0.3 g, 2.24 mmol) dissolved in methanol (55 mL) were
added, under N2, phenylhydrazine (242 mg, 2.24 mmol) and then
one drop of glacial AcOH. After 1 h at rt, the yellow solution
was evaporated under vacuum. The viscous residue was washed
with Et2O (2 × 15 mL), which was discarded. The remaining
substance was dissolved in AcOEt (7 mL), the obtained solution
was washed twice with H2O (10 mL), and the organic layer was
dried (Na2SO4) and evaporated under vacuum to give the
hydrazone 8 (0.36 g, 72%): mp 78-80 °C; IR (neat) 3325, 1603
cm-1; 1H NMR (CD3OD) 1.25 (d, 3H, J ) 6.3), 3.43 (dd, 1H, J
) 3.6, 7), 3.83 (qd, 1H, J ) 6.6, 6.6), 4.42 (dd, 1H, J ) 3.6, 5.8),
4.87 (s, 4H), 6.71-7.21 (m, 6H); 13C NMR (CD3OD) 19.6, 68.4,
72.3, 78.4; 113.1, 119.9, 129.9, 176.4, 150.0; MS (CI/tBuH) m/ z
1
(19 mg, 75%): mp > 300 °C (lit.12 mp > 300 °C); H NMR (3 N
DCl) 1.68 (d, 3H, J ) 6.4), 4.62 (qd, 1H, J ) 6.5, 5), 5.40 (d,
1H, J ) 5.0), 6.10 (large s, 5H), 9.46 (s, 1H); 13C NMR (3 N NaOD
+ dioxane) 19.4, 71.6, 79.0, 127.5, 148.5, 154.0, 155.4, 163.8,
173.5; MS (FAB + Xe, 6 kV, 10 mA, glycerol + 0.1% TFA) m/ z
138 [M + H]+; [R]22 -65.0 (c 0.2, 0.1 N HCl) (lit.12 [R]24 -66.8
D
D
(c 0.2, 0.1 N HCl)).
Ack n ow led gm en t. We thank Dr. J acques Madd-
aluno for his linguistic help and for valuable discussions.
207 [M + H - H2O]+, 225 [M + H]+; [R]23 +2.8 (c 1.1, EtOH).
D
Anal. Calcd for C11H16N2O3: C, 58.91; H, 7.19; N, 12.49.
Found: C, 58.61; H, 6.82; N, 12.25.
J O961426S