Studies on oxidation of ergot alkaloids: oxidation and desaturation of dihydrolysergol-stereochemical requirements

Article abstract of DOI:10.1016/j.tet.2007.07.099

A new method for the oxidation of ergoline alcohols to aldehydes was found (TFFA-DMSO, -78 °C, then DIPEA). Structural features of ergolines required for successful C7-C8 double bond introduction via Polonovski-Potier reaction of respective 6-N-oxides were defined and experimentally confirmed: (i) the presence of electron-withdrawing group at C-8; (ii) trans-diaxial orientation of N6-O and C7-H bonds (both requirements are fulfilled for dihydrolyserg-17-al and its 2,4-dinitrophenyl hydrazone prepared in this work).

Full text of DOI:10.1016/j.tet.2007.07.099

Tetrahedron 63 (2007) 10466–10478
Studies on oxidation of ergot alkaloids: oxidation and desaturation
of dihydrolysergol—stereochemical requirements
a
a,
a
b
ꢀa
*
ˇꢀ
ꢀ
ˇ
Radek Gazak, Vladimır Kren, Petr Sedmera, Daniele Passarella, Michaela Novotna
and Bruno Danielib
aInstitute of Microbiology, Academy of Sciences of the Czech Republic, Vꢀıdenꢁskaꢀ 1083, CZ 14220 Prague 4, Czech Republic
bDipartimento di Chimica Organica e Industriale, Universitaꢂ degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
Received 6 June 2007; revised 24 July 2007; accepted 26 July 2007
Available online 1 August 2007
Abstract—A new method for the oxidation of ergoline alcohols to aldehydes was found (TFFA–DMSO, ꢀ78 ꢁC, then DIPEA). Structural
features of ergolines required for successful C7–C8 double bond introduction via Polonovski–Potier reaction of respective 6-N-oxides were
defined and experimentally confirmed: (i) the presence of electron-withdrawing group at C-8; (ii) trans-diaxial orientation of N6–O and C7–H
bonds (both requirements are fulfilled for dihydrolyserg-17-al and its 2,4-dinitrophenyl hydrazone prepared in this work).
Ó 2007 Published by Elsevier Ltd.
1. Introduction
Many therapeutically used EA belong to the peptide alka-
loids, but a significant number is semisynthetically prepared
whose production is based on few basic precursors (Fig. 1),
e.g., lysergic acid (1) and 9,10-dihydrolysergic acid (2),
lysergol (3), 9,10-dihydrolysergol (4) (available from the
seeds of some Ipomoea species2), and elymoclavine (5) pro-
duced in good yields by the submerged cultivation of some
Claviceps strains (e.g., C. fusiformis).3 The conformation
Ergot alkaloids (EA) cover a broad range of therapeutic uses
as the drugs of high potency in the treatment of various
disorders, such as, e.g., uterine atonia, postpartum bleeding,
migraine, orthostatic circulatory disturbances, senile cere-
bral insufficiency, hypertension, hyperprolactinemia, acro-
megaly, and parkinsonism.1
17
R
R
D
CH2OH
8
9
N6
H
H
10
H
5
N
H
N
H
CH3
CH3
CH3
A
C
3
B
HN
HN
HN
elymoclavine (5)
1
2
R = COOH, lysergic acid (1)
R = CH2OH, lysergol (3)
R = COOH, dihydrolysergic acid (2)
R= COOMe, 2a
R = CH2OH, dihydrolysergol (4)
OAc
CHO
HC
MeO
N
H
N
H
CH3
CH3
HN
HN
6
7
Figure 1. Natural ergolines, ergolenes, and their semisynthetic oxidation derivatives.
Keywords: Ergot alkaloids; Lysergol; Oxidation; Desaturation, Polonovski–Potier reaction.
* Corresponding author. Tel.: +420 296 442 510; fax: +420 296 442 509; e-mail: kren@biomed.cas.cz
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.07.099

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10467
of the D-ring of ergot alkaloids substantially influences bind-
ing to the different receptor class4 as nicely demonstrated
by the different biological activities displayed by the pairs
1 versus 2 and 3 versus 4. Thus, the desaturation of D-ring
at positions C5–C10 and C7–C8 could lead to new classes
of ergot alkaloid derivatives with unprecedented biological
activities. The new compounds could also became valuable
intermediates for further modifications, as shown by the
stereoselective addition of MeOH to the 9,10 double bond
of lysergol to form the pharmaceutically valuable 10-a-
methoxylysergol (or lumilysergol). Furthermore, changes
in electronic densities of the piperidine ring and possible
conjugations with the indole system could also lead to change
of reactivity at the neighboring positions—e.g., at C-4 that
still remains a challenge for any substitution. So far a single
ergolene containing the C5–C10 double bond has been re-
ported in the literature—5,10-dehydroelymoclavine—as
a metabolite from the roots of African plant Securidaca long-
ipedunculata Fres.5 However, the compound was never iso-
lated as a pure substance and its structure was suggested
only on the basis of mass spectroscopic considerations.
(Fig. 1) and the oxidation of 5 with dimethyl sulfoxide—ace-
tic anhydride provided the enol acetate 7 (Fig. 1) in 15%
yield.10 Attempts to oxidize elymoclavine following the Op-
penauer protocol led only to traces of the required product.11
Mantegani et al.12 reported a successful oxidation of 9,10-di-
hydrolysergol (4) by modified Parikh–Doering oxidation13
employing SO3$Et3N complex instead of an original
SO3$Py for DMSO activation (according to our experiments,
SO3$Py–DMSO is ineffective in this type of oxidation).
However, this method failed with ergolenes as well.
Many other oxidation methods led to decomposition of ergo-
line skeleton, starting often at the C-2 position (most of the
chromate-based oxidation procedures) or introduced new
OH group into C-8 position (penniclavine, isopennicla-
vine).14
In addition, numerous oxidative biotransformations using
isolated enzymes or whole cells were tested, but they af-
forded various products15 and the respective aldehyde or
acid were never obtained.
First, and so far the only one documented introduction of
a double bond into the position 7,8 of an ergoline was accom-
Therefore, we decided to investigate if modern oxidation
methods are applicable for the transformation of ergoline
alcohols to aldehydes (or acids) and whether the resulting
aldehyde (or its protected derivative) could consecutively
be tested in the Polonovski–Potier reaction for the desatura-
tion of ring D.
6
€
plished by Stutz and Stadler by means of the Polonovski–
Potier reaction performed on the 6-N-oxide of 2a. The
same authors6 suggested that electron withdrawing character
of carboxymethyl group at C-8, which causes acidity of H-8
and thus facilitates the stabilization of the intermediate immi-
nium salt, is crucial in the mechanism of Polonovski–Potier
reaction in this case. Although 6-N-oxide preparations of
ergolines were extensively studied,7 except the single report,6
their use for a desaturation of the D-ring was never reported.
2. Results and discussion
2.1. N-1 protected derivates of ergolines and ergolenes
To corroborate the assumption given in the above paper,6 it
is necessary to prepare ergoline derivatives, containing elec-
tron-withdrawing group. Aldehyde derived from alcohol 4
(oritsprotectedderivatives)appearstobesuitable forthistask.
Ergolines and ergolenes are usually poorly soluble in non-
polar organic solvents such as CH2Cl2. This fact is incon-
venient for many organic reactions, e.g., for oxidation
reactions mostly requiring dichloromethane as a solvent.
However, the oxidation of these alcohols into their respec-
tive aldehydes and acids remains a challenge so far, although
it may seem, at the first sight, quite surprising since the sub-
strates are relatively simple and bear a primary alcoholic
group.
Their solubility might be improved by substitution of the po-
lar functionalities of the ergoline skeleton, e.g., alkylation or
acylation/sulfonylation at N-1 position.
Dihydrolysergol (4) was selectively benzylated at N-1 to
yield 8 by the action of BnBr in DMSO after deprotonization
of indole nitrogen by KOH. The same procedure was used
also for N-1 benzylation of lysergol to yielded 9 (Fig. 3).
The only ergot aldehyde obtained in good yield is chanocla-
vine-I-aldehyde (Fig. 2) that can be produced by chemical
oxidation of chanoclavine-I (Fig. 2; MnO2/acetone, reflux).8
Oxidation of ‘activated’ allylic alcohol group of elymocla-
vine (5) using manganese dioxide oxidation in MeOH (the re-
action in acetone does not proceed)9 yields an aldehyde 6
Acetylation of 4 carried out in DMF using NaH and acetyl
chloride (Scheme 1) gave a mixture of the acetyl derivatives
12, 12a, and 12b from which the desired 1-N-acetyl-9,10-
R
CH2OH
N
R
CH3
H
H
NHCH3
H
N
H
CH3
CH3
H
HN
BnN
BnN
R = CH2OH: chanoclavine-I
R = CHO: chanoclavine-I-aldehyde
8 R = CH2OH
16 R = CHO
9
Figure 2.
Figure 3.

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10468
11 R1 = PMBS,
a, f
12b R1 = H, R2 = Ac
R
2 = H (31% overall)
(95%)
c
CH2OR2
12 R1 = Ac, R2 = H (19%)
H
N
+
11 R1 = PMBS,
2 = H (19%)
b
a
CH3
H
12a R1 = R2 = Ac (31%)
R
+
12b R1 = H, R2 = Ac (10%)
R1N
4 R1= R2= H
d
b, e
13 R1 = H, R2 = TBDMS
12 R1 = Ac, R2 = H (43% overall)
(94%)
Scheme 1. Reagents and conditions: (a) 4-(MeO)PhSO2Cl(PMBSCl), NaH, 30 min at 0 ꢁC, 12 h at rt; (b) AcCl, NaH, DMF, 30 min at 0 ꢁC, 2.5 h at rt; (c) Py,
Ac2O, 12 h at rt; (d) TBDMSCl, imidazole, DMF, 4 h, rt; (e) BF3$Et2O, CH2Cl2, 3 h, rt; and (f) K2CO3, MeOH/H2O (9:1), 1.5 h.
dihydrolysergol (12) could be isolated in 19% yield only. A
better yield of 12 (43%) could be obtained by protecting the
primary hydroxyl as TBDMS ether first, followed by acety-
lation and deprotection. Similarly, 1-N-(4-methoxybenzene-
sulfonyl)-9,10-dihydrolysergol (11) was obtained in poor
yield by direct sulfonylation of 4 with PBMSCl and
NaH, but more satisfactorily, by selectively acetylating the
17-OH group first with Py/Ac2O to give 12b.
2.2.1. Swern oxidation (DMSO–oxalyl chloride) of dihy-
drolysergol silyl-ether 15. The failure of the Swern
DMSO–oxalyl chloride procedure to perform the oxidation
of the primary alcohol function in ergoline was confirmed
by the behavior of the 17-TES-ether of dihydrolysergol. In
fact the conversion of the primary alcoholic group to the
corresponding TES-ether represents another possibility of
improving the low solubility of the studied compounds in
various organic solvents. The advantage of this strategy
consists of the fact that these groups could be oxidatively
removed by DMSO–oxalyl chloride procedure affording re-
spective aldehyde.20 Unfortunately, the use of this method
led to the complete decomposition of the 17-O-TES-dihy-
drolysergol. Not a trace of aldehyde was formed according
to a negative reaction with Ehrlich’s reagent.
Although the benzenesulfonyl group attached to an amine is
usually rather resistant to hydrolysis, it was reported that this
group can be removed from indole nitrogen under very mild
conditions (Mg/MeOH).16 Unfortunately, the method failed
in the case of compound 11, which, therefore, was not used
in the following oxidative step.
2.2. Oxidation of ergolines and ergolenes to (the
corresponding) aldehydes and acids
2.2.2. Swern oxidation (DMSO/TFAA). In contrast to
oxalyl chloride, trifluoroacetic anhydride proved to be an
effective activator in the Swern oxidation of ergolines but
the original procedure21 afforded rather low yield of the re-
spective aldehyde. 1-N-Benzyl-dihydrolysergol (8) was cho-
sen as a starting ‘model’ compound for the optimization of
reaction conditions due to its good solubility in dichloro-
methane (even at low temperatures required for this method).
The optimization is summarized in Table 2. The best con-
ditions for oxidation to the aldehyde 16 are as follows: an
excess of DMSO (6.0 equiv) and trifluoroacetic anhydride
(4.5 equiv) at ꢀ78 ꢁC with subsequent addition of DIPEA
1-N-protected derivatives 8 and 9 were first used as a starting
material for oxidation experiments because of their sufficient
solubilityinorganicsolvents. Oxidationswerecarriedoutwith
modern, mild, and selective oxidation methods; nevertheless,
all the experiments were unsuccessful (Table 1) leaving the
starting materials unaffected, or giving complete or partial de-
compositionwithtracesofoxidative products. Onlyinthecase
of Swern oxidation of 8 (using TFAA for DMSO activation),
a low yield of the aldehyde 16 was obtained.
Table 1. Overview of the tested oxidation experiments of the ergoline derivatives
Starting compound
Method
Result of reaction
1-N-Benzyl-dihydrolysergol (8)
1-N-Benzyl-dihydrolysergol (8)
1-N-Benzyl-dihydrolysergol (8)
1-N-Benzyl-dihydrolysergol (8)
1-N-Benzyl-dihydrolysergol (8)
1-N-Benzyl-lysergol (9)
1-N-Benzyl-lysergol (9)
1-N-Benzyl-lysergol (9)
1-N-Benzyl-lysergol (9)
1-N-Benzyl-lysergol (9)
Dihydrolysergol (4)
TEMPO/NaOCl17
TEMPO/laccase18
No reaction
No reaction
Partial decomposition
Decomposition
16 (15%)
Decomposition
Traces of oxidative product
No reaction
Decomposition
Total decomposition
No reaction
19
Bu4NCrO3
Swern (DMSO/oxalyl chloride)20
Swern (DMSO/TFAA)21
Dess–Martin22
Dess–Martin, Py (1.5 equiv)23
TEMPO/NaOCl17
Swern (DMSO/TFAA)21
CrO3/H5IO6, wet MeCN24
Bu4NMnO4
25
Elymoclavine (5)
Elymoclavine (5)
BaMnO4, DMF26
Partial decomposition
Decomposition
Swern (DMSO/TFAA)21

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10469
Table 2. Optimization of reaction conditions for Swern oxidation21 (DMSO/
TFAA) of 1-N-benzyl-dihydrolysergol (8) to aldehyde 16
the 1-N-benzyl derivative 8 (Scheme 2); however, the addi-
tion of DMSO to the dichloromethane solution of 12 was
necessary for its complete dissolution. Nevertheless, it has
to be noted that during this oxidation reaction partial iso-
merization of 17 to isodihydrolysergal-derivative 17a oc-
curred via the enol form of aldehyde (Scheme 2). The
formation of similar side products (with 8S absolute config-
uration) was observed (according to our experiments) also in
the reaction reported by Mantegani et al.12 and in the Swern
oxidation of 8 (giving the isodihydrolysergal-derivative
16a). Hydrolysis of 17 with K2CO3/MeOH/H2O afforded
a mixture of dihydrolysergal (18) accompanied by its hemi-
acetal 18a and by traces of the presumed 8-epi analogues.
DMSOa TFAAa Reaction time Conversionb
Yield of
aldehydeb
(%)
(equiv)
(equiv) after base
addition (h)
(%)
1.c 2.0
1.5
2.2
4.4
4.5
4.5
0.25
0.5
2.0
12
12
Not estimated 15
2.
3.
4.
3.0
6.0
6.0
50
89
82
82
26
37
43
58
5.d 6.0
All reactions were accomplished by DMSO/trifluoroacetic anhydride
(TFAA) oxidation at ꢀ78 ꢁC. The reaction was terminated by using N-ethyl-
diisopropylamine (7–10 equiv).
a
For 1 equiv of 1-N-benzyl-dihydrolysergol.
Isolated yields.
Et3N (2.2 equiv) was used to terminate the reaction.
Reaction was carried out in the dark.
b
c
2.2.3. Oxidation of ergolines to carboxylic acids. The oxi-
dation of 17 to dihydrolysergic acid (2) was accomplished by
Ag2O/NaOH in MeOH (Scheme 2). The advantage of this
method consists in a simultaneous deprotection of N-1 position
during oxidation. The respective acid was transformed into
its methyl ester 2a for its an easier purification. The yield of
this reaction was rather low (24%) but alternative and widely
used method exploiting NaClO2 as an oxidation reagent (with
resorcinol as a scavenger of chlorine species forming during
this reaction) did not lead to the corresponding acid and con-
siderable decomposition of the starting aldehyde occurred.
TEMPO/NaOCl procedure in the presence of Bu4NBr failed
as well.17
d
as a base. The application of Et3N instead of DIPEA
increases side product formation. An excess of reagents is
essential for a satisfactory yield of 1-N-benzyl-dihydrolyser-
gal (16) due to the presence of tertiary amine group in the
starting compound, which can presumably decompose the
activated complex of DMSO–TFAA. A further decrease in
the side product formation was achieved when the reaction
was performed in dark, allowing the isolation of 16 in fairly
good yield (58%).
However, the hydrogenolytic deprotection (Pd/C–H2,
MeOH) of 1-N-benzyl-dihydrolysergal (16) to dihydrolyser-
gal (18) led to the reduction of the carbonyl group, while the
benzyl group remained untouched. This highlights once
again the peculiar reactivity of the ergoline moiety toward
the common chemical reagents and force us to use an alter-
native protection strategy at N-1. The acetylation of the N-1
position in 4 overcame the problem since rather mild condi-
tions (K2CO3, MeOH/H2O) could be used for deprotection
after primary alcoholic group oxidation.
CHO
COOCH3
N
H
H
N
H
CH3
CH3
a-c
H
HN
HN
18
2a
Scheme 3. Reagents and conditions: (a) MCPBA, DMF, 0 ꢁC, 1 h; (b) H2–
Pd/C, MeOH, 12 h, rt; (c) H2SO4 (cat.), MeOH (dry), 12 h, rt, ca. 80% (after
a–c).
Thus oxidation of 12 to the corresponding aldehyde 17 was
achieved according to optimized conditions developed for
2a R1 = H, R2 = COOCH3
(24%)
c, d
R2
R2
R2
H
H
H
N
H
N
H
N
H
CH3
a
CH3
CH3
+
R1N
R1N
12 R1 = Ac, R2 = CH2OH
R1N
17a R1 = Ac, R2 = CHO
17 R1 = Ac, R2 = CHO
(13%)
(62%)
b
18 R1 = H, R2 = CHO
+
18a R1 = H, R2 = CHOH(OMe)
(90% of the mixture 18 and 18a)
Scheme 2. Reagents and conditions: (a) DMSO/TFAA, CH2Cl2, ꢀ78 ꢁC, 45 min, then DIPEA, rt, 4 h; (b) K2CO3, MeOH/H2O (9:1, v/v), 2–3 h, rt; (c) Ag2O,
THF/MeOH/aqueous NaOH (10% w/w), 45 min; and (d) H2SO4 (cat.), MeOH (dry), 12 h, rt.

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10470
An alternative, very efficient method for the oxidation of
dihydrolysergal (18) to dihydrolysergic acid (2) was devel-
oped in this work using excess of MCPBA (Scheme 3).
reaction mentioned above (direct N-oxidation of aldehyde
by MCPBA led simultaneously to oxidation of its carbonyl
group to a carboxyl). Protection of the carbonyl group of
18 as 2,4-dinitrophenyl hydrazone gave, after 6-N-oxidation
and Polonovski–Potier reaction (Scheme 4), a comparable
yield of 7,8-ergolene as was reported6 for compound 23 de-
spite that DMF was used instead of ‘traditional’ CH2Cl2 (for
solubility reasons). Thus, although the acidity of the a-posi-
tion of hydrazones is rather low, the course of this reaction is
very similar to the reaction of the ester 23.
A drawback of this oxidation method consists in the necessity
of the intermediate N-oxide reduction; however, rather high
yield and low side products formation are unquestionable
advantages in comparison with other methods tested.
2.3. Desaturation of the D-ring of ergolines—
Polonovski–Potier reaction
R1
R2
R1
R2
Introduction of new double bond into the position 7,8 of
9,10-dihydroergoline derivatives was accomplished by the
Polonovski–Potier reaction,6 starting from the correspond-
ing 6-N-oxides. In principle, the double bond could also be
introduced between position 5 and 10, but steric and elec-
tronic factors suggest that formation of the C7–C8 double
bond should be strongly favored.
H
a,b
H
N
H
N
H
CH3
CH3
NH
HN
HN
18 R1 = H, R2 = O
25 R1 = H, R2
19 R1= OH, R2= O
26 R1= H, R2 =
NH
N
Ergoline/ergine N-oxidations usually employ H2O2 or
m-chloroperbenzoic acid (MCPBA).7 Bulkier MCPBA is
more selective than H2O2 and often produces only single N-
oxidediastereomer.7a Thisfactisveryimportant forthecourse
of Polonovski–Potier reaction, because the reaction outcome
is dictated by the configuration of the starting N-oxide.
=
N
O2N
NO2
O2N
NO2
Scheme 4. Reagents and conditions: (a) MCPBA, DMF, 0 ꢁC, 0.5 h and
(b) Ac2O, Et3N, DMF, 0 ꢁC, 1 h.
However, the acidity of H-8 in ergolines and ergolenes is not
the only requirement for a successful Polonovski reaction
since the introduction of C7–C8 double bond to the methyl
lysergate via its 6-N-oxide 24 failed as well.
17-O-Acetyl-lysergol 6-N-oxide (21; both possible stereo-
isomers in the ratio a/b ca. 4:1), 17-O-acetyl-dihydrolysergol
6-N-oxide (22; single stereoisomer with a-configuration),
methyl dihydrolysergate 6-N-oxide (23; single stereoisomer
with a-configuration), and methyl lysergate 6-N-oxide (24;
both possible stereoisomers in the ratio a/b ca. 4:1) were
prepared according to the described methods7a (Fig. 4).
Moreover, MCPBA oxidation of 20 (product described in
Ref. 6) gave mixture of two 6-N-oxides (in the ratio ca.
1:1), which led after attempted Polonovski–Potier reaction
to the partial decomposition of these intermediates (without
C7–C8 double bond formation).
Polonovski reaction (Ac2O/Et3N) of the 6-N-oxides 21 and
22 did not lead to the C7–C8 double bond formation and
only complete decomposition of starting N-oxides was ob-
served, in accordance with the fact that they do not exhibit
any acidity at the C-8 position.
These experiments indicate two important requirements for
successful course of the Polonovski–Potier reaction in the
ergoline D-ring:
To confirm the role of the acidity of H-8, we tried to intro-
duce C7–C8 double bond into the molecule of dihydrolyser-
gal (18); however, these attempts failed due to the side
1. The hydrogen at the position C-8 of the D-ring should
posses an acidic character, which probably facilitates
the stabilization of intermediate imminium salt (Fig. 5).
The role of H-8 on the course of Polonovski–Potier reac-
tion was suggested previously6 but without comparison
with another related compounds (alcohol or its ester
and aldehyde derived from the dihydrolysergic acid (2)).
2. Trans-diaxial relationship of N-oxide bond and one of the
H-7 bonds must occur. This is the case of compound 23
but not the case of compound 24 (Fig. 6) where the pres-
ence of the C9–C10 double bond limits the possibility to
satisfy this stereochemical requirement and therefore the
reaction failed to give the desired product.
CH2OAc
COOCH3
N
CH2OAc
O
N
H
O
N
H
CH3
CH3
H
H
CH3
H
HN
HN
HN
20
21
22
COOCH3
COOCH3
O
N
O
N
H
H
COOCH3
H
COOCH3
COOCH3
CH3
H
CH3
H
H
H
+
N
B-
H
H
+
N
H
H
N
CH2
CH3
HN
HN
CH3
23
24
Figure 4. 6-N-Oxides used for Polonovski–Potier reaction. Compound 20
represents a single product with D7,8 described so far.
Figure 5. The role of acidic hydrogen at C-8 on the intermediate salt stabi-
lization.

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10471
H
H
H
COOMe
H
H
H
H
H
H
COOMe
CH3
H
CH3
N
O
H
N
H
H
H
O
H
H
23
24
Figure 6. Conformations of the D-ring in dihydrolysergate 23 and lysergate 24 6-N-oxides (according to the Ref. 7a).
To assess the influence of acylating reagent on the course
of reaction, we also applied TFAA instead of acetic anhydride
(without base addition). However, this modification in all the
cases led to the decomposition of starting 6-N-oxides (prod-
ucts with C7–C8 double bond were not formed).
High resolution mass spectrometric experiment was per-
formed on a commercial APEX-Qe FTMS instrument equip-
ped with a 9.4 T superconducting magnet and a Combi ESI/
MALDI ion source (Bruker Daltonics, Billerica MA) using
electrospray ionization. One milligram of each sample (8,
9, 11, 12, 13, 25, and 26) was dissolved in 1 mL of MeOH
and one microliter of stock solution was diluted in 1 mL of
0.1% formic acid and 80% MeCN afterward. One milligram
of 16 and 17 was dissolved in 1 mL of MeCN and one micro-
liter of stock solution was diluted in 1 mL of MeCN after-
ward. The flow rate was 1 mL/min and the temperature of
dry gas (nitrogen) was set to 230 ꢁC. The Q front-end con-
sists of a quadrupole mass filter followed by a hexapole
collision cell. By switching the potentials on the exit lenses
appropriately under the control of the data acquisition com-
puter, ions could be accumulated either in the hexapole of
the Combi ESI source, or in the hexapole collision cell of
the Q front-end, prior to transfer to the FTMS analyzer
cell. Mass spectra were obtained by accumulating ions in
the collision hexapole and running the quadrupole mass filter
in nonmass-selective (RF-only) mode so that ions of a broad
m/z range (200–2500) were passed to the FTMS analyzer
cell. The accumulation time in collision cell was set at
0.5 s, the cell was opened for 4500 ms, 16 experiments
were collected for one spectrum. The instrument was exter-
nally calibrated using quadruple-, triple- and double- charged
ions of angiotensin I, quintuple- and quadruple- charged ions
of insulin. It results in typical mass accuracy below 1 ppm.
After the analysis the spectra were apodized using sin apod-
ization with one zero fill.
3. Conclusions
A further demonstration of the peculiar reactivity of ergo-
lines and ergolenes has been given. In fact the versatile meth-
odologies that found general application in the preparative
organic chemistry failed or highlighted highly demanding
requisites. Three different tasks have been faced in this study:
(1) the solubility improvement of the studied compounds; (2)
the oxidation of CH2OH to aldehyde or to carboxylic acid;
and (3) the desaturation of D-ring. A particular success was
achieved for the oxidation of 9,10-dihydrolysergol to an
aldehyde by DMSO/TFAA and the subsequent treatment
with DIPEA. The experimental evidence has been given to
the supposed necessary trans-diaxial disposition of H-7 and
N–O bonds. The relevance of the biological and pharmaco-
logical activities of these compounds justifies the efforts
and stresses the importance of even small advances in this
field.
4. Experimental section
4.1. General
NMR spectra were recorded on a Varian INOVA-400 spec-
trometer (399.89 MHz for 1H, 100.55 MHz for 13C) in
CDCl3 or DMSO-d6 at 30 ꢁC. Chemical shifts were refer-
enced to the residual solvent signal (dH 7.265, dC 77.00; dH
2.50, dC 39.60). Digital resolution used justified reporting
the protonandcarbonchemicalshiftstothree andtwodecimal
places, respectively. Coupling constants [J] are given in Hz.
All 2D NMR experiments (HOM2DJ, gCOSY, TOCSY,
HMQC, and HMBC) were performed using standard manu-
facturers’ software. The sequence for 1D-TOCSY experi-
ments was obtained through Varian User Library; the
employed sequence gHMQC was obtained from Varian
Application Laboratory in Darmstadt (DE).
4.1.1. 1-N-Benzyl-9,10-dihydrolysergol (8). 9,10-Dihydro-
lysergol (4, 0.5 g, 1.953 mmol) was dissolved in DMSO
(6.25 mL) and powdered KOH (0.334 g, 5.964 mmol) was
added. The mixture was stirred at room temperature for
10 min benzyl bromide (0.3 mL, 2.53 mmol) was added
and the mixture was stirred at room temperature in the dark
under argon. After 3 h, the mixture was diluted with water
(50 mL) and extracted with CH2Cl2 (2ꢂ25 mL). Organic
layers were combined, washed with saturated aqueous solu-
tion of NaCl, and dried over anhydrous Na2SO4. Flash chro-
matography (CHCl3/MeOH/NH4OH 95:5:1) afforded 8
(0.414 g, 61%) as a white amorphous solid.
1H NMR (CDCl3): 1.181 (1H, ddd, J¼12.5, 12.3, 12.3, H-
9a), 2.018 (1H, dd, J¼11.3, 11.3, H-7a), 2.202 (1H, ddd,
J¼11.1, 9.7, 4.3, H-5), 2.206 (1H, m, H-8), 2.498 (3H, s,
NMe), 2.718 (1H, m, H-9e), 2.737 (1H, ddd, J¼14.7, 11.1,
1.7, H-4a), 3.025 (1H, m, H-10), 3.179 (1H, ddd, J¼11.3,
3.6, 1.9, H-7e), 3.406 (1H, dd, J¼14.7, 4.3, H-4e), 3.584
(1H, dd, J¼10.7, 6.9, H-17u), 3.675 (1H, dd, J¼10.7, 5.8,
H-17d), 5.260 (2H, s, CH2), 6.800 (1H, d, J¼1.7, H-2),
Positive-ion electrospray ionization (ESI) mass spectra were
recorded on a double-focusing instrument Finnigan MAT 95
(Finnigan MAT, Bremen, DE) with BE geometry. Samples
dissolved in methanol/water (2:1, v/v) were continuously
infused through a stainless capillary held at 3.3 kV into
Finnigan ESI source via a linear syringe pump at a flow
rate of 40 mL/min.

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R. Gazaꢀk et al. / Tetrahedron 63 (2007) 10466–10478
10472
H
7
6.930 (1H, ddd, J¼7.1, 1.3, 0.8, H-12), 7.081 (1H, ddd,
J¼8.2, 0.8, 0.8, H-14), 7.149 (1H, dd, J¼8.2, 7.1, H-13),
7.163 (2H, m, 2ꢂH-ortho), 7.276 (1H, m, H-para), 7.306
(2H, m, 2ꢂH-meta); 13C NMR (CDCl3): 26.19 (C-4),
30.78 (C-9), 38.68 (C-8), 40.33 (C-10), 43.28 (NMe),
50.18 (CH2), 60.69 (C-7), 66.32 (C-17), 67.41 (C-5),
107.19 (C-14), 111.35 (C-3), 112.90 (C-12), 121.77 (C-2),
122.82 (C-13), 126.73 (C-16), 126.95 (2ꢂC-ortho), 127.52
(C-para), 128.68 (2ꢂC-meta), 133.54 (C-11), 134.103 (C-
15), 137.92 (C-ipso). Positive ESIMS (m/z): 347 [M+H]+;
HRMS (ESI FTMS) calcd for C23H27N2O 347.2118, found
for [M+H+] 347.2116.
H
OH
H
5
8
N
H
CH3
Figure 8. Flap-up conformation of the D-ring.
Positive ESIMS (m/z): 345 [M+H]+; HRMS (ESI FTMS)
calcd for C23H25N2O 345.1961, found for [M+H+]
345.1958.
According to COSY, the molecule of 9 contains a 9-ergolene
skeleton substituted by benzyl, N-methyl, and CH2OH
groups. The benzylation at N-1 is evident from the absence
of indole NH and its coupling to H-2 in the 1H NMR spec-
trum and the heteronuclear couplings of the benzylic CH2
to C-2, C-15, and C-16 (Fig. 7). The chemical shift of H-5
(3.305 ppm) indicates that H-5 and the N-6 lone electron
pair are antiperiplanar.27 Couplings J7a,8¼8.6 Hz and
J8,9¼3.0 Hz require a pseudoaxial H-8. Therefore, the ergo-
lene D-ring adopts a flap-up conformation14c,28 (Fig. 8) with
pseudoequatorial (i.e., 8b) CH2OH group.
According to COSY, the molecule of 8 contains an ergoline
skeleton substituted by benzyl, N-methyl, and CH2O–
groups. The N-benzylation is evident from the absence of in-
dole NH and its coupling to H-2 in the 1H NMR spectrum and
the heteronuclear couplings of the benzylic CH2 to C-2 and
C-15 (Fig. 7). The coupling J5,10¼9.7 Hz means a trans-
C/D ring junction. The long-range couplings of H-10 to
H-12 and H-14 further support the dihydro derivative
character of the compound. Large values of J8,9a and J7a,8 in-
dicate an axial positionof H-8, i.e., an 8b-CH2OH orientation.
4.1.3. Preparation of 1-N-(4-methoxybenzenesulfonyl)-
9,10-dihydrolysergol (11).
4.1.3.1. Method I. 9,10-Dihydrolysergol (4, 200 mg,
0.781 mmol) and NaH (30 mg, 1.015 mmol, 80% w/w dis-
persion in min. oil) were dissolved under cooling to 0 ꢁC
in 5 mL DMF (not dissolved completely) and stirred at
0 ꢁC under argon for 10 min. 4-Methoxybenzenesulfonic
chloride (194 mg, 0.939 mmol) was then added and the
reaction mixture was stirred at 0 ꢁC for 30 min and then
overnight at room temperature. The reaction mixture was
then diluted with saturated aqueous solution of NaHCO3
(30 mL) and extracted with ethyl acetate (2ꢂ15 mL).
Organic layers were combined, washed with brine, and dried
over anhydrous Na2SO4. Flash chromatography (CH2Cl2/
MeOH/NH4OH 89:10:1) yielded title compound 11
(63 mg, 19%) as a white amorphous solid.
N
H
H2C
H
Figure 7. Some diagnostic HMBC contacts observable in compounds 8
and 9.
4.1.2. 1-N-Benzyl-lysergol (9). Powdered KOH (0.167 g,
2.982 mmol) was added to a stirred solution of 3 (0.250 g,
0.984 mmol) in DMSO (3 mL). After 10 min of stirring at
room temperature, benzyl bromide (0.150 mL, 1.26 mmol)
was added and the mixture was stirred at room temperature
in the dark under argon. After 3 h, the mixture was diluted
with water (50 mL) and extracted with CH2Cl2 (2ꢂ25 mL).
Organic layers were combined, washed with brine, and
dried over Na2SO4. Flash chromatography (CHCl3/MeOH/
NH4OH 95:5:1) afforded 9 (0.214 g, 63%) as a white amor-
phous solid.
1H NMR (DMSO): 0.882 (1H, ddd, J¼12.4, 12.2, 12.2, H-
9a), 1.884 (1H, dd, J¼11.1, 10.7, H-7a), 1.908 (2H, m, H-
5, H-8), 2.322 (3H, s, NMe), 2.437 (1H, ddd, J¼14.7, 11.5,
1.8, H-4a), 2.538 (1H, m, H-9e), 2.728 (1H, m, H-10),
2.994 (1H, m, H-9e), 3.287 (1H, dd, J¼14.7, 4.2, H-4e),
3.288 (1H, m, H-17u), 3.267 (1H, m, H-17d), 3.768 (3H, s,
OCH3), 4.540 (1H, br s, 17-OH), 7.044 (2H, AA0BB0,
SJ¼9.0, 2ꢂH-ortho), 7.066 (1H, d, J-7.4, H-12), 7.282
(1H, dd, J¼8.2, 7.4, H-13), 7.402 (1H, d, J¼1.8, H-2),
7.657 (1H, d, J¼8.2, H-14), 7.881 (2H, AA0BB0, SJ¼9.0,
2ꢂH-meta); 13C NMR (DMSO): 25.89 (C-4), 30.48 (C-9),
37.98 (C-8), 39.42 (C-10), 43.75 (NMe), 55.84 (OCH3),
60.35 (C-7), 64.36 (C-17), 66.20 (C-5), 110.85 (C-14),
114.97 (2ꢂC-ortho), 117.71 (C-12), 118.47 (C-3), 119.80
(C-2), 125.72 (C-13), 128.31 (C-16), 128.96 (C-ipso),
128.99 (2ꢂC-meta), 132.20 (C-15), 134.43 (C-11), 163.62
(C-para). Positive ESIMS (m/z): 427 [M+H]+; HRMS (ESI
FTMS) calcd for C23H27N2O4S 427.1686, found for
[M+H+] 427.1685.
1H NMR (CDCl3): 2.425 (1H, dd, J¼11.2, 8.6, H-7a), 2.581
(3H, s, NMe), 2.764 (1H, ddd, J¼14.4, 11.4, 1.8, H-4a),
2.850 (1H, m, H-8), 3.126 (1H, dd, J¼11.2, 4.9, H-7e),
3.305 (1H, dddd, J¼11.4, 5.4, 3.1, 2.1, H-5), 3.455 (1H,
dd, J¼14.4, 5.4, H-4e), 3.704 (1H, dd, J¼10.4, 6.2, H-
17u), 3.793 (1H, dd, J¼10.4, 5.2, H-17d), 5.264 (2H, s,
CH2), 6.386 (1H, dd, J¼3.0, 2.0, H-9), 6.815 (1H, d,
J¼1.8, H-2), 7.095 (1H, m, H-14), 7.139 (2H, m, 2ꢂortho-
Ph), 7.153 (1H, m, H-13), 7.170 (1H, m, H-12), 7.275 (1H,
m, para-Ph), 7.302 (2H, m, 2ꢂmeta-Ph); 13C NMR
(CDCl3): 25.85 (C-4), 38.38 (C-8), 43.15 (NMe), 50.22
(CH2), 55.76 (C-7), 62.57 (C-5), 65.51 (C-17), 108.19 (C-
14), 110.19 (C-3), 111.84 (C-12), 121.69 (C-9), 122.44 (C-
2), 123.06 (C-13), 126.62 (C-16), 126.88 (2ꢂC-ortho),
127.56 (C-para), 128.70 (2ꢂC-meta), 128.76 (C-11),
134.73 (C-15), 135.05 (C-10), 137.82 (C-ipso).
According to COSY and HSQC, the molecule contains an
ergoline substructure. The shape of the H-10 multiplet

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10473
indicates a large (axial–axial) coupling to H-5 which means
a trans-C/D ring junction. The couplings J7a,8 and J8,9a are
also large so that H-8 is axial. The OH signal at
4.540 ppm, coupled to both H-17 protons is an evidence
for a CH2OH group that should have an 8b-configuration.
1H NMR (DMSO): 0.915 (1H, ddd, J¼12.3, 12.3, 11.4, H-
9a), 1.799 (1H, dd, J¼11.3, 11.0, H-7a), 1.909 (1H, ddd,
J¼11.4, 9.5, 4.2, H-5), 1.929 (1H, m, H-8), 2.330 (3H, s,
NMe), 2.462 (1H, ddd, J¼15.3, 11.4, 2.2, H-4a), 2.577
(1H, ddd, J¼12.3, 3.8, 1.8, H-9e), 2.589 (3H, s, Ac), 2.753
(1H, m, H-10), 3.000 (1H, ddd, J¼11.0, 3.5, 1.8, H-7e),
3.285 (1H, J¼15.3, 4.2, H-4e), 3.287 (1H, ddd, J¼10.5,
5.2, 1.6, H-17u), 3.396 (1H, ddd, J¼10.5, 5.3, 5.2, H-17d),
4.534 (1H, dd, J¼5.3, 5.2, 17-OH), 7.088 (1H, dd, J¼7.5,
0.8, H-12), 7.220 (1H, dd, J¼8.1, 7.5, H-13), 7.471 (1H, d,
J¼2.2, H-2), 7.919 (1H, dd, J¼8.1, 0.8, H-14); 13C NMR
(DMSO): 23.64 (Ac), 26.16 (C-4), 30.73 (C-9), 38.17
(C-8), 39.67 (C-10), 42.95 (NMe), 60.58 (C-7), 64.50 (C-
17), 66.71 (C-5), 113.57 (C-14), 117.57 (C-3), 117.80 (C-
12), 119.99 (C-2), 125.64 (C-13), 128.18 (C-16), 132.61
(C-15), 133.78 (C-11), 169.18 (C]O). Positive ESIMS
(m/z): 299 [M+H]+; HRMS (ESI FTMS) calcd for
C18H23N2O2 299.1754, found for [M+H+] 299.1752.
1
The absence of NH signal in the H NMR spectrum could
be explained by CH3OC6H4SO2 substitution at N-1.
4.1.3.2. Method II (via acetylation of primary hydr-
oxyl group). (a) Preparation of 17-O-acetyl-9,10-dihydro-
lysergol (12b): 9,10-dihydrolysergol (4, 0.350 g,
1.367 mmol) was dissolved in 4 mL of dry pyridine and
1.5 mL of acetic anhydride and the reaction mixture was
stirred at room temperature for 12 h. The mixture was treated
with ice-cold water solution of saturated NaHCO3 (30 mL),
stirred for 30 min and then extracted three times with
20 mL of the mixture CH2Cl2/MeOH (9:1, v/v). The com-
bined extracts were dried over anhydrous Na2SO4. The resid-
ual pyridine was removed by co-evaporation with toluene.
After the evaporation, the sufficiently pure title compound
12b (0.40 g, 95%) was obtained.
According to COSYand HSQC, the molecule of 12 contains
an ergoline skeleton substituted by a CH2OH group at C-8, by
an N-methyl, and one acetyl. The ample evidence for an
unsubstituted primary alcoholic group is the triplet at
4.534 ppm giving no crosspeaks in gHSQC but coupled to
both H-17 protons. The acetyl is easily located at N-1 as
seen from the 4J coupling of acetyl protons to C-2. A trans-
C/D ring junction was confirmed by large J5,10¼9.5 Hz.
The CH2OH substituent has an 8b-configuration since
J7a,8¼11.3 Hz and J8,9¼12.3 Hz.
(b) 1-N-(4-Methoxybenzenesulfonyl)-9,10-dihydrolysergol
(11) from 17-O-acetyl-9,10-dihydrolysergol (12b): 9,10-
dihydrolysergol acetate (12b, 400 mg, 1.342 mmol) and
NaH (60 mg, 2.030 mmol, 80% w/w dispersion in min.
oil) were dissolved under cooling to 0 ꢁC in DMF (5 mL)
and stirred at 0 ꢁC under argon for 10 min. 4-Methoxy-
benzenesulfonic chloride (361 mg, 1.747 mmol) was then
added and the reaction mixture was stirred at 0 ꢁC for
30 min and then overnight at room temperature. The reaction
mixture was then diluted with saturated aqueous solution of
NaHCO3 (50 mL) and extracted two times with 20 mL of
CH2Cl2. Organic layers were combined, washed with satu-
rated aqueous solution of NaCl, and dried over anhydrous
Na2SO4.
4.1.4.2. Method II. 17-O-(tert-Butyldimethylsilyl)-
9,10-dihydrolysergol (13): 9,10-dihydrolysergol (4,
640 mg, 2.500 mmol), TBDMSCl (490 mg, 3.251 mmol),
and imidazole (400 mg, 5.882 mmol) were dissolved in dry
DMF (6 mL) and the reaction mixture was stirred under
argon at room temperature. The reaction was quenched after
4 h with saturated aqueous solution of NaHCO3 (50 mL), the
precipitate was filtered off, washed with water, and dried to
afford the pure title compound 13 (870 mg, 94%) as a slightly
pink amorphous solid.
The crude 1-N-(4-methoxybenzensulfonyl)-9,10-dihydroly-
sergol acetate was dissolved in the mixture of MeOH/H2O
(11 mL, 10:1, v/v) and K2CO3 (200 mg, 1.449 mmol) was
then added. The resulting mixture was stirred at room tem-
perature for 1.5 h. The solvent was then evaporated and
the mixture was directly transferred to a silica gel chromato-
graphy column (CH2Cl2/MeOH/NH4OH 89:10:1). Pure 11
(178 mg, 31%) was obtained as a white amorphous solid.
For MS and NMR data see above.
1H NMR (CDCl3): 0.092 (3H, s, SiMe), 0.097 (3H, s, SiMe),
0.932 (9H, s, CMe3), 1.175 (1H, ddd, J¼12.5, 12.3, 12.3, H-
9a), 2.006 (1H, dd, J¼11.2, 11.2, H-7a), 2.177 (1H, ddd,
J¼11.3, 11.0, 4.4, H-5), 2.182 (1H, m, H-8), 2.513 (3H, s,
NMe), 2.655 (1H, dddd, J¼12.5, 3.9, 3.9, 1.9, H-9e),
2.752 (1H, ddd, J¼14.7, 11.0, 1.8, H-4a), 3.015 (1H, m,
H-10), 3.158 (1H, ddd, J¼11.2, 3.6, 1.9, H-7e), 3.428 (1H,
dd, J¼14.7, 4.4, H-4e), 3.543 (1H, dd, J¼10.1, 6.9, H-
17u), 3.645 (1H, dd, J¼10.1, 5.3, H-17d), 6.887 (1H, dd,
J¼1.8, 1.8, H-2), 6.937 (1H, m, H-12), 7.142 (1H, m, H-
13), 7.189 (1H, m, H-14), 8.026 (1H, br s, NH);13C NMR
(CDCl3): ꢀ5.37 (SiMe), ꢀ5.32 (SiMe), 18.34 (SiC), 25.96
(CMe3), 26.96 (C-4), 30.70 (C-9), 38.55 (C-8), 40.41 (C-
10), 43.33 (NMe), 60.93 (C-7), 65.50 (C-17), 67.42 (C-5),
108.45 (C-14), 112.03 (C-3), 113.18 (C-12), 117.67 (C-2),
123.09 (C-13), 126.24 (C-16), 133.35 (C-15), 132.56 (C-
11). Positive ESIMS (m/z): 371 [M+H]+; HRMS (ESI
FTMS) calcd for C22H35N2OSi 371.2513, found for
[M+H+] 371.2511.
4.1.4. 1-N-Acetyl-9,10-dihydrolysergol (12).
4.1.4.1. Method I. 9,10-Dihydrolysergol (4, 500 mg,
1.953 mmol) and NaH (96 mg, 2.400 mmol, 60% w/w dis-
persion in min. oil) were dissolved under cooling to 0 ꢁC in
dry DMF (5 mL) and stirred at 0 ꢁC under argon for
30 min. Acetyl chloride (0.190 mL, 2.676 mmol) was then
added and the reaction mixture was stirred at 0 ꢁC for
30 min and then for 2 h at room temperature. The reaction
mixture was then diluted with saturated aqueous solution of
NaHCO3 (50 mL) and extracted with ethyl acetate
(2ꢂ30 mL). Organic layers were combined, washed with
brine, and dried over anhydrous Na2SO4.
Flash chromatography (CHCl3/MeOH/NH4OH 95:5:1)
yielded 1-N-acetyl-dihydrolysergol (12, 170 mg, 19%) as
a white amorphous solid.
According to COSY, the molecule of 13 contains an ergoline
skeleton substituted by N-methyl and TBDMS groups. The

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10474
preserved indole ring is evident from the observed indole
NH and its coupling to H-2 in the 1H NMR spectrum.
Although there is no direct evidence available, the TBDMS
group has to be attached to C-17 OH. The upfield shift of both
H-17 protons with respect to the parent compound is a
supporting argument. Large J5,10¼11.0 Hz indicates
a trans-C/D ring junction. The configuration 8bresults from
the magnitude of vicinal coupling constants J7a,8¼11.2 Hz
and J8,9a¼12.3 Hz (ring D adopting a chair form).
7.165 (2H, m, 2ꢂH-ortho), 7.286 (1H, m, H-para), 7.310
(2H, m, 2ꢂH-meta), 9.786 (1H, dd, J¼1.0, 1.0, H-17); minor
component: 1.657 (1H, ddddd, J¼12.6, 12.6, 4.8, 1.1, 1.1,
H-9a), 2.465 (3H, s, NMe), 2.647 (1H, m, H-4a), 2.903
(1H, m, H-10), 3.152 (1H, m, H-9e), 3.378 (1H, dd,
J¼14.7, 4.2, H-4e), 3.475 (1H, m, H-7e), 5.257 (2H, s,
CH2), 6.779 (1H, d, J¼1.3, H-2), 9.944 (1H, dd, J¼1.2, 1.1,
H-17); 13C NMR (CDCl3), major component: 26.86 (C-4),
27.84 (C-9), 40.03 (C-10), 43.14 (NMe), 48.67 (C-8), 50.24
(CH2), 56.45 (C-7), 66.98 (C-5), 107.51 (C-14), 111.05 (C-
3), 112.91 (C-12), 121.94 (C-2), 122.90 (C-13), 126.64 (C-
16), 126.96 (2ꢂC-ortho), 127.57 (C-para), 128.72 (2ꢂ
C-meta), 132.66 (C-11), 134.13 (C-15), 137.84 (C-ipso),
202.51 (C-17); minor component: 26.62 (C-4), 27.74 (C-9),
37.52 (C-10, 43.49 (NMe), 46.18 (C-8), 50.19 (CH2), 56.88
(C-7), 67.30 (C-5), 107.25 (C-14), 111.22 (C-3), 112.95 (C-
12), 121.76 (C-2), 122.84 (C-13), 126.64 (C-16), 126.96
(2ꢂC-ortho), 127.53 (C-para), 128.69 (2ꢂC-meta), 133.48
(C-11), 133.76 (C-15), 137.84 (C-ipso), 204.64 (C-17). Pos-
itive ESIMS (m/z): 345 [M+H]+; HRMS (ESI FTMS) calcd
for C23H25N2O 345.1961, found for [M+H+] 345.1958.
1-N-Acetyl-9,10-dihydrolysergol (12): 17-O-(tert-butyldi-
methylsilyl)-9,10-dihydrolysergol (13, 600 mg, 1.621 mmol)
and NaH (71 mg, 1.775 mmol, 60% w/w dispersion in min.
oil) were dissolved under cooling to 0 ꢁC in dry DMF
(6 mL)andstirredat0 ꢁCunderargonfor30 min.Acetylchlo-
ride (0.140 mL, 1.972 mmol) was then added and the reaction
mixture was stirred at 0 ꢁC for 30 min and then for 2 h at room
temperature. The reaction mixture was then diluted with satu-
ratedaqueoussolutionofNaHCO3 (50 mL)andextractedwith
dichloromethane (2ꢂ30 mL). Organic layers were combined,
dried over anhydrous Na2SO4, and evaporated. The crude
mixture from acetylation was dissolved in dry CH2Cl2
(25 mL), BF3$Et2O (2.0 mL, 50% solution) was added and
the mixture was stirred for 3 h at room temperature. The mix-
ture was then poured into the saturated aqueous solution of
NaHCO3 (40 mL) and shortly stirred. The organic layer was
separated and the aqueous phase was extracted with CH2Cl2
(2ꢂ20 mL). Organic layers were combined and dried over
anhydrous Na2SO4. Flash chromatography (CHCl3/MeOH/
NH4OH 95:5:1) afforded 1-N-acetyl-9,10-dihydrolysergol
(12, 210 mg, 43%) as a white amorphous solid. For MS and
NMR data see above.
1
Some signals in the H NMR spectrum occur twice: e.g.,
CH]O, H-2, CH2, NMe. Therefore, the sample is a mixture
of two compounds in the ratio 83:17 (w4:1). All spectral
properties extracted by COSY and gHSQC correspond to
an ergoline skeleton carrying an aldehyde group at C-8
and a benzyl group. No signal of indole NH was observed.
The benzylic methylene is coupled to C-2 and C-15 so that
N-1 is benzylated. Both J7a,8 and J8,9a in the major compo-
nent are large, so that the configuration at C-8 is 8b. The
magnitude of J5,10¼9.5 Hz confirms a trans-C/D ring junc-
tion. Therefore, the prevailing component is 16.
4.1.5. 1-N-Benzyl-9,10-dihydrolysergal (16) (according
to optimized conditions). Trifluoroacetic anhydride
(0.330 mL, 2.371 mmol) in dichloromethane (0.450 mL)
was added dropwise to a solution of dichloromethane
(0.600 mL) and dimethyl sulfoxide (0.228 mL, 3.055 mmol)
under argon at ꢀ78 ꢁC. The solution was stirred for 10 min
at ꢀ78 ꢁC and then a solution of 1-N-benzyl-9,10-dihydroly-
sergol (8, 0.186 mg, 0.537 mmol) in CH2Cl2 (1 mL) was
added dropwise. The mixture was stirred for another 30 min
at ꢀ78 ꢁC and then at the same temperature it was treated
with N-ethyldiisopropylamine (1.2 mL, 6.902 mmol). The
mixture was stirred for 10 min, allowed to warm up to room
temperature and stirred in dark (under argon) for another
12 h. The mixture was diluted with brine (30 mL) and ex-
tracted with CH2Cl2 (3ꢂ25 mL). The combined organic
layers were washed with brine (3ꢂ50 mL) and dried over
anhydrous Na2SO4. Flash chromatography (CHCl3/MeOH/
NH4OH 95:5:1) yielded 1-N-benzyl-9,10-dihydrolysergal
(16, 108 mg, 58%) as a white amorphous solid and 33 mg
of the starting material (18%) was recovered.
The minor component shares most of the structural features
with the major one. Its C-13 chemical shifts are slightly
different as well as the multiplicity of H-9a (one large cou-
pling is replaced by a medium one (4.8 Hz)). Thus, this com-
pound is the 8a-epimer 16a.
4.1.6. 1-N-Acetyl-9,10-dihydrolysergal (17). Trifluoro-
acetic anhydride (0.6 mL, 4.311 mmol) in 1.0 mL of
dichloromethane was added dropwise to a solution of
dichloromethane (1.0 mL) and dimethyl sulfoxide (0.4 mL,
5.360 mmol) under argon at ꢀ78 ꢁC. The solution was stirred
for 10 min at ꢀ78 ꢁC and then a solution of 12 (0.280 g,
0.940 mmol) in the mixture of CH2Cl2 (2 mL) and DMSO
(1 mL) was added dropwise. The mixture was stirred for
another 30 min at ꢀ78 ꢁC and then at the same temperature
it was treated with N-ethyldiisopropylamine (2.0 mL,
11.504 mmol). The mixture was stirred for 10 min, allowed
to warm up to room temperature and stirred in dark (under
argon) for another 4 h. The mixture was diluted with brine
(40 mL) and extracted with CH2Cl2 (3ꢂ20 mL). The com-
bined organic layers were washed with brine (10 mL) and
dried over anhydrous Na2SO4. Flash chromatography
(CHCl3/MeOH/Et3N 95:5:0.5) yielded 1-N-acetyl-dihydro-
lysergal (17, 200 mg, 62%) as a white amorphous solid and
30 mg of the starting material (10%) was recovered.
1H NMR (CDCl3), major component: 1.456 (1H, ddd,
J¼12.2, 12.1, 12.1, H-9a), 2.218 (1H, ddd, J¼11.1, 9.5,
4.2, H-5), 2.269 (1H, J¼11.8, 11.5, H-7a), 2.530 (3H,
NMe), 2.731 (1H, ddd, J¼14.7, 11.1, 1.5, H-4a), 2.934
(1H, m, H-8), 2.988 (1H, m, H-9e), 3.044 (1H, m, H-10),
3.314 (1H, ddd, J¼11.5, 3.4, 2.2, H-7e), 3.408 (1H, dd,
J¼14.7, 4.3, H-4e), 5.269 (2H, s, CH2), 6.816 (1H, d,
J¼1.3, H-2), 7.070 (1H, ddd, J¼7.1, 2.1, 0.9, H-12), 7.104
(1H, ddd, J¼8.2, 1.8, 0.9, H-14), 7.160 (1H, m, H-13),
1H NMR (DMSO): 1.214 (1H, ddd, J¼12.6, 12.6, 11.9, H-
9a), 2.005 (1H, m, H-5), 2.100 (1H, dd, J¼11.6, 11.5, H-
7a), 2.395 (3H, s, NMe), 2.496 (1H, ddd, J¼15.4, 11.4,

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R. Gazaꢀk et al. / Tetrahedron 63 (2007) 10466–10478
10475
2.2, H-4a), 2.594 (3H, s, Ac), 2.849 (1H, m, H-8), 2.868 (1H,
m, H-10), 2.881 (1H, ddd, J¼12.6, 3.8, 1.9, H-9e), 3.194
(1H, m, H-7e), 3.259 (1H, dd, J¼15.4, 4.2, H-4e), 7.145
(1H, d, J¼7.5, H-12), 7.283 (1H, dd, J¼8.0, 7.5, H-13),
7.494 (1H, d, J¼2.2, H-2), 7.950 (1H, d, J¼8.0, H-14),
9.677 (1H, d, J¼0.8, H-17); 13C NMR (DMSO): 23.62
(Ac), 25.91 (C-4), 27.41 (C-9), 38.91 (C-10), 42.46
(NMe), 47.45 (C-8), 55.79 (C-7), 65.96 (C-5), 113.78
(C-14), 117.19 (C-3), 117.86 (C-12), 120.14 (C-2), 125.70
(C-13), 128.07 (C-16), 132.61 (C-15), 132.95 (C-11),
169.18 (C]O), 203.56 (C-17). Positive ESIMS (m/z): 297
[M+H]+; HRMS (ESI FTMS) calcd for C18H21N2O2
297.1598, found for [M+H+] 297.1595.
multiplet). The other significant component is a methyl
hemiacetal derived from the major component, responsible
for H-17 at 4.274 ppm (dd, J¼6.7 and 6.4 Hz), dC 99.14;
CH3O at 3.271 ppm (dC 53.79), and 17-OH at 6.139 ppm
(d, J¼6.7 Hz). This deduction was supported by coupling
of the methoxyl to C-17 and H-17 to the methoxyl carbon
(HMBC). The trace components might be the products of
C-8 epimerization and its methyl hemiacetal.
4.1.8. Methyl 9,10-dihydrolysergate (2a).
4.1.8.1. Compound 2a via Ag2O oxidation of 17. Aque-
ous solution of NaOH (0.5 mL, 10% w/w) was quickly added
to a stirred solution of 1-N-acetyl-9,10-dihydrolysergal (17)
(90 mg, 0.304 mmol) and Ag2O (140 mg, 0.604 mmol) in
the mixture of THF/MeOH (6 mL, 1:1, v/v). After 45 min
the mixture was filtered, neutralized by the addition of concd
HCl (0.5 mL, 36% w/w) and evaporated to dryness. The res-
idue was dissolved in dry MeOH (15 mL) and concd H2SO4
(0.5 mL, 96% w/w) was added. The resulting mixture was
stirred at room temperature for 12 h then it was diluted with
ice-cold saturated NaHCO3 (50 mL), stirred for 5 min and
extracted with CH2Cl2 (3ꢂ30 mL). The collected organic
layers were dried over anhydrous Na2SO4 and evaporated.
After flash chromatography (CHCl3/MeOH/NH4OH 95:5:1),
the title compound 2a (20 mg, 24%) was obtained as a
pink-red amorphous solid. Analytical data were in accor-
dance with those reported previously.6
The 1H NMR spectrum of 17 exhibits features required by an
ergoline skeleton. The absence of indole NH signal and its
coupling to H-2 indicates a substitution at N-1. The substit-
uent is an acetyl as its protons are coupled to C-2 (4J). The
shape of the H-10 multiplet inferred from gHSQC confirms
a trans-C/D ring junction. The configuration at C-8 is 8b
since both J7a,8 and J8,9a are large. Characteristic signals
(dH 9.677, dC 203.56) support the presence of a CH]O
moiety (1J¼182.9 Hz).
4.1.7. 9,10-Dihydrolysergal (18) and its hemiacetal 18a.
1-N-Acetyl-9,10-dihydrolysergal (4) (171 mg, 0.578 mmol)
and K2CO3 (150 mg, 1.085 mmol) were dissolved in the mix-
ture of MeOH (15 mL), CH2Cl2 (5 mL), and water (1.5 mL)
and stirred at room temperature for 2 h. The reaction mixture
was then poured into water (50 mL) and extracted with the
mixture of CH2Cl2/MeOH (9:1, v/v, 3ꢂ25 mL). The col-
lected organic layers were dried over anhydrous Na2SO4
and evaporated in vacuo. Flash chromatography on silica
gel (CHCl3/MeOH/NH4OH 90:10:1) afforded an inseparable
mixture of 18 and its hemiacetal 18a (139 mg) as a white
amorphous solids.
4.1.8.2. Compound 2a via MCPBA oxidation of 18.
MCPBA (0.190 g, 0.771 mmol, 70% w/w) was portionwise
added to a stirred and cooled (0 ꢁC) solution of dihydroly-
sergal (18, 0.070 g, 0.273 mmol) in DMF (2 mL) and the
stirring was continued for another 1 h. Reaction mixture
was then diluted with ice-cold saturated NaHCO3 (25 mL)
and extracted with CH2Cl2 (3ꢂ15 mL). The collected or-
ganic layers were dried over anhydrous Na2SO4 and evapo-
rated. Crude solid was dissolved in MeOH (10 mL), Pd/C
(10 mg, 5% w/w) was added and the mixture was stirred un-
der hydrogen for 12 h. The solution was filtered through the
Celite pad, which was then washed by MeOH. Collected
filtrates were evaporated. The residual solid was re-dis-
solved in dry MeOH (10 mL) and concd H2SO4 (0.5 mL,
96% w/w) was added. The resulting mixture was stirred at
room temperature for 12 h then it was diluted with ice-
cold saturated NaHCO3 (50 mL), stirred for 5 min and
extracted with CH2Cl2 (3ꢂ30 mL). The combined organic
layers were dried over anhydrous Na2SO4 and evaporated.
Flash chromatography on silica gel (CHCl3/MeOH/
NH4OH 9:1:0.1, then 8:2:0.1) afforded the title compound
2a (63 mg, 80%) as a brownish amorphous solid.
Positive ESIMS (m/z): 255 and 287 [M+H]+. Compound 18:
1H NMR (DMSO): 1.240 (1H, ddd, J¼12.1, 11.5, 11.5,
H-9a), 2.039 (1H, m, H-5), 2.114 (1H, dd, J¼11.7, 11.3,
H-7a), 2.407 (3H, s, NMe), 2.547 (1H, ddd, J¼14.7, 11.4,
1.8, H-4a), 2.837 (1H, m, H-8), 2.865 (1H, m, H-10),
2.877 (1H, m, H-9e), 3.196 (1H, m, H-7e), 3.314 (1H, dd,
J¼14.7, 4.3, H-4e), 6.823 (1H, ddd, J¼7.1, 1.2, 0.7, H-
12), 6.982 (1H, dd, J¼1.8, 1.8, H-2), 7.029 (1H, dd,
J¼8.1, 7.1, H-13), 7.138 (1H, ddd, J¼8.1, 0.7, 0.6, H-14),
9.687 (1H, d, J¼0.5, H-17), 10.638 (1H, br s, NH); 13C
NMR (DMSO): 26.45 (C-4), 27.56 (C-9), 39.20 (C-10),
42.62 (NMe), 47.61 (C-8), 55.97 (C-7), 66.68 (C-5),
108.88 (C-14), 109.90 (C-3), 112.10 (C-12), 118.64 (C-2),
122.10 (C-13), 125.92 (C-16), 132.10 (C-11), 132.22
(C-15), 203.75 (C-17). Compound 18a: 25.80 (C-4), 28.84
(C-9), 40.72 (NMe), 45.65 (C-8), 53.79 (OMe), 57.97
(C-7), 99.14 (C-17), 118.75 (C-2), 122.18 (C-13), 125.81
(C-16).
6-N-Oxides 21–24 were prepared according to the described
procedure.7a
4.1.9. 2,4-Dinitrophenyl hydrazone of 9,10-dihydrolyser-
gal 25. 2,4-Dinitrophenyl hydrazine (0.585 g, 2.952 mmol)
was portionwise added to a stirred mixture of ethanol
(7 mL) and H2SO4 (0.5 mL, 96%, v/v) and stirred for
10 min at room temperature. The clear solution of corre-
sponding hydrazine sulfate was dropwise added to the etha-
nolic solution of dihydrolysergal (18, 0.250 g, 0.977 mmol,
in 10 mL of ethanol). Reaction mixture was stirred for
30 min at room temperature. Precipitated product was filtered
This sample is evidently a mixture consisting of two main
components accompanied by traces of analogues, as judged
from the signals of indole NH around 10.6 ppm. The major
component has an ergoline skeleton substituted by an alde-
1
hyde group at C-8 (dH 9.687, dC.203.75, JC,H¼183.7 Hz).
The configuration is 8b since both J7a,8 and J8,9a are large.
Also the C/D ring junction is trans (the shape of H-10

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R. Gazaꢀk et al. / Tetrahedron 63 (2007) 10466–10478
10476
off, washed with ethanol (2ꢂ5 mL), and dried. The crude
product (in the form of sulfate) was re-dissolved in CH2Cl2/
MeOH mixture (100 mL, 3:1, v/v), washed with saturated so-
lution of NaHCO3 (2ꢂ75 mL), and finally with water. The or-
ganic layer was dried over anhydrous Na2SO4, evaporated,
and the product was crystallized from methanol. The title
compound 25 (278 mg, 65%) was obtained as an orange-
ROESY and HMBC contacts of the compound 25 are high-
lighted in Figures 9 and 10.
There are 22 signals in the 13C NMR spectrum of 25a (Fig.
11). Their distribution—one methyl, three methylenes (ali-
phatic), eleven methines (eight ]CH and three CH), and
seven sp2-hybridized quaternary carbons—fulfills the re-
quirements of a hydrazone derived from an ergine-related
alkaloid 25. Only three-spin systems—an ABC one of the
three vicinal aromatic protons, a 1,2,4-trisubstituted benz-
ene, and –NHCH]CCH2CHCHCH2CH(CH]N–)CH2– were
1
red needles. H NMR (DMSO): 1.360 (1H, ddd, J¼12.3,
12.3, 12.2, H-9a), 2.078 (1H, m, H-5), 2.205 (1H, dd,
J¼11.3, 11.1, H-7a), 2.426 (3H, s, NMe), 2.561 (1H, ddd,
J¼14.6, 11.1, 1.7, H-4a), 2.828 (1H, dm, J¼12.3, H-9e),
2.908 (1H, m, H-10), 3.150 (1H, dm, J¼11.3, H-7e), 3.330
(1H, dd, J¼14.6, 4.3, H-4e), 6.836 (1H, dd, J¼7.1, 0.4, H-
12), 6.985 (1H, dd, J¼2.0, 1.7, H-2), 7.030 (1H, J¼8.1, 7.1,
H-13), 7.137 (1H, dd, J¼8.1, 0.4, H-14), 7.894 (1H, d,
J¼9.7, H-60), 8.043 (1H, d, J¼4.6, H-17), 8.356 (1H, dd,
J¼9.7, 2.7, H-50), 8.841 (1H, d, J¼2.7,H-30), 10.623 (1H,
br s, indole NH), 11.366 (1H, s, ]N–NH–); 13C NMR
(DMSO): 26.57 (C-4), 31.33 (C-9), 38.93 (C-8), 39.72 (C-
10), 42.67 (NMe), 59.38 (C-7), 66.69 (C-5), 108.80 (C-14),
110.04 (C-3), 112.08 (C-12), 116.40 (C-60), 118.61 (C-2),
122.08 (C-13), 123.04 (C-3’), 125.98 (C-16), 128.97 (C-10),
129.87 (C-50), 132.30 (C-11), 133.23 (C-15), 136.71 (C-20),
144.84 (C-40), 155.65 (C-17). Positive ESIMS (m/z): 435
[M+H]+; HRMS (ESI FTMS) calcd for C22H23N6O4
435.1775, found for [M+H+] 435.1770.
1
found in the H NMR spectrum besides two NH signals
(no crosspeaks in gHSQC) and one N-methyl. The HMBC
experiment was used to prove a closure of the D-ring
(through the coupling of NMe protons to C-5 and C-7), the
attachment of –CH] to C-8, the nature of the A and B rings,
and the details of the hydrazone moiety (the coupling of N00-
H to C-10, C-20, C-60, and C-17). Furthermore, an NOE
between N00-H and H-17 indicates their mutual cis-relation-
ship. The examination of proton–proton vicinal couplings
proved: (i) the trans-C/D ring junction (J5,10¼9.6 Hz) and
(ii) the equatorial (8b) position of H-8 (J7a,8¼3.4 Hz,
J8,9a¼4.9 Hz). This implies an axial C-8 side chain in the
O2N
NO2
H
N
N
Mother liquor from crystallization of 25 was evaporated and
purified by column chromatography (CHCl3/toluene/
MeOH/NH4OH 85:10:5:0.5) affording 25a (42 mg, 10%)
as an orange-red solid.
H
H
H
H
H
H
H
N
H
CH3
1H NMR (CDCl3): 1.837 (1H, ddd, J¼13.3, 12.6, 4.9, H-9a),
2.261 (1H, ddd, J¼11.2, 9.6, 4.3, H-5), 2.485 (3H, s, NMe),
2.652 (1H, dd, J¼11.9, 3.4, H-7a), 2.685 (1H, ddd, J¼14.7,
11.2, 1.8, H-4a), 3.006 (1H, m, H-8), 3.080 (1H, m, H-9e),
3.180 (1H, ddd, J¼11.9, 2.2, 2.2, H-7e), 3.219 (1H, m, H-10),
3.406 (1H, dd, J¼14.7, 4.3, H-4e), 6.888 (1H, dd, J¼1.9, 1.8,
H-2), 6.956 (1H, m, H-12), 7.183 (2H, m, H-13, H-14), 7.887
(1H, d, J¼9.6, H-60), 7.900 (1H, d, J¼4.4, H-17), 8.076 (1H,
br s, NH), 8.235 (1H, dd, J¼9.6, 2.6, H-50), 9.072 (1H, d,
J¼2.6, H-30), 11.074 (1H, s, N0-H); 13C NMR (CDCl3): 26.77
(C-4), 30.02 (C-9), 36.85 (C-10), 37.01 (C-8), 43.53 (NMe),
60.17 (C-7), 67.76 (C-5), 108.69 (C-14), 111.66 (C-3),
113.02 (C-2), 116.41 (C-60), 117.86 (C-2), 123.16 (C-13),
123.41 (C-30), 126.17 (C-16), 128.71 (C-20), 129.88 (C-50),
133.14 (C-11), 133.30 (C-15), 137.75 (C-40), 145.05 (C-10),
155.04 (C-17). Positive ESIMS (m/z): 435 [M+H]+.
HN
H
Figure 9. Diagnostic ROESY contacts of the compound 25.
O2N
H
NO2
N
N
H
H
H
N
H
H
H
CH3
HN
H
Twenty-two signals were observed in the 13C NMR spec-
trum of 25: one methyl, three methylenes, eleven methines
(three sp3-, eight sp2-hybridized), and seven quaternary car-
bons (all of sp2-type). Eighteen protons are attached to the
carbons, the remaining two are bonded to heteroatoms.
The 1H NMR spectrum contains one-proton singlet
(assigned to N–H), a three-proton singlet (N–CH3), and
two three-spin systems representing 1,2,3- and 1,2,4-trisub-
stituted aromatic rings, and a partial structure –NHCH]
CCH2CHCHCH2CH(CH])CH2– (ergoline, from indole
NH to C-7). Large couplings J7a,8¼11.3 and J8,9a¼12.3 Hz
indicate an axial H-8 (D-ring in the chair form), and conse-
quently 8b-CH]N–. An NOE between H-17 and hydrazone
NH dictates a mutual cis-relationship. Some diagnostic
Figure 10. Selected HMBC contacts of the compound 25.
NO2
O2N
H
N
N
H
H
N
H
CH3
HN
Figure 11. The structure of 25a.

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R. Gazaꢀk et al. / Tetrahedron 63 (2007) 10466–10478
10477
D-ring adopting a chair conformation. This deduction is
consistent with a strong NOE between H-10 and H-17.
H
N
H
H
N
4.1.10. D7,8-Didehydrolysergal 2,4-dinitrophenylhydr-
azone (26). To a solution of 25 (0.118 g, 0.272 mmol) in
dry DMF (3 mL) was added MCPBA (70%, 0.100 g,
0.406 mmol) portionwise and the mixture was stirred at
0 ꢁC for 30 min. Then Ac2O (0.080 mL, 0.848 mmol) and
Et3N (0.565 mL, 3.968 mmol) were added and this mixture
was stirred at 0 ꢁC for an additional 1 h. The reaction mixture
was poured into a saturated solution of NaHCO3 (100 mL),
stirred for 10 min, and the resulting suspension was filtered
off. Insoluble material was washed by water, dried, and
then re-dissolved in the mixture CH2Cl2/MeOH (100 mL,
8:2, v/v). After evaporation, flash chromatography (CHCl3/
toluene/MeOH/NH4OH 85:10:5:1) afforded the title
compound 26 (60 mg, 51%) as a dark-violet amorphous
solid.
H
H
N
CH3
H
H
H
H
Figure 13. Selected HMBC contacts of the compound 26.
trans-oriented. The chemical shift of NMe indicates a possi-
ble protonation.
Acknowledgements
ˇ
Authors are especially indebted to Dr. Zdenek Veselꢀy for his
valuable suggestions and comments. Grants from Czech
Ministry of Education (1P05OC073), bilateral Czech-Italian
project Kontakt No. 15 Area CH8, prog. N.9 (V.K. & B.D.),
COST Chemistry D28/006/04 and Research concept No.
AV0Z50200510 (Inst. Microbiol., Prague) are gratefully
1H NMR (DMSO): 2.247 (1H, ddd, J¼16.1, 11.7, 1.2, H-9a),
2.776 (1H, ddd, J¼14.4, 11.4, 1.7, H-4a), 3.109 (3H, s,
NMe), 3.322 (1H, ddd, J¼11.7, 9.6, 5.2, H-10), 3.377 (1H,
ddd, J¼11.4, 9.6, 4.4, H-5), 3.416 (1H, dd, J¼16.1, 5.2,
H-9e), 3.540 (1H, dd, J¼14.4, 4.4, H-4e), 6.934 (1H, d,
J¼1.2, H-7), 6.995 (1H, ddd, J¼7.1, 1.3, 0.8, H-12), 7.068
(1H, dd, J¼1.7, 1.7, H-2), 7.115 (1H, dd, J¼8.1, 7.1, H-13),
7.201 (1H, ddd, J¼8.1, 0.8, 0.8, H-14), 7.968 (1H, d, J¼9.7,
H-60), 8.133 (1H, br s, H-17), 8.272 (1H, dd, J¼9.7, 2.7, H-
50), 8.851 (1H,d, J¼2.7, H-30), 10.735 (1H, d, J¼1.7, indole
NH), 11.409 (1H, s, ]N–NH–); 13C NMR (DMSO), HSQC
and HMBC readouts: 23.8 (C-9), 26.1 (C-4), 37.2 (C-10),
39.3 (NMe), 59,1 (C-5), 109.1 (C-3), 109.3 (C-14), 112.9
(C-12), 116.6 (C-60), 119.2 (C-2), 122.2 (C-13), 124.0 (C-
30), 126.1 (C-16), 127.4 (C-10), 129.7 (C-50), 132.0 (C-11),
133.2 (C-15), 153.5 (C-17). Positive ESIMS (m/z): 433
[M+H]+; HRMS (ESI FTMS) calcd for C22H21N6O4
433.1619, found for [M+H+] 433.1615.
ꢀ
acknowledged. Dr. P. Novak (Inst. Microbiol., Prague) is
thanked for ESIMS and FTMS measurements.
References and notes
ˇ
1. Kren, V.; Cvak, L. Ergot—Genus Claviceps, Medicinal &
Aromatic Plants; Harwood Academic: Amsterdam, London,
1999; Berde, B.; Schild, H. O. Ergot Alkaloids and Related
Compounds; Springer: Berlin, 1978.
€
2. Groger, D.; Mothes, K.; Floss, H. G.; Weygand, F.
Z. Naturforsch. 1963, 18b, 157.
ˇ
3. Kren, V.; Chomatova, S.; Bremek, J.; Pilat, P.; Rehacek, Z.
ˇ
Biotechnol. Lett. 1986, 8, 327.
ꢀ
ꢀ
ˇ
ꢀ
ꢀˇ
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1
The H NMR spectrum of 26 displays signals of two NHs
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parent compound). According to COSY, the investigated
molecule contains two aromatic rings, one 1,2,3- and the
other 1,2,4-trisubstituted (A-ring and the dinitrophenyl moi-
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two olefinic protons (a 1.2 Hz doublet at 6.934 and a broad
singlet at 8.133 ppm). These features are consistent with
a 7-ergolene structure. Both olefinic protons exhibit a homo-
nuclear long-range coupling as well as mutual heteronuclear
couplings so that they belong to a conjugated system. They
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(Fig. 12) and HMBC (Fig. 13) experiments. A strong NOE
between H-7 and H-17 means that both double bonds are
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€
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H
N
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H
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Figure 12. Diagnostic ROESY contacts of the compound 26.

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R. Gazaꢀk et al. / Tetrahedron 63 (2007) 10466–10478
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