Ryanoids and related compounds - Chemoselective electrocatalytic hydrogenation of alkyl α-pyrrole carboxylates: Selective hydrogenation of ryanodine

Article abstract of DOI:10.1139/v02-182

A study of the electrocatalytic hydrogenation (ECH) process of pyrrote and different alkyl pyrrole-2-carboxylates is presented. Once hydrogenated, the alkyl pyrrole-2-carboxylate becomes an ester of proline, an important natural amino acid. The process is chemoselective to the pyrrole ring. Ryanodine is a natural ryanoid known to be biologically active. The tetrahydroryanodine derivative thus obtained may now represent a molecule of high biological interest. The hydrogenation of ryanodine is possible with electrocatalytic and catalytic processes. In both cases the reaction is not diastereoselective.

Full text of DOI:10.1139/v02-182

1
662
Ryanoids and related compounds —
Chemoselective electrocatalytic hydrogenation of
alkyl ␣-pyrrole carboxylates: Selective
hydrogenation of ryanodine
Luc Ruest, Hugues Ménard, Vincent Moreau, and François Laplante
Abstract: A study of the electrocatalytic hydrogenation (ECH) process of pyrrole and different alkyl pyrrole-2-
carboxylates is presented. Once hydrogenated, the alkyl pyrrole-2-carboxylate becomes an ester of proline, an important
natural amino acid. The process is chemoselective to the pyrrole ring. Ryanodine is a natural ryanoid known to be bio-
logically active. The tetrahydroryanodine derivative thus obtained may now represent a molecule of high biological in-
terest. The hydrogenation of ryanodine is possible with electrocatalytic and catalytic processes. In both cases the
reaction is not diastereoselective.
Key words: electrocatalytic hydrogenation, proline esters, ryanodine, tetrahydroryanodine.
Résumé : Une étude sur l’hydrogénation électrocatalytique (HEC) du pyrrole et de quelques esters de l’acide pyrrole-
2
-carboxylique est présentée. Une fois hydrogéné, le pyrrole-2-carboxylate d’alkyle devient un ester de la proline, un
acide aminé naturel important. Le procédé est chimiosélectif au cycle pyrrole. La ryanodine est un ryanoïde connu pour
son activité biologique. Le dérivé tétrahydroryanodine ainsi obtenu peut maintenant présenter un grand intérêt
biologique. L’hydrogénation de la ryanodine est possible par le procédé électrocatalytique et catalytique. Dans les deux
cas, la réaction n’est pas diastéréosélective.
Mots clés: hydrogénation électrocatalytique, esters de proline, ryanodine, tétrahydroryanodine.
Ruest et al. 1667
Introduction
these molecules have a pyrrole ring and, except for pyrrole
and pyrrole-2-carboxylic acid, an ester group, as seen in
ryanodine. With these simple molecules we determined the
best conditions (electrocatalyst and electrolyte) for the
electrocatalytic hydrogenation (ECH) process of ryanodine.
The ECH process is achieved at room temperature and at-
mospheric pressure, unlike most of the classical catalytic hy-
drogenation methods. The classical process often requires a
Ryanodine (Fig. 1) is a natural ryanoid extracted from the
plant Ryania speciosa. This molecule is known to be a po-
tent modulator of the sarcoplasmic reticulum calcium release
channel (1). The interesting functional group of ryanodine in
the present study is the aromatic pyrrole ring attached to the
main polycyclic structure (ryanodol) by an ester function.
Once hydrogenated, this heterocycle becomes an ester of
proline, a natural amino acid. This tetrahydroryanodine de-
rivative may now represent a molecule of high biological in-
terest. Theoretically, removal of the pyrrole moiety and then
esterification of the free hydroxyl group in position 3 with
proline could lead to the desired compound, but in fact it has
been shown that specific esterification at this endo hydroxyl
group is not possible (1c and references therein).
high pressure of hydrogen to reduce an aromatic pyrrole ring
5
(
2, 3). Recently, a pressure of 20 bar (1 bar = 10 Pa) was
used to hydrogenate a compound with a pyrrole ring (4).
Previous works in our laboratory used the ECH of phenol,
cyclohexanone, and 2-cyclohexen-1-one to develop new
electrocatalysts (5–7). The ECH of alkyl pyrrole-2-
carboxylate molecules proceeds in acidic medium to prevent
the poisoning of the catalyst by pyrrole or its derivatives (8, 9)
The ECH mechanism can be explained by the equations
presented in Fig. 2. The electrocatalysts used in an ECH are
constituted of a metallic part (M) and an adsorbent part (A).
In the first step there is an electroadsorption of hydrogen at-
oms on the metallic part resulting from the reduction of wa-
ter (eq. [1]). The alkyl pyrrole-2-carboxylate compound is
adsorbed by the adsorbent of the electrocatalyst (eq. [2]).
The hydrogenation is possible when the site of adsorption of
the molecule is near to the electroadsorbed hydrogen
We began the present study with simple molecules like
pyrrole (1), pyrrole-2-carboxylic acid (3A), and its methyl
(
3B), ethyl (3C), and isopropyl (3D) esters (Fig. 1). All
Received June 26 2002. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 12 December 2002.
1
L. Ruest, H. Ménard, V. Moreau, and F. Laplante. Centre
de Recherche en Électrochimie et Électrocatalyse,
Département de Chimie, Université de Sherbrooke,
Sherbrooke, QC J1K 2R1, Canada.
(
eq. [3]); this site is called the “triple point” (5). After satu-
1Corresponding author (e-mail: Luc.Ruest@USherbrooke.ca).
ration of the ring, the hydrogenated molecule is liberated by
Can. J. Chem. 80: 1662–1667 (2002)
DOI: 10.1139/V02-182
© 2002 NRC Canada

Ruest et al.
1663
Fig. 1. Simple alkyl pyrrole-2-carboxylates and their hydrogenated products, ryanodine and anhydroryanodine.
grade. The electrolyte solutions were made with deionized
water.
Fig. 2. The electrocatalytic hydrogenation (ECH) mechanism of
alkyl pyrrole-2-carboxylate compound.
Starting materials
Pyrrole-2-carboxylic acid and pyrrole were purchased
from Sigma-Aldrich. Commercial pyrrole was distilled be-
fore use. Compounds 3B, 3C, and 3D were synthesized by
the following procedure: a solution of N,N>-dicyclohexyl-
carbodiimide (4 g, 19 mmol) in distilled CH Cl (10 mL)
2
2
was transferred (cannula) to a solution of pyrrole-2-
carboxylic acid (1.9 g, 17 mmol) dissolved in 25 mL of the
corresponding alcohol used as solvent (methanol for 3B, eth-
anol for 3C, and isopropanol for 3D). After the addition of
1
00 mg of 4-dimethylaminopyridine, the mixture was stirred
the adsorbent (eq. [4]). These equations represent the global
hydrogenation process of the alkyl pyrrole-2-carboxylate
compounds.
for 12 h at ambient temperature and under an inert atmo-
sphere. The mixture was filtered on silica gel (40% EtOAc –
6
0% hexane) before purification by flash chromatography to
give esters 3B, 3C, and 3D in 90% yield.
Experimental section
Melting points were recorded on a Melter Toledo FP62
hot stage apparatus and are uncorrected. Mass spectra (MS)
and peak matching (HR-MS) data were determined at 70 eV
on a VG Micromass ZAB-1F spectrometer. The H (300 MHz)
NMR spectra were recorded on a Bruker AC-300 instrument
Methyl pyrrole-2-carboxylate (3B)
White crystalline solid; mp 71°C (lit. (10) value mp 72–
1
7
3°C). H NMR (CD OD) (ppm): 6.95 (m, 1H, HC5), 6.84
1
3
(
m, 1H, HC3), 6.18 (m, 1H, HC4), 3.80 (s, 3H, O-CH ). MS
3
+
m/e: 125 ([M] ). HR-MS calcd. for C H NO : 125.0477;
6
7
2
with CD HOD as internal standard centered at 3.30. The
2
found: 125.0474.
usual standard abbreviations have been used to indicate the
multiplicity of the proton signals. Column chromatography
(
flash) was performed with Merck silica gel (200–400
Ethyl pyrrole-2-carboxylate (3C)
Beige solid; mp 38°C (lit. (11) value mp 40–42°C). H NMR
1
mesh). All the electrocatalysts (5% Pd/Al O , 5% Pt/Al O ,
2
3
2
3
5
% Rh/Al O , and 5% Rh/C) were purchased from Sigma-
(CD OD) (ppm): 6.94 (m, 1H, HC5), 6.84 (m, 1H, HC3),
2
3
3
Aldrich. The solvents used for chromatography were HPLC
6.17 (m, 1H, HC4), 4.27 (q, 7.1 Hz, 2H, O-CH -CH ), 1.33
2
3
©
2002 NRC Canada

1
664
Can. J. Chem. Vol. 80, 2002
+
(
t, 7.1 Hz, 3H, O-CH -CH ). MS m/e: 139 ([M] ). HR-MS
electrode and the electrocatalyst (200 mg). A platinum
counter electrode was used in the anodic compartment. Me-
chanical stirring was applied during the ECH. When another
electrolyte was used, the anodic compartment was filled
with 2 M NaOH (5). A constant current of 5 mA was ap-
plied during the electrolysis. After passing 50 C of electric-
ity to condition the working electrode, a solution of 0.6 M of
starting material in methanol (1.0 mL) was added to the
cathodic compartment.
The electrical charge passed through the system was noted
in Faraday equivalents. A Faraday equivalent is the minimal
amount of electrical charge needed to hydrogenate all the
starting material in the cell. The equivalent charge can be
calculated by the multiplication of the quantity of starting
material by the number of electrons required to complete the
reaction and by the Faraday constant (96 485 C per mole of
electrons). Thus, 1 Faraday equivalent for 0.6 mmol of a
simple alkyl pyrrole-2-carboxylate compound is 232 C, and
2
3
calcd. for C H NO : 139.0633; found: 139.0627.
7
9
2
Isopropyl pyrrole-2-carboxylate (3D)
1
White solid; mp 41°C. H NMR (CD OD) (ppm): 6.93
m, 1H, HC5), 6.82 (m, 1H, HC3), 6.16 (m, 1H, HC4), 5.12
h, 6.3 Hz, 1H, O-CH-(CH ) ), 1.31 (d, 6.3 Hz, 6H, O-CH-
3
(
(
(
1
3
2
+
CH ) ). MS m/e: 153 ([M] ). HR-MS calcd. for C H NO :
3 2 8 11 2
53.0790; found: 153.0793.
Ryanodine used in the study was purified by a known pro-
cedure (1).
Hydrogenated products
All the products obtained by ECH were characterized by
H NMR and a comparison with authentic samples was
done. Pyrrolidine, proline, and proline methyl ester hydro-
chloride (4B) were purchased from Sigma-Aldrich.
1
1
Faraday equivalent for 0.08 mmol ryanodine is 32 C.
Proline ethyl ester hydrochloride (4C)
This material was prepared by a very slow addition of
SOCl (300 ꢀL, 3.6 mmol) to a solution of proline (244 mg,
Analysis
The hydrogenation process was tracked by monitoring the
2
2
(
.1 mmol) in ethanol (6 mL) following a known method
12). The mixture was kept at 0°C during the addition. After
h, the solvent was evaporated to leave a pure product, an
consumption of the starting material according to the Fara-
day equivalent. Aliquots of 500 ꢀL were collected in the
cathodic compartment during the ECH and analysed by
HPLC (ZORBAX Eclipse XDB-C8 column (4.6 mm (i.d.) ×
150 mm)) with an isocratic elution (40% acetonitrile – 60%
water). Before the HPLC analysis, the aliquots were filtered
on a 0.2 ꢀm syringe filter. The HPLC system was an Agilent
1100 Series. A diode array detector performed the data ac-
quisition. The wavelength was set to 265 nm for 3A, 3B, 3C,
and ryanodine; 280 nm for 3D; and 207 nm for pyrrole.
5
1
amorphous beige solid (mp 55°C) (99%). H NMR
CD OD) (ppm): 4.42 (m, 1H, HC2), 4.30 (q, 7.1 Hz, 2H,
(
3
O-CH -CH ), 3.38 (m, 2H, H C5), 2.42 (m, 1H, H C3), 2.12
2
3
2
A
(
1
1
m, 3H, H C3, H C4), 1.32 (t, 3H, O-CH -CH ). MS m/e:
43 ([M] ). HR-MS calcd. for C H NO : 143.0946; found:
7 13 2
43.0950.
B 2 2 3
+
Proline isopropyl ester hydrochloride (4D)
Synthesis of proline isopropyl ester hydrochloride (4D)
was prepared by the previous procedure using isopropanol
Recovery of the hydrogenated products
1
(
99%). The product obtained was a yellowish oil. H NMR
The recovery of the hydrogenated simple alkyl pyrrole-2-
carboxylate molecules, except pyrrolidine, was achieved by
first evaporating water from the solution on a rotatory evapo-
rator after filtration to remove the electrocatalyst. The product
was then recovered by trituration with distilled chloroform.
For pyrrolidine, the solution was saturated with K3PO4 to
adjust the pH to 12. Pyrrolidine was extracted with ether
(
(
CD OD) (ppm): 5.12 (h, 6.2 Hz, 1H, O-CH-(CH ) ), 4.35
3
3 2
m, 1H, HC2), 3.35 (m, 2H, H C5), 2.40 (m, 1H, H C3),
2 A
2
6
.05 (m, 3H, H C3, H C4), 1.30 and 1.31 (two d, 6.3 Hz,
B 2
+
H, O-CH-(CH ) ). MS m/e: 157 ([M] ). HR-MS calcd. for
3
2
C H NO : 157.1103; found: 157.1098.
8
15
2
(
15 mL). The combined organic phases were dried (Na SO )
Electrolysis
2 4
and analysed by GC (HP-5890 with DB-1 column (30 m ×
0
The electrolysis was carried out in a two-compartment
jacketed glass H-cell having a Nafion-324 (E.I. Dupont de
Nemours & Co.) membrane as separator. The cell tempera-
ture was fixed at 21°C during the ECH by a circulating
thermostated bath (VWR 1160A). The working electrode
was a reticulous vitreous carbon (RVC) foam (25 × 20 ×
.25 mm (i.d.), J&W Scientific)).
The product obtained after the hydrogenation of ryanodine
was recovered with a C-18 SPE cartridge. The pH of the so-
lution was adjusted to 8 for the elution. Distilled methanol
was used to recover the product from the cartridge.
6
mm, 80 pores per inch (ppi; 1 inch = 25.4 mm), Electro-
synthesis Co.). The electrode was mounted by inserting a
glass rod (o.d. 5–6 mm, i.d. 3.5 mm) in the horizontal axis
of the piece of RVC. The excess RVC was then removed and
a copper wire was inserted into the RVC to be further ce-
mented with silver epoxy (Epoxy Technology). Finally, the
electrical contact zone on the RVC matrix was fixed to the
glass rod with epoxy to isolate the electrical contact from
the electroactive part of the electrode (5).
Results and discussion
Influence of the electrocatalyst
Figure 3 shows the evolution of the ECH process of 3B
(in 0.1 M NaCl at pH = 1.2 as the electrolyte (saline solu-
tion)) with the use of different electrocatalysts. The best re-
sults were obtained with the 5% Rh/Al O electrocatalyst.
2
3
The other electrocatalysts (5% Pd/Al O and 5% Pt/Al O )
2
3
2
3
Both compartments were filled with the 0.1 M NaCl solu-
tion whose pH was adjusted to 1.2 with concentrated HCl.
The ECH process occurred in the cathodic compartment
allowed for only a 35% reduction of the starting material for
the same Faraday equivalent. These results are consistent
with the literature (2–4, 8, 9) where rhodium is the metal
that is most effective in the hydrogenation of a pyrrole ring
(
filled with 24 mL of the electrolyte) containing the working
©
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Ruest et al.
1665
Fig. 3. The influence of the electrocatalyst on the ECH of
methyl pyrrole-2-carboxylate (3B) in saline solution.
Fig. 4. The ECH process of the simple alkyl pyrrole-2-carboxylate
molecules with 5% Rh/Al O electrocatalyst and saline solution.
2
3
Table 1. The ECH process of ethyl pyrrole-2-carboxylate (3C)
Table 2. The ECH process of pyrrole and pyrrole-2-carboxylic
acid (3A) according the electrolyte (saline or phosphate solution)
with 5% Rh/Al O electrocatalyst.
with 5% Rh/Al O electrocatalyst and different electrolytes.
2
3
2
3
Faraday
equivalent
Electrolyte
% of 3Ca
Faraday
Starting material Electrolyte
equivalent % of SMa
Methanol solution
Saline solution
Borate solution
Phosphate solution
a
1.5
1.5
1.5
1.5
69
0
0
Pyrrole
Pyrrole
3A
Saline solution
Phosphate solution 1.3
Saline solution
Phosphate solution 1.4
2.7
81
0
58
0
0
2.0
3A
Percentage of ethyl pyrrole-2-carboxylate (3C) remaining at the
a
indicated Faraday equivalent.
Percentage of starting material (SM) remaining at the indicated Faraday
equivalent.
compound in classical catalytic hydrogenation. The stability
of the metal in the electrolyte is critical: rhodium and plati-
num electrocatalysts are resistant to acidic conditions but
palladium was observed to dissolve in these conditions. The
rhodium electrocatalyst was used for the remainder of the
experiment.
hydrogenated product and its recovery. The hydrogenated
products are not stable in the phosphate solution: hydrolysis
is rapid, leading to proline, not to ester. The recovery of the
hydrogenated product with this electrolyte is also quite diffi-
cult owing to the presence of the phosphate salts. All the
alkyl pyrrole-2-carboxylate molecules used in this study are
stable in this electrolyte. We did not use boric acid (borate
solution) in the case of ryanodine owing to the formation of
a complex between boric acid and the numerous hydroxyl
groups of the molecule (1c).
Influence of the electrolyte
Several types of electrolyte were tested: phosphate solu-
tion (1 M KH PO – 1 M NaOH; pH = 7.0), borate solution
2
4
(
0.1 M NaCl – 0.05 M boric acid; pH = 2.5), aqueous meth-
anol solution (0.1 M NaCl in 5% H O – MeOH), and saline
solution (0.1 M NaCl; pH = 1.2).
A limiting factor in the choice of the electrolyte is its pH.
A high pH results in hydrolysis of the ester group of the
starting material, giving the pyrrole-2-carboxylic acid and
the alcohol residue (ryanodol for ryanodine). At low pH
The best electrolyte was the saline solution, and we ob-
tained the best recovery of hydrogenated products with this
electrolyte. The ECH process of pyrrole and pyrrole-2-
carboxylic acid were more effective with the phosphate solu-
tion than with the saline solution (Table 2). These results
suggest that the adsorption of the molecule on the
electrocatalyst is influenced by the nature and the pH of the
electrolyte.
2
(
pH < 0), ryanodine loses water through an important cleav-
age of the diterpenic skeleton leading to the anhydro series
(
anhydroryanodine (6)) (1).
An ECH of 3C was performed with each electrolyte, us-
ECH process of the simple alkyl pyrrole-2-carboxylate
molecules
ing 5% Rh/Al O as the electrocatalyst. The results are shown
2
3
in Table 1. Aqueous methanol solution was shown to be a
relatively poor electrolyte for the reaction. These results sug-
gest a modification in quality of adsorption of the pyrrole
ring onto the electrocatalyst (eq. [2]) due to the different sol-
vents used.
The results for the other electrolytes were approximately
similar. The difference between them is the stability of the
Figure 4 shows the ECH of the different alkyl pyrrole-2-
carboxylate molecules under the same conditions (5%
Rh/Al O and saline solution). We can see that the rate of
2
3
hydrogenation of pyrrole and pyrrole-2-carboxylic acid is
very different from that of the other molecules, as mentioned
before. The complete ECH of 3B, 3C, and 3D was achieved
using from 1.5 to 1.7 Faraday equivalents. Thus, we can
©
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1
666
Can. J. Chem. Vol. 80, 2002
Fig. 6. Electrocatalytic hydrogenation of ryanodine.
Fig. 5. The ECH process of ryanodine with two different
electrocatalysts (5% Rh/Al O and 5% Rh/C) in saline solution.
2
3
under UV and are very close in polarity; we did not attempt
to separate them.
Tetrahydroryanodine (3-O-prolinylryanodol) (7)
1
White solid. H NMR (CD OD) (ppm): 5.55 and 5.58
3
(
2 × s, 1H, HC3), 3.77 (d, 1H, 10.2 Hz, HC10), 3.73 (m, 1H,
HC2>), 3.06 (m, 1H, H C5>), 2.86 (m, 1H, H C5>), 2.33 (m,
A
B
1
2
1
1
3
H, H C14), 2.25–2.00 (m, 3H, HC3>, HC13 and H C7),
A
a
x
suppose that the differences between these molecules are not
large enough to have a significant influence on the ECH pro-
cess.
Even if the hydrogenation was shown to be complete, we
did not succeed in recovering all of the hydrogenated prod-
uct. With the techniques used, in the best case, we were able
to recover only 59% of the hydrogenated product of 3C
.00–1.70 (m, 5H, HC3>, H C4>, HC9 and H C14), 1.59–
2
B
.49 (m, 2H, H C7 and H C8), 1.36 (s, 3H, CH (C1)),
eq
ax
3
.30–1.25 (m, 1H, H C8), 1.10 (d, 3H, CH (C18)), 1.02 (d,
eq
3
H, CH (C9)), 0.98 (d, 3H, CH (C5)), 0.75 (2d, 3H,
3
3
+
CH (C19)). MS m/e: 498 ([MH] ). HR-MS calcd. for
C H NO : 498.2703; found: 498.2706.
3
2
5
40
9
(
proline ethyl ester (4C)). We recovered 75% of the hydro-
Catalytic hydrogenation of ryanodine
genated product of 3B (proline methyl ester (4B)) and 87%
To our knowledge, the pyrrole ring of ryanodine has never
been reduced by a classical catalytic hydrogenation. In our
experiments, palladium and platinum catalysts over different
supports were not effective in reducing the aromatic ring at
atmospheric pressure. The electrocatalytic hydrogenation
gave us excellent results. The classical catalytic hydrogena-
tion with 5% Rh/Al O in methanol allowed for only 33%
hydrogenation of ryanodine after 4 days. When the saline
solution (0.1 M NaCl; pH = 1.2) and the same catalyst were
used in classical hydrogenation, the reaction was completed
after 6 to 12 h. These results can be explained by the differ-
ence of adsorption of ryanodine onto the catalyst according
to the solvent used. The quantity of solvent, catalyst, and
starting material were the same as for the ECH process. All
the classical catalytic hydrogenation experiments of this
study were done at atmospheric pressure.
of the hydrogenated product of 3D (proline isopropyl ester
(
4D)). The recovery of the hydrogenated pyrrole-2-carboxylic
acid (proline) was difficult owing to the phosphate salts
ECH with phosphate electrolyte). We recovered, in the best
(
case, only 28% of proline. The yield of recovery of
pyrrolidine is quite difficult to determine owing to its great
volatility. The purity of recovered pyrrolidine was evaluated
by GC to be 95%. The SPE technique cannot be used to re-
cover the hydrogenated product of the simple alkyl pyrrole-
2
3
2
-carboxylate molecules.
ECH process of ryanodine
The results of the ECH of ryanodine are presented in
Fig. 5. The ECH was attempted with two electrocatalysts,
5
% Rh/Al O and 5% Rh/C (activated charcoal). With
2 3
ryanodine more Faraday equivalents are needed to hydroge-
nate the totality of the starting material owing to the greater
dilution (3.2 mM of ryanodine vs. 24 mM for a simple alkyl
pyrrole-2-carboxylate molecule). The ECH process with 5%
Rh/C electrocatalyst seems to be faster than with 5%
Conclusion
The hydrogenation of an alkyl pyrrole-2-carboxylate com-
pound is possible using an electrocatalytic hydrogenation
(ECH) process. We have shown that the hydrogenation reac-
tion is specific to the pyrrole ring of alkyl pyrrole-2-
carboxylate and does not modify the ester function of the
molecule. The ECH of 3B, 3C, and 3D was found to be
most effective with rhodium electrocatalyst (5% Rh/Al O )
in saline solution (0.1 M NaCl at pH = 1.2). Pyrrole and
pyrrole-2-carboxylic acid ECH gave better results in phos-
phate solution (1 M KH PO – 1 M NaOH; pH = 7.0). All
Rh/Al O , but there is stronger adsorption of the hydroge-
2
3
nated product. With 5% Rh/C, we recovered only 7% of the
hydrogenated ryanodine vs. 73% with 5% Rh/Al O electro-
2
3
catalyst.
Tetrahydroryanodine (7) (hydrogenated ryanodine) (Fig. 6)
2
3
1
can be identified by H NMR spectroscopy. The proton sup-
porting the proline moiety (HC(3)) appears at a different
1
position for each diastereomers (D or L). The H NMR spec-
2
4
trum of hydrogenated ryanodine shows an equal amount of
the two diastereomers. This reveals the equal accessibility of
both sides of the pyrrole ring. These epimers are invisible
the simple alkyl pyrrole-2-carboxylate compounds were to-
tally hydrogenated after the passage of 1.7 Faraday equiva-
lents of electrical charge.
©
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Ruest et al.
1667
The ECH process can be used to hydrogenate a complex
molecule like ryanodine. Once again, the hydrogenation was
complete but there was no diastereoselection in the formation
of the reduced compound because of easy access of hydro-
gen to both sides of the pyrrole ring. The hydrogenation of
ryanodine proves that the ECH process can be used effi-
ciently in the selective modification of complex molecules.
The biological activity of the new tetrahydroryanodines is
currently under study by W. Welch, University of Nevada at
Reno, Nevada.
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Acknowledgments
We are grateful to Professor W. Welch, Department of
Biochemistry, University of Nevada, Reno, who allowed us
to do this work with subcontracts of research funded by the
National Science Foundation (NSF). We also thank Profes-
sor Alan J. Williams, Department of Cardiac Medicine, Im-
perial College School of Medicine at the National Heart and
Lung Institute (NHLI), London, U.K., for a research contract
from the British Heart Foundation. The study was also finan-
cially supported by the Natural Sciences and Engineering
Research Council of Canada (NSERC) and the Fonds FCAR
du Québec. We wish to thank Dr. N. Pothier and Mr. G.
Boulay, Département de Chimie, Université de Sherbrooke,
for their technical assistance (NMR spectroscopy and MS).
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©
2002 NRC Canada