Intramolecular alkylation of aromatic compounds XXXVI [1]. Stereoselective synthesis of C/D-cis-configured ergolines

Article abstract of DOI:10.1007/s007060200071

The stereoselective synthesis of cis-ergoline is presented. Starting from rac-N-benzoyl tryptophan methyl ester, the key compound indolinylmethylpyridin-3-one was prepared via a sevenstep reaction in good yield. Since its cyclization to the desired ergoli

Full text of DOI:10.1007/s007060200071

Monatshefte fur Chemie 133, 1017±1030 ꢀ2002)
Intramolecular Alkylation of Aromatic
Compounds XXXVI [1]. Stereoselective
Synthesis of C/D-cis-Con®gured Ergolines
Ã
and Hermann Lotter
Eberhard Reimann , Wolfgang Erdle [2], Eugen Hargasser,


Department Pharmazie ± Zentrum fur Pharmaforschung, Ludwig-Maximilians-Universitat
 
Munchen, D-81377 Munchen, Germany
Summary. The stereoselective synthesis of cis-ergoline is presented. Starting from rac-N-benzoyl
tryptophan methyl ester, the key compound indolinylmethylpyridin-3-one was prepared via a seven-
step reaction in good yield. Since its cyclization to the desired ergolinone failed, the key compound
was reduced to yield the two diastereomeric pyridin-3-ols; only one of them cyclized in tri¯uoro-
methanesulfonicacid, affording cis-ergoline. Catalytichydrogenation of the latter gave N,N0-dimethyl-
dihydroergoline, the X-ray crystallography of which revealed both the correct structure and identical
relative con®gurations at C-5a and C-6a ꢀSS or RR). Hydroboration and subsequent perruthenate
oxidation of the Á9-ergoline provided access to the regioisomeric ergolinols and ergolinones.
Keywords. Á4-Piperidinone; Diastereoselective cyclization; X-Ray crystal structure analysis; Deter-
mination of relative con®guration; 9- and 10-Hydroxy- and -oxoergolines.
Introduction
Dihydroergolines with C=D-trans ring fusion, e.g. the so-called hydrogenated
1
ergot alkaloids [3] or the semisyntheticdopamine agonist terguride ꢀMysalfon
,
Teluron1) [4, 5] play an important role in therapy. Corresponding cis-con®gured
active substances, particularly derivatives of C=D-cis-dihydrolysergicacid ꢀdihy-
drolysergicacid II [6]) seem to be not available hitherto. Only the cis-terguride has
been synthesized, but it is lacking pharmacological activity [5].
In connection with our investigations relating to the stereochemistry of the
intramolecular alkylation of aromatic compounds we were interested in an ef®cient
stereoselective approach to C=D-cis-con®gured ergolines. As recently reported, the
Á4-piperidinone 1 has been intended to serve as a key precursor [7] ꢀScheme 1).
Unfortunately, compound 1 could not be synthesized by a convergent route starting
from conveniently available indolines with a preshaped pyridine moiety, because
partial reduction of these educts yields preferably the isomeric Á5-piperidinones
being inappropriate for our syntheticapproach [1].
Ã
Corresponding author. E-mail: ebrei@cup.uni-muenchen.de

1018
E. Reimann et al.
Scheme 1
For this reason, the required educt had to be prepared by a linear sequence
generating the piperidone moiety from the amino acid function of tryptophan 4 and
an appropriate C-3 compound, for example iodoacetone. In this paper we present
the preparation and cyclization of the precursor 1 to the ergoline 3 as well as its
further functionalization.
Results and Discussion
The syntheticpathway is outlined in Shcemes 1 and 2. Thus, rac-N-benzoyl-
tryptophan methyl ester ꢀ4) was reduced by diisobutyl aluminum hydride to the
corresponding labile aldehyde 5 in excellent yield. The success of the reduction
depends on the size of the N-substituent R2. Thus, 4 substituted by small acyl
groups, e.g. acetyl, carboxymethyl, or carboxyethyl, provides hardly suf®cient
quantities of the corresponding aldehydes.
1
The H NMR spectrum of 5 is remarkable concerning the number of multiple
peaks with varying intensities, which presumably are caused by different rotamers
and conformers ®xed by H-bridges. By-products affecting the spectroscopic behav-
iour could be excluded because of the chromatographical purity of the compound.
The aldehyde 5 could be smoothly converted to the stable diethylacetal 6; its NMR
spectrum was lacking double and multiple peaks.
After removing the benzoyl group, 7 was reacylated by methyl chloroformate,
affording the diurethane 8 which in turn was catalytically hydrogenated by an
approved procedure [8] giving the indoline 9. The NMR spectrum of 9 indicated
a 1:1-mixture of diastereomers which could not be separated by chromatography.
Lithium aluminum hydride reduction provided the N,N0-dimethyl compound 10.
N-Alkylation of 10 using iodoacetone as a suitable C-3 building block afforded 11
which was cyclized with tri¯uoromethane sulfonic acid to the desired Á4-piper-
idinone 1 in high yield. Treatment of 11 with other acids, e.g. HBr in glacial acetic
acid, caused degradation to the hydroxyketone 12 ꢀScheme 2). In contrast to 9,
compounds 1 and 11 could be separated by ¯ash chromatography yielding the two
diastereomericraecmates 1a,b and 11a,b. According to the concept mentioned
above, the desired educt 1 for the intended cyclizations to the target compounds
3 and 17 now was easily available ꢀoverall yield 39% based on 4).

C=D-cis-Con®gured Ergolines
1019
Scheme 2
First it was attempted to obtain the ergolinone 17 by immediate cyclization of 1
using an established approach with a closely related ꢀ,ꢁ-unsaturated piperidone
[9]. However, upon treatment of 1 with tri¯uoromethane sulfonic acid no reaction
occurred. Therefore, 1 was reduced by NaBH4, yielding a mixture of diastereo-
mericpiperidinols 2a and 2b which in turn could be cyclized to the C=D-cis-
con®gured ergoline 3. Analytical data indicating the corresponding trans-stereomer
were not observed, signifying that the cyclization had occurred stereoselectively.
The rather low yields ꢀ<50%) of 3 were not unexpected; they are in line with the
result of preceding investigations showing that cyclizations of the type 2 ! 3
strongly depend on the con®guration of the educts [10]. Thus, starting with the
separated diastereomers 2a or 2b, only 2a cyclized to 3 in quantitative yield,
whereas 2b was gradually decomposed under the same reaction conditions.
The structure of 3 was proven by NMR spectroscopy. Moreover, the catalytic
hydrogenation of 3 led to the parent compound 13 whose X-ray data con®rmed
the above results and, in addition, allowed to deduce the relative con®gurations
of the three chiral centers C-5a, C-6a, and C-10a ꢀR,R,S) or ꢀS,S,R) respectively
ꢀFig. 1; crystallographic data: see Table 3).
From compound 3 the relative con®gurations of C-30 and C-6 of the precursors
2 could also be deduced. Assuming that the conversion 2 ! 3 occurs with
retention of con®guration, the diastereomer 2a undergoing cyclization must have
identical con®gurations at C-30 and at C-6 ꢀi.e. ꢀ30R,6R) or ꢀ30S,6S)), whereas the

1020
E. Reimann et al.
Fig. 1. Molecular structure of 13
uncyclizeable 2b is oppositely con®gured at these centers ꢀi.e. ꢀ30R,6S) or
ꢀ30S,6R)). Corresponding assignments could be achieved for compounds 1 and 11.
The target compound 3 allowed a further functionalization of ring D for the
®rst time. Thus, hydroboration gives a mixture of the conceivable regioisomeric
9- and 10-hydroxy derivatives 15 and 14. The two diastereomers of 15 were
successfully separated. The relative con®guration of the new chiral center C-9
could be deduced from the different 13C NMR shift increments caused by an axial
or equatorial orientation of the hydroxy group [11]. Thus, 15a exhibits a smaller
ꢂ-value than 15b ꢀ64.67 vs. 66.26 ppm) which is characteristic for an axial OH;
consequently, in 15b the OH is equatorially orientated. In the case of 14, an
additional stereomer was not detectable; the reaction presumably occurred diaste-
reoselectively ꢀScheme 3).
Finally, the hydroxy compounds 14 and 15 were oxidized with ammonium
perruthenate yielding the regioisomericketones 16 and 17. Compound 17 is of
special interest concerning further conversions with respect to natural lead struc-
tures like lysergic acid and agroclavine. In contrast, other functionalizations of the
ole®nicmoiety, e.g. addition of bromine or epoxidation, failed hitherto. The overall
yield of the syntheticsequence up to the ergoline 3 amounts to about 12%, but it is
to be considered that the result is limited to at most 50% due to the uncyclizable
diastereomer 2b.
In conclusion, we have developed a short stereoselective approach to C=D-cis-
con®gured ergolines. This may be of special importance in so far as an obviously
more ef®cient pathway, i.e. the catalytic hydrogenation of natural alkaloides, can-
not be applied because it is known that the resulting hydrogenated ergot alkaloids
are C=D-trans-con®gured [12±14].

C=D-cis-Con®gured Ergolines
1021
Scheme 3
Experimental
Melting points were measured with a Reichert hot-stage microscope and are uncorrected. IR: Perkin
Elmer FT-IR Paragon 1000; NMR: Jeol GSX 400 ꢀ1H: 400 MHz, 13C: 100MHz, CDCl3, TMS as
internal reference); MS ꢀ70 eV): Hewlett Packard MS-Engine; elemental analyses: Heraeus CHN-
Rapid, the results are in good agreement with the calculated values; thin layer chromatography
ꢀTLC): aluminum sheets Kieselgel 60 F254 ꢀMerck), thickness of layer 0.2 mm; ¯ash chromatography
ꢀFC): ICN-Silica 32±36 60 A; X-ray structure determination: Siemens R3m diffractometer. rac-3-ꢀ1H-
Indol-3-yl)-2-ꢀbenzoylamino)-propionicacid methyl ester ꢀ DL-N-benzoyl-tryptophan methyl ester, 4)
was prepared according to Ref. [15].
N-ꢀ1-Formyl-2-ꢀ1H-indol-3-yl)-ethyl)-benzamide ꢀ5; C18H16N2O2)
To a solution of 40g 4 ꢀ124.1mmol) in 200 cm3 anhydrous THF ꢀdried over LiAlH4), 60 cm3 of a
solution of DIBAH ꢀ45% in toluene) were added dropwise under an N2 atmosphere and stirring at
À 72ꢀC over ca. 100 min. After stirring the mixture for further 20min at the same temperature it was

1022
E. Reimann et al.
poured into an ice cold mixture of a saturated solution of 500 cm3 HN4Cl, 500 cm3 2 N H2SO4, and
500 cm3 diethyl ether. The addition was completed within 15min, and stirring was continued for
further 20 min. After decanting from some precipitate, the aqueous layer was extracted several times
with diethyl ether. The combined organic layers were washed with saturated NaHCO3 ꢀonce) and brine
ꢀtwice), dried over Na2SO4, and ®ltered over silica gel ꢀthickness of layer: 5 cm). The solvents were
removed in vacuo. According to TLC ꢀCHCl3:CH3OH ˆ 19:1), the crude product ꢀyield: 40 g;
Rf ˆ 0.44) contained some educt ꢀRf ˆ 0.74) and small amounts of a by-product ꢀRf ˆ 0.32); it was
used for the next step without further puri®cation. An analytical sample was obtained by FC ꢀeluent:
see TLC).
‡ ꢁ
IR ꢀ®lm): ꢃ~ ˆ 1725 ꢀCHO), 1640 ꢀCONH) cmÀ 1; MS: a) CI: m=z ꢀ%) ˆ 293 ꢀM ‡ 1, 95), 275
ꢀ20), 130 ꢀ100); b) EI: m=z ꢀ%) ˆ 292 ꢀM‡ ꢁ, 5), 130 ꢀ100).
N-ꢀ2,2-Diethoxy-1-ꢀ1H-indol-3-ylmethyl)-ethyl)-benzamide ꢀ6; C22H26N2O3)
A mixture of 40 g crude aldehyde 5 ꢀ137mmol), 400cm3 EtOH, 31cm3 triethyl orthoformate, and
1.4 g NH4NO3 was re¯uxed for 2.5 h; then, 80g solid KOH and 40 cm3 H2O were added. Heating
was continued for further 20 min. The solvent was removed in vacuo, and the residue was extracted
with diethyl ether ꢀ3Â330 cm3). The combined ether extracts were washed with saturated NaHCO3
and brine, dried over Na2SO4, and ®ltered over a short silica gel column ꢀdÂh ꢂ 7Â7 c m).
After washing the column with a few cm3 diethyl ether, the combined eluates were concentrated
in vacuo.
Yield: 38.2 g ꢀ84% based on 4); TLC ꢀCHCl3:CH3OHˆ 19:1): Rf ˆ 0.78 ꢀeduct: Rf ˆ 0.44); IR
‡ ꢁ
ꢀ®lm): ꢃ~ ˆ 1650 ꢀCONH2) c mÀ 1; MS: a) CI: m=z ꢀ%) ˆ 367 ꢀM ‡ 1, 2), 321 ꢀ100), 275 ꢀ15), 130
1
ꢀ20); b) EI: m=z ꢀ%) ˆ 366 ꢀM‡ ꢁ, 5), 320 ꢀ70), 274 ꢀ40), 200 ꢀ40), 130 ꢀ65), 105 ꢀ100); H NMR
ꢀCDCl3): ꢂ ˆ 8.26 ꢀs, 1H), 7.73±7.67, 7.48±7.43 ꢀm each, 3 and 1 arom. H), 7.40±7.30 ꢀm, 3 arom. H),
7.19±7.14, 7.13±7.09 ꢀeach m, each 1 arom. H), 7.05 ꢀd, J ˆ 2.3Hz, 1 arom. H), 6.50 ꢀd, J ˆ 9.0 Hz,
CONH), 4.72±4.62 ꢀm, 1H), 4.52 ꢀd, J ˆ 3.0 Hz, 1H), 3.84±3.76, 3.64±3.44 ꢀeach m, overall 4H, 2
OCH2), 3.16 ꢀd, J ˆ 7.0 Hz, 2H), 1.26, 1.16 ꢀeach t, each J ˆ 7.1 Hz, 2±CH3) ppm.
2,2-Diethoxy-1-ꢀ1H-indol-3-ylmethyl)-ethylamine ꢀ7; C15H22N2O2)
Compound 6 ꢀ38.2 g, 104 mmol) and 10g solid KOH were dissolved under N2 in 300cm3 diethylene
glycol at 100ꢀC. Further 140 g KOH were added portionwise, the temperature of the heating bath was
increased to 160ꢀC, and the volatile compounds were removed under slightly reduced pressure.
Heating and stirring under N2 was continued for further 15h. The mixture was allowed to cool to
3
100ꢀC, diluted with H2O ꢀ®rst 500 c m and after cooling to room temperature further 2500cm3), and
500 cm3 diethyl ether. After separating the organicphase, the aqueous layer was extracted twice with
the same solvent. The combined organic extracts were washed consecutively with small quantities of
H2O ꢀtwice) and brine ꢀonce) and dried over Na2SO4. The solvent was removed in vacuo yielding
25.0g ꢀ92%) of a brown oil.
‡ ꢁ
TLC ꢀEtOAc:CH3OH:25% NH3 ˆ 18:2:0.15): Rf ˆ 0.49; MS: a) CI: m=z ꢀ%) ˆ 303 ꢀM ‡ 49,
‡ ꢁ
10), 263 ꢀM ‡ 1, 15), 217 ꢀ65), 158 ꢀ15), 130 ꢀ100); b) EI: m=z ꢀ%) ˆ 262 ꢀM‡ ꢁ, 15), 159 ꢀ75), 131
1
ꢀ100), 130 ꢀ90), 103 ꢀ75); H NMR ꢀCDCl3): ꢂ ˆ 8.61 ꢀs, 1H), 7.63 ꢀd, J ˆ 7.8 Hz, 1H), 7.32 ꢀdt,
J ˆ 1.0=8.2 Hz, 1H), 7.19±7.15, 7.12±7.08 ꢀeach m, each 1H), 7.00 ꢀd, J ˆ 2.3 Hz, 1H), 4.31 ꢀd,
J ˆ 5.8 Hz, 1H), 3.82±3.73, 3.65±3.54 ꢀeach m, 2 OCH2), 3.26 ꢀddd, J ˆ 3.9=5.8=9.4 Hz, 1H), 3.16,
2.68 ꢀeach dd, J ˆ 3.9=14 and 9.4=14.3Hz, each 1H), 1.43 ꢀs, NH2), 1.27, 1.25 ꢀeach t, each J ˆ 7.0 Hz,
2 CH3) ppm; 13C NMR ꢀCDCl3): ꢂ ˆ 136.45, 127.63 ꢀ2 s, each 1C), 122.77, 121.87, 119.18, 118.96 ꢀ4
d, each 1C), 112.58 ꢀs, 1C), 111.17, 106.14 ꢀ2 d, each 1C), 63.59, 63.09 ꢀ2 t, 2 CH2), 53.62 ꢀd, 1C),
28.13 ꢀt, 1C), 15.51, 15.47 ꢀ2 q, 2 CH3) ppm.

C=D-cis-Con®gured Ergolines
1023
3-ꢀ3,30-Diethoxy-2-methoxycarbonylamino-propyl)-indol-1-carbonic acid
methyl ester ꢀ8; C19H26N2O6)
To a mixture of 25g 7 ꢀ95.3 mmol), 350 mg ꢀca. 0.01mol%) tetrabutylammonium hydrogensulfate and
16.0g of ®nely grounded NaOH ꢀ0.4mol) in 250 cm3 CH2Cl2, 18.9g methyl chloroformate ꢀ15.4 cm3,
0.2 mol) were added dropwise under vigorous stirring and weak re¯uxing ꢀabout 40ꢀC) over 30min,
and stirring was continued for several minutes. Because residual educt was detected by TLC ꢀEtOAc:n-
hexaneˆ 3:2; Rf ˆ 0.0; product: Rf ˆ 0.55), an additional small amount of acid chloride was added.
The mixture was ®ltered over a silica gel column ꢀdÂh ˆ 13Â1.5 cm) covered with a thin layer of sand.
The adsorbent was eluted with EtOAc, the combined ®ltrates were concentrated in vacuo, and the
residue was recrystallized from EtOH and ®nally washed with n-hexane.
Yield: >25 g ꢀat least 70%); some additional product was obtained from the mother liquor; m.p.:
130ꢀC ꢀEtOH); IR ꢀKBr): ꢃ~ ˆ 1732, 1689 ꢀhet-N±CO and NH±CO) cmÀ 1; MS: a) CI: m=z ꢀ%) ˆ 333
ꢀM‡ ꢁ ± EtOH, 5), 287 ꢀM‡ ꢁ ± 2EtOH, 100), 188 ꢀ40), 103 ꢀ15); b) EI: m=z ꢀ%) ˆ 378 ꢀM‡ ꢁ, 1), 346
ꢀ10), 286 ꢀ10), 188 ꢀ25), 103 ꢀ100); 1H NMR ꢀCDCl3): ꢂ ˆ 8.14, 7.31 ꢀeach d, J ˆ 8.3 and 7.9 Hz, each
1H), 7.44 ꢀs, 1H), 7.34±7.29, 7.27±7.23 ꢀeach m, each 1H), 4.97 ꢀbr s, 1H), 4.42 ꢀd, J ˆ 3.0 Hz, 1H),
4.12 ꢀm, 1H), 4.01 ꢀs, OCH3), 3.80±3.72, 3.68±3.57, 3.57±3.45 ꢀeach m, 1H, 4H, and 2H, OCH3 and 2
OCH2), 3.03, 2.87 ꢀeach dd, J ˆ 6.0=15.0 and 7.2=15.0Hz, each 1H), 1.23, 1.18 ꢀeach t, each
J ˆ 7.1 Hz, each 3H, acetal) ppm; 13C NMR ꢀCDCl3): ꢂ ˆ 156.91, 151.50, 135.60, 130.92 ꢀ4 s, 2
CO and 2C), 124.69, 123.24, 122.90, 119.24, 118.12, 115.21, 102.56 ꢀeach d, each 1C), 63.94, 63.86
ꢀeach t, 2C, 2 OCH2), 53.60 ꢀq, 1C, OCH3), 53.22 ꢀd, 1C), 52.09 ꢀq, 1C, OCH3), 25.57 ꢀt, 1C), 15.31,
15.27 ꢀeach q, 2C, 2 CH3) ppm.
3-ꢀ3,3-Diethoxy-2-methoxycarbonylamino-propyl)-2,3-dihydroindol-1-carbonic acid
methyl ester ꢀdiastereomeric mixture) ꢀ9; C19H28N2O6)
A mixture of 10.0g ꢀ26.4 mmol) 8, 2.0 g 5% Pd±C catalyst, and 400 cm3 absolute EtOH was hydro-
genated for 70h at ambient temperature and 8.5Â106 Pa initial pressure of H2. The c atalyst was ®ltered
off, and the ®ltrate was concentrated in vacuo.
Yield: 10.0 g ꢀ100%); colorless oil; TLC ꢀn-hexane=EtOAcˆ 3:2): Rf ˆ 0.36 ꢀeduct: Rf ˆ 0.46);
‡ ꢁ
IR ꢀ®lm): ꢃ~ ˆ 1713 ꢀCˆO) cmÀ 1; MS: a) CI: m=z ꢀ%) ˆ 335 ꢀM ‡ 1 À EtOH, 100), 303
‡ ꢁ
‡ ꢁ
ꢀM ‡ 1 À EtOH ± MeOH, 20), 289 ꢀM ‡ 1 ± 2EtOH, 10), 145 ꢀ30), 103 ꢀ30); b) EI:
m=z ꢀ%) ˆ 380 ꢀM‡ ꢁ, 2), 334 ꢀ10), 189 ꢀ85), 145 ꢀ55), 103 ꢀ100); H NMR ꢀCDCl3, 50ꢀC):
1
ꢂ ˆ 7.86 ꢀs, 1H), 7.37, 7.12 ꢀeach d, J ˆ 7.4 and 7.5 Hz, each 0.5H), 7.22±7.14, 7.00±6.92 ꢀeach m,
each 1H), 5.09, 5.04 ꢀeach d, J ˆ 9.5 and 10.0Hz, each 0.5H, NH±CO2R), 4.38, 4.34 ꢀeach d, each
J ˆ 3.0 Hz, each 0.5H), 4.25±4.18, 4.15±4.07, 4.07±3.98 ꢀeach m, each 0.5H), 3.93±3.63 ꢀm, 9.5H),
3.57±3.45 ꢀm, 2H), 3.47±3.36 ꢀm, 1H), 2.07±1.97, 1.95±1.86, 1.83±1.73, 1.73±1.62 ꢀeach m, each
0.5H), 1.18 ꢀm, 6H, 2 C±CH3) ppm; 13C NMR ꢀCDCl3, 50ꢀC): ꢂ ˆ 157.22, 157.08 ꢀeach s, 1C, CˆO),
153.67, 153.64 ꢀeach s, 1C, CˆO), 142.50, 142.19 ꢀeach s, 1C), 134.75, 134.56 ꢀeach s, 1C), 127.85,
127.81 ꢀeach d, 1C), 124.67, 123.70 ꢀeach d, 1C), 122.68, 122.57 ꢀeach d, 1C), 114.68 ꢀd, 1C), 103.58,
103.54 ꢀeach d, 1C), 64.21, 64.05 ꢀeach t, 1C, OCH2), 63.94, 63.88 ꢀeach t, 1C, OCH2), 54.55, 53.66
ꢀeach t, 1C), 52.47, 52.19 ꢀeach q, 2C, 2 OCH3), 51.46, 51.32 ꢀeach t, 1C), 36.76, 36.25 ꢀeach d, 1C),
35.92, 35.41 ꢀeach t, 1C), 15.29, 15.25 ꢀeach q, 2C, 2 CH3) ppm.
2,2-Diethoxy-1-ꢀꢀ1-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-ethyl)-methylamine
ꢀdiastereomeric mixture) ꢀ10; C17H28N2O2)
To a mixture of 10.0g 9 ꢀ26.3 mmol) in 100cm3 anhydrous THF, 5.2 g LiAlH4 ꢀ137 mmol) were
slowly added at 0ꢀC under stirring and N2 over ca. 20min. After removing the ice bath the mixture
started to foam; the reaction was controlled by repeated cooling. After about 40min the mixture was
heated for 1 h at 50ꢀC with stirring, then cooled in an ice bath, diluted with 200 cm3 diethyl ether, and

1024
E. Reimann et al.
poured into a mixture of 200 cm3 diethyl ether and 500 cm3 2 N NaOH under N2 and stirring. Stirring
was continued for 10 min; then the organic phase was separated, and the aqueous layer was extracted
several times with diethyl ether. The combined organic phases were consecutively washed with a small
volume of H2O and twice with brine. After drying over Na2SO4, the solvent was removed in vacuo
yielding 7.53 g ꢀ98%) of a colorless oil.
TLC ꢀEtOAc:CH3OH:25% NH3 ˆ 17:3:0.3): Rf ˆ 0.75; IR ꢀ®lm): ꢃ~ ˆ 3348 ꢀNH) cmÀ 1; MS: a)
‡ ꢁ
‡ ꢁ
‡ ꢁ
CI: m=z ꢀ%) ˆ 293 ꢀM ‡ 1, 100), 247 ꢀM ‡ 1 ± EtOH, 85), 231 ꢀM
± EtOH ± CH3, 20), 189
‡ ꢁ
ꢀ25), 127 ꢀ65); b) EI: m=z ꢀ%) ˆ 292 ꢀM‡ ꢁ, 2), 246 ꢀM ± EtOH, 5), 231 ꢀM ± EtOH ± CH3, 5),
189 ꢀ20), 149 ꢀ60), 132 ꢀ100); 1H NMR ꢀCHCl3): ꢂ ˆ 7.12±7.07 ꢀm, 2H), 6.71±6.69, 6.50±6.47 ꢀeach
m, each 1H), 4.42, 4.41 ꢀeach d, J ˆ 5.4 and 5.6 Hz, each 0.5H), 3.78±3.67 ꢀm, OCH2), 3.60±3.51 ꢀm,
OCH2 ‡ 1H), 3.47±3.39 ꢀm, 1H), 2.94 ꢀt, J ˆ 8.2 Hz, 1H), 2.75 ꢀs, N±CH3), 2.69±2.62 ꢀm, 1H), 2.46,
2.45 ꢀeach s, each 1.5H, N±CH3), 2.04, 1.92 ꢀeach ddd, J ˆ 5.6=6.8=14.0 and 4.4=8.8=14.4 Hz,
each 0.5H), 1.78, 1.66 ꢀeach ddd, J ˆ 4.0=10.0=14.4 and 5.6=9.2=14.0 Hz, each 0.5H), 1.58 ꢀs, NH),
1.20 ꢀm, 2 C±CH3) ppm; 13C NMR ꢀCDCl3): ꢂ ˆ 153.12, 153.04 ꢀ2 s, 1C), 134.41, 134.37 ꢀ2 s, 1C),
127.48 ꢀd, 1C), 123.38, 123.27 ꢀ2 d, 1C), 117.69 ꢀd, 1C), 107.19, 107.16 ꢀ2 d, 1C), 105.16, 104.73
ꢀ2 d, 1C), 63.74, 63.56, 63.47, 63.34, 63.16, 62.64 ꢀm, overall 3C), 59.81, 59.61 ꢀ2 d, 1C), 37.88 ꢀd,
1C), 36.16, 36.13 ꢀ2 q, 1C, het-N±CH3), 34.30 ꢀq, 1C, N±CH3), 33.97, 33.69 ꢀ2 t, 1C), 15.44, 15.41
ꢀ2 q, 2 CH3) ppm.
‡ ꢁ
1-ꢀꢀ2,2-Diethoxy-1-ꢀ1-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-ethyl)-methylamino)-
propan-2-one ꢀmixture of diastereomers) ꢀ11a ‡ 11b; C20H32N2O3)
To a solution of 7.53 g ꢀ25.8 mmol) 10 in 75cm3 THF, 30% K2CO3 ꢀ35 cm3) and, after heating to 60ꢀC,
a solution of 5.69 g ꢀ1.2 equiv.) iodoacetone in 12cm3 THF ꢀgenerated according to the Finkelstein
reaction from chloroacetone and KI [16]) were added dropwise under stirring. Stirring was continued
for further 5 min; then the cold mixture was diluted with 300 cm3 diethyl ether, the organicphase was
separated, and the aqueous layer was extracted with diethyl ether. The combined ether extracts were
®rst extracted with 20 cm3 2 N H2SO4 and then with 0.1 N H2SO4 ꢀ1Â200 cm3 and 2Â100 cm3). The
combined acid extracts were washed with diethyl ether ꢀtwice) and, after addition of 300 cm3 diethyl
ether, rendered alkaline by K2CO3. After separation the organicphase was washed with brine and dried
over Na2SO4. The solvent was evaporated in vacuo, and the residue ꢀ8g) was dissolved in a few cm3 of
EtOAc. The solution was rapidly ®ltered over a short silica gel column covered with a layer of sand
ꢀdÂh ˆ 9.5Â3.5cm; sand layer: h ˆ 1.5 cm). The adsorbent was eluted with EtOAc ꢀ700 cm3), and the
combined ®ltrates were concentrated in vacuo.
Yield: 7.2 g ꢀ80%); yellowish, instable oil; TLC ꢀEtOAc): Rf ˆ 0.78; IR ꢀ®lm): ꢃ~ ˆ 1713 ꢀCˆO)
‡ ꢁ
‡ ꢁ
cmÀ 1; MS: a) CI: m=z ꢀ%) ˆ 349 ꢀM ‡ 1, 70), 303 ꢀM ‡ 1 ± EtOH, 100), 245 ꢀ20), 172 ꢀ20),
132 ꢀ30); b) EI: m=z ꢀ%) ˆ 348 ꢀM‡ ꢁ, 2), 302 ꢀM
‡ ꢁ
1
± EtOH, 2), 245 ꢀ20), 132 ꢀ100); H NMR
ꢀCDCl3): ꢂ ˆ 7.11±7.05 ꢀm, 2H), 6.71±6.65, 6.50±6.47 ꢀeach m, each 1H), 4.47, 4.46 ꢀeach d, J ˆ 5.4
and 6.1 Hz, each 0.5H), 3.75±3.62 ꢀm, 2H), 3.56±3.39 ꢀm, 6H), 3.00 ꢀdd, J ˆ 6.7=8.4Hz, 0.5H),
2.96±2.89 ꢀm, 0.5H), 2.83 ꢀdt, J ˆ 5.5=8.4 Hz, 0.5H), 2.76±2.71 ꢀm, 0.5H), 2.75, 2.74 ꢀeach s, each
1.5H, het-N±CH3), 2.39, 2.38 ꢀeach s, each 1.5H, N±CH3), 2.17, 2.16 ꢀeach s, each 1.5H, CO±CH3),
2.06±1.94 ꢀm, 1H), 1.77±1.69 ꢀm, 0.5H), 1.63 ꢀdt, J ˆ 8.0=14.2Hz, 0.5H), 1.26±1.15 ꢀm, 2 CH3) ppm;
13C NMR ꢀCDCl3): ꢂ ˆ 209.95, 209.42 ꢀeach s, 2C, 2 CˆO), 153.16, 153.07, 134.31 ꢀeach s, 3C),
127.52 ꢀd, 1C), 123.54, 123.02 ꢀeach d, 1C), 117.63, 117.59 ꢀeach d, 1C), 107.26, 107.15 ꢀeach d, 1C),
104.61, 104.44 ꢀeach d, 1C), 65.98, 65.49 ꢀeach t, 1C, CH2±CO), 64.05, 63.50 ꢀeach d, 1C), 63.17,
63.09 ꢀeach t, 1C), 62.98, 62.20 ꢀeach t, 1C), 38.84, 38.53 ꢀeach q, 1C, N±CH3), 38.42, 37.77 ꢀeach d,
1C), 36.12 ꢀq, 1C, het-N±CH3), 31.66, 31.49 ꢀeach t, 1C), 27.21, 27.09 ꢀeach t, 1C, CH3±CO), 15.60,
15.56 ꢀeach t, 1C, CH3), 15.44 ꢀt, 1C, CH3) ppm; separation of diastereomers ꢀn-hexane:EtOAcˆ 3:2):
Rf ˆ 0.51 and 0.46 ꢀ11a and 11b).

C=D-cis-Con®gured Ergolines
1025
1-Methyl-6-ꢀ1-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-1,6-dihydro-
2H-pyridin-3-one ꢀmixture of diastereomers) ꢀ1a ‡ 1b; C16H20N2O)
1.59g ꢀ4.48 mmol) 11a=11b ꢀmixture of diastereomers) were dissolved in 10cm3 F3CSO3H under N2
and cooling ꢀwater bath, 20ꢀC). The mixture was stirred at ambient temperature for 30min and
cautiously poured into 120 cm3 crushed ice=H2O. The acid solution was washed with diethyl ether,
rendered alkaline with K2CO3, and extracted several times with diethyl ether. The combined ether
extracts were washed with 10% Na2CO3 and brine and dried over Na2SO4. After evaporation of the
solvent in vacuo, the residue was dissolved in EtOAc, and the solution was rapidly ®ltered over a short
silica gel column ꢀdÂh ˆ 2Â2 cm). The solvent was removed in vacuo affording 1.06g ꢀ91%) of a
slightly colored oil of suf®cient purity for the next step. Puri®cation and separation of the diastereo-
mers was accomplished by FC ꢀsilica gel, n-hexane:EtOAc ˆ 3:2).
TLC ꢀeluent: see FC): Rf ˆ 0.40 ꢀ1b) and 0.47 ꢀ1a); IR ꢀ®lm): ꢃ~ ˆ 1682 ꢀCˆO) cmÀ 1; MS: a) CI:
‡ ꢁ
m=z ꢀ%) ˆ 257 ꢀM ‡ 1, 100), 255 ꢀ100), 132 ꢀ25), 112 ꢀ25); b) EI: m=z ꢀ%) ˆ 256 ꢀM‡ ꢁ, 10), 239
1
ꢀ12), 132 ꢀ40), 110 ꢀ100); H NMR ꢀCDCl3): see Table 1; 13C NMR ꢀCDCl3): see Table 2.
1-Hydroxy-3-ꢀ1-methyl-2,3-dihydro-1H-indol-3-yl)-propan-2-one ꢀ12; C12H15NO2)
A solution of 70mg ꢀ0.2mmol) 11a ‡ 11b in 0.75 cm3 26% HBr=glacial acetic acid was stirred for
12h at ambient temperature, the color changing from emerald green to deep blue. After diluting with a
few cm3 H2O, the acidic solution was extracted twice with diethyl ether, rendered alkaline with solid
NaHCO3, and extracted with diethyl ether again. The ether extracts were washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was puri®ed by FC ꢀEtOAc:n-hexane ˆ 3:2).
Yield: 23mg ꢀ33%); colorless oil; TLC ꢀeluent: see FC): Rf ˆ 0.44 ꢀeduct: Rf ˆ 0.52); IR ꢀ®lm):
1
ꢃ~ ˆ 3047 ꢀOH), 1753, 1731 ꢀCˆO) cmÀ 1; H NMR: ꢂ ˆ 7.12 ꢀpseudo-t, J ˆ 7.2=8.0 Hz, 60-H), 7.00
ꢀd, J ˆ 7.2 Hz, 40-H), 6.68 ꢀdt, J ˆ 0.8=7.2 Hz, 50-H), 6.50 ꢀd, J ˆ 8.0 Hz, 70-H), 4.23 ꢀs, 1-H),
Table 1. 1H NMR data of the diastereomers of 1
ꢂ=ppm
Multiplicity No. of
H-Atoms
J=Hz
Assignment
1a
1b
1a
1b
7.14±7.10 7.15±7.11
7.06±7.05 7.07±7.05
m
m
dd
dt
d
1
60-H
40-H
5-H
50-H
70-H
4-H
1
1
1
1
1
1
1
1
2
1
1
1
6.88
6.70
6.51
6.11
3.52
3.53
6.91
3.2=10.4
0.8=7.6
8.0
3.2=10.4
0.8=7.6
7.6
6.71
6.52
6.11
dd
d
2.0=10.4
16.8
2.0=10.4
16.39
8.4
3.53
2-H
3.50
t
8.4
20-H
30-H
30-H, 6-H
6-H
3.44±3.36
m
m
m
dd
dd
3.38±3.30
3.29±3.24
3.12
3.09
2.99
2.0=16.8
7.2=8.4
2.0=16.4
6.8=8.4
2-H
20-H
2.97
2.75
2.44
2.20
1.91
2.76
2.48
2.14
1.94
s
3
3
1
1
ind-N±CH3
pip-N±CH3
s
ddd
ddd
4.8=6.8=14.4
5.6=9.2=14.4
5.2=7.2=14.0
6.0=8.8=14.0 C-100

1026
E. Reimann et al.
Table 2. 13C NMR data of the diastereomers of 1
ꢂ=ppm
DEPT
Assignment
1a
1b
196.34
152.92
CˆO
C-7a0
C-5
C-3a0
C-60
151.30
133.36
127.92
127.43
123.23
117.79
107.46
62.69
151.18
133.16
127.96
127.30
123.39
117.89
107.50
62.80
CH
CH
CH
C-4
C-40
C-50
C-70
C-20
CH
CH
CH
CH2
CH2
CH
60.46
60.35
C-2
59.67
59.38
C-6
42.45
42.17
CH3
CH
pip-N±CH3
C-30
37.82
37.44
36.04
36.08
CH3
CH2
ind-N±CH3
C-100
34.86
35.02
3.75±3.67 ꢀm, 30-H), 3.52 ꢀt, J ˆ 8.8 Hz, 20-H), 3.10 ꢀs, OH), 2.98 ꢀdd, J ˆ 5.6=8.8 Hz, 20-H), 2.84 ꢀdd,
J ˆ 6.0=17.2Hz, 3-H), 2.74 ꢀs, N±CH3), 2.67 ꢀdd, J ˆ 8.4=17.2Hz, 3-H) ppm.
1-Methyl-6-ꢀ1-methyl-2,3-dihydro-1H-indol-3-yl-methyl)-1,2,3,6-tetrahydropyridin-3-ol
ꢀmixture of diastereomers) ꢀ2a ‡ 2b; C16H22N2O)
To a solution of 960 mg ꢀ3.75 mmol) crude 1a=1b in 15cm3 MeOH, 1.63g CeꢀNO3)3 Á 6H2O and, after
stirring for 5 min, 100 mg NaBH4 were added portionwise. After further 10min, Ce3 ‡ was precipitated
by about 30 drops 30% K2CO3, and stirring was continued for 5 min. The mixture was diluted with
100 cm3 Et2O and ®ltered over a silicagel=Kieselgur layer ꢀporcelain ®lter funnel, dÂh ˆ 2Â2 c m).
After washing the ®lter with Et2O and evaporation of the combined ®ltrates in vacuo, the residue was
puri®ed by FC ꢀEtOAc:CH3OH:25% NH3 ˆ 18:2:0.2).
Yield: 670 mg ꢀ70%; if using the chromatographically puri®ed educt, the yield was quantitative);
colourless oil; TLC ꢀeluent: see FC): Rf ˆ 0.43 ꢀeduct: Rf ˆ 0.80); IR ꢀ®lm): ꢃ~ ˆ 3374 ꢀOH) cmÀ 1
;
‡ ꢁ
MS: a) CI: m=z ꢀ%) ˆ 259 ꢀM ‡ 1, 100), 241 ꢀ20), 216 ꢀ5), 144 ꢀ5), 132 ꢀ20), 110 ꢀ10), 108 ꢀ10);
b) EI: m=z ꢀ%) ˆ 257 ꢀM‡ ꢁ ± 1, 2), 240 ꢀ2), 144 ꢀ30), 132 ꢀ98), 117 ꢀ45), 112 ꢀ100), 109 ꢀ70); 1H NMR
ꢀCDCl3): ꢂ ˆ 7.12±7.08, 7.06±7.01, 6.73±6.67 ꢀeach m, each 1H, 60-H, 40-H, and 50-H), 6.50 ꢀbr d,
J ˆ 7.8 Hz, 70-H), 6.04±5.95, 5.87±5.73 ꢀeach m, 4-H and 5-H), 4.34±4.28, 4.01±3.97 ꢀeach m, 3-H),
3.61±3.51 ꢀm, 20-H), 3.45±3.30, 3.30±3.17 ꢀeach m, 30-H), 3.10±2.80 ꢀm, 3H), 2.74±2.73 ꢀ4 s, ind-N±
CH3), 2.61±2.47 ꢀm, total 1.2H, 2-H, therein at 2.59 s, OH), 2.40±2.35 ꢀ4 s, py-N±CH3), 2.34±2.24 ꢀm,
0.8H, 2-H), 2.21±1.98, 1.94±1.74 ꢀeach m, each 1H, bridge-CH2) ppm.
ꢀ5aS,6aS,10aR)-4,7-Dimethyl-4,5,5a,6,6a,7,8,10a-octahydroindolo[4,3-fg]quinoline
ꢀ3; C16H20N2)
A solution of 1.27 g ꢀ4.92 mmol) diastereomericmixture 2a=2b in 10 cm3 F3CSO3H was stirred for
14h at ambient temperature under N2 and thereafter added dropwise to 120 cm3 H2O=crushed ice. The

C=D-cis-Con®gured Ergolines
1027
Table 3. Crystallographicdata of 13a
Formula
C16H22N2
Formula weight
Temperature=K
Color, shape
242.37
298
Colorless, transparent platelets
0.50 Â 0.50 Â 0.1
monoclinic
Crystal dimensions=mm
Crystal system
Space group
P2ꢀ1)=n
Cell dimensions:
Ê
a=A
7.669ꢀ2)
Ê
b=A
13.463ꢀ3)
13.504ꢀ4)
105.84ꢀ2)
1341.41ꢀ0)
Ê
c=A
ꢁ=ꢀ
Ê 3
VA
Ê
Radiation
CuKꢀ ꢀꢄ ˆ 1.54178 A)
Z
4
Fꢀ000)
ꢅ=mmÀ 1
528
0.536
Density=g Á cmÀ 3
Re¯ections collected
Independent re¯ections
Observed re¯ections
No. of parameters re®ned
1.200
1446
1376 ꢀRi ˆ 1.97%)
1198 ꢀI>4ꢆI)
163
R-values:
Final R indices ꢀobserved data)
R indices ꢀall data)
Goodness of Fit
R ˆ 5.95%, wR ˆ 6.37%
R ˆ 6.68%, wR ˆ 6.62%
1.15
Siemens SHELXTL PLUS ꢀPC-version)b
System used
a
Further details of the crystal structure determination are available from Cambridge Crystallographic
Data Center, 12 Union Road, GB Cambridge CB21EZ quoting the deposition number CCDC 174949
and the complete literature source ꢀe-mail: deposit@ccdc.cam.ac.uk); b G.M. Sheldrick: A Program

for Crystal Structure Determination: SHELXTL ꢀRelease 4.2), Gottingen ꢀ1991)
mixture was washed with 50 cm3 diethyl ether, rendered alkaline with solid K2CO3 after addition of
further 50cm3 diethyl ether, and extracted three times with the same solvent. During this procedure,
some dark brown resinous substance was separated. The organic extracts were washed with 10%
Na2CO3 ꢀtwice) and brine and dried over Na2SO4. After evaporation of the solvent in vacuo, the
residue was puri®cated by FC ꢀEtOAc:MeOH:25% NH3 ˆ 18:1.5:0.2).
Yield: 500 mg ꢀ42%; caution: a too long contact with the sorbent decreased the yield; using the pure
diastereomer 2a as educt, the yield was quantitative); colourless oil; TLC ꢀeluent: see FC): Rf ˆ 0.55
‡ ꢁ
ꢀeduct ꢀdiastereomeric mixture 2a=2b): Rf ˆ 0.39 and 0.35); MS: a) CI: m=z ꢀ%) ˆ 241 ꢀM ‡ 1, 100);
‡ ꢁ
b) EI: 240 ꢀM‡ ꢁ, 65), 239 ꢀM
± 1, 70), 182 ꢀ45); 1H NMR ꢀCDCl3): ꢂ ˆ 7.05 ꢀdd, J ˆ 0.8=7.6 Hz,
2-H), 6.64, 6.32 ꢀeach d, each J ˆ 7.6 Hz, each 1H, 1-H and 3-H), 6.25±6.19 ꢀm, 10-H), 5.78 ꢀddt,
J ˆ 2.0=4.7=10.0Hz, 9-H), 3.62 ꢀt, J ˆ 7.8 Hz, 5-Htrans rel. to 5a-H), 3.39±3.33 ꢀm, 5a-H and 10a-H),
3.33±3.26 ꢀm, 8-H), 2.84 ꢀdddd, J ˆ 2.0=2.7=3.4=16.7 Hz, 8-H), 2.78 ꢀm, 6a-H), 2.71 ꢀs, 4-N±CH3),
2.62 ꢀdd, J ˆ 7.8=12.3 Hz, 5-Hcis rel. to 5a-H), 2.50 ꢀdt, J ˆ 4.0=13.5Hz, 6-H), 2.39 ꢀs, 7-N±CH3), 1.50
ꢀddd, J ˆ 2.8=9.5=13.5 Hz, 6-H) ppm; 13C NMR ꢀCDCl3): ꢂ ˆ 152.95, 134.61, 130.60 ꢀeach s, each 1C,

1028
E. Reimann et al.
C-3a, C-10c, and C-10b), 128.01, 126.71, 124.73, 115.99, 104.52 ꢀeach d, each 1C, C-2, C-10, C-9, C-1,
and C-3), 64.95 ꢀt, 1C, C-5), 58.80 ꢀd, 1C, C-6a), 55.48 ꢀt, 1C, C-8), 42.05 ꢀq, 1C, 7-N±CH3), 38.80 ꢀd,
1C, C-10a), 37.00 ꢀq, 1C, 4-N±CH3), 31.88 ꢀd, 1C, C-5a), 29.76 ꢀt, 1C, C-6) ppm.
ꢀ5aS,6aS,10aR)-4,7-Dimethyl-4,5,5a,6,6a,7,8,9,10,10a-decahydroindolo[4,3-fg]quinoline
ꢀDimethyldihydroergoline) ꢀ13; C16H22N)
3
A mixture of 27 mg ꢀ0.11 mmol) 3, 3 c m MeOH p.a., and 12mg 5% Pd±C catalyst was hydrogenated
for 2 h at ambient temperature and 6Â106 Pa initial pressure of H2. The catalyst was ®ltered off, the
solvent removed in vacuo, and the colorless oily residue crystallized from diethyl ether at À 20ꢀC.
Yield: 27 mg ꢀ100%); m.p.: 77ꢀC; TLC ꢀEtOAc:MeOH:25% NH3 ˆ 18:1.5:0.2): Rf ˆ 0.55 ꢀeduct:
‡ ꢁ
‡ ꢁ
±
Rf ˆ 0.59); MS: a) CI: m=z ꢀ%) ˆ 243 ꢀM ‡ 1, 100); b) EI: m=z ꢀ%) ˆ 242 ꢀM‡ ꢁ, 35), 241 ꢀM
‡ ꢁ
H, 35), 227 ꢀM
± CH3, 20), 149 ꢀ25); 1H NMR ꢀCDCl3): ꢂ ˆ 7.06 ꢀdt, J ˆ 1.0=7.0 Hz, 2-H), 6.64,
6.35 ꢀeach d, each J ˆ 7.70Hz, each 1H, 1-H and 3-H), 3.57 ꢀt, J ˆ 7.7 Hz, 5-Htrans rel. to 5a-H),
3.40±3.30, 2.92±2.87 ꢀeach m, 5a-H and 10a-H), 2.87±2.81 ꢀdq, 8-H), 2.72 ꢀs, 4-N-CH3), 2.61 ꢀdd,
J ˆ 7.7=12.8Hz, 5-Hcis rel. to 5a-H), 2.50±2.47 ꢀm, 6a-H), 2.43 ꢀdt, J ˆ 4.8=12.9Hz, 6-H),
2.39±2.30 ꢀm, 10-H), 2.31 ꢀs, 7-N±CH3), 2.17 ꢀdt, J ˆ 3.1=11.0Hz, 8-H), 1.69±1.55, 1.55±1.41 ꢀeach
m, each 2H, 9-H, 10-H or 6-H, 9-H) ppm; 13C NMR ꢀCDCl3): ꢂ ˆ 153.00, 135.40, 132.19 ꢀeach s,
each 1C, C-3a, C-10c, and C-10b), 127.74, 114.87, 104.74 ꢀeach d, each 1C, C-2, C-1, and C-3), 64.96
ꢀt, 1C, C-5), 62.23 ꢀd, 1C, C-6a), 56.77 ꢀt, 1C, C-8), 43.34 ꢀq, 1C, 7-N±CH3), 38.39 ꢀd, 1C,
C-10a), 37.09 ꢀq, 1C, 4-N±CH3), 32.81 ꢀd, 1C, C-5a), 29.92, 27.19, 22.57 ꢀeach t, each 1C, C-6,
C-10 and C-9) ppm.
Hydroboration of 3 to the hydroxy compounds 14 and 15
ꢀmixture of regio- and diastereomers)
A mixture of 360 mg ꢀ1.50 mmol) 3 and 2.0 cm3 Et3N BH3 was stirred under slightly reduced pressure
and N2 at 100ꢀC ꢀbath temperature) until the reaction was complete ꢀabout 4 h; TLC monitoring). After
cooling to ambient temperature, the mixture was diluted with 3 cm3 acetone, acidi®ed with 2 N HCl,
diluted again with 10cm3 of THF, and rendered alkaline with 2 N NaOH. Under vigorous stirring,
3
2 c m 30% H2O2 were added dropwise; stirring was continued for further 10min, and the mixture was
partitioned between Et2O and H2O. The organicphase was separated, and the aqueous layer was
extracted several times with EtOAc. The combined organic extracts were washed with saturated
NaHCO3 and brine, dried over Na2SO4, and the solvents were removed in vacuo. The residue was
fractionated twice by FC: a) ꢀEtOAc:MeOH:25% NH3 ˆ 18:1.5:0.2): fraction I contained 13 and 15a,
fraction II contained 14 and 15b; separation of I and II with CHCl3:MeOH:25% NH3 ˆ 18:1.5:0.15
provided the pure compounds.
ꢀ5aS,6aS,10S=R,10aR=5aR,6aR,10R=S,10aS)-4,7-Dimethyl-4,5,5a,6,6a,7,8,9,10,10a-
decahydroindolo[4,3-fg]quinolin-10-ol ꢀ14; C16H22N2O)
Yield: 128 mg ꢀ33%); m.p.: 147ꢀC ꢀEt2O=n-hexane=CHCl3); IR ꢀ®lm): ꢃ~ ˆ 3355 ꢀOH) cmÀ 1; MS: a)
‡ ꢁ
‡ ꢁ
‡ ꢁ
CI: m=z ꢀ%) ˆ 287 ꢀM ‡ 29, 5), 259 ꢀM ‡ 1, 100), 241 ꢀM ‡ 1 ± H2O, 45); b) EI:
m=z ꢀ%) ˆ 258 ꢀM‡ ꢁ, 80), 257 ꢀM
± 1, 100), 241 ꢀM
± OH, 20), 225 ꢀ20), 196 ꢀ10), 170 ꢀ20),
‡ ꢁ
‡ ꢁ
144 ꢀ20); 1H NMR ꢀCDCl3): ꢂ ˆ 7.05 ꢀdt, J ˆ 1.0=7.7 Hz, 2-H), 6.60, 6.38 ꢀeach d, each J ˆ 7.7 Hz, each
1H, 1-H and 3-H), 4.31±4.26 ꢀm, 10-H), 3.63 ꢀt, J ˆ 7.9 Hz, 5-H), 3.37±3.27, 2.99±2.95, 2.86±2.82 ꢀeach
m, each 1H, 5a-H, 6a-H, and 10a-H), 2.72 ꢀs, 4-N±CH3), 2.69±2.58 ꢀm, 3H, 5-H and 2Â8-H), 2.38 ꢀdd,
J ˆ 6.3=13.6Hz, 6-H), 2.35 ꢀs, 7-N±CH3), 1.92±1.81, 1.70±1.62 ꢀeach m, 2H and 1H, 9-H=OH and
9-H), 1.41 ꢀddd, J ˆ 4.5=10.3=13.6Hz, 6-H) ppm; 13C NMR ꢀCDCl3): ꢂ ˆ 152.95, 133.36, 131.50 ꢀeach
s, each 1C, C-3a, C-10c, and C-10b), 127.88, 115.90, 105.51, 67.22 ꢀeach d, each 1C, C-2, C-1, C-3, and

C=D-cis-Con®gured Ergolines
1029
C-10), 65.50 ꢀt, 1C, C-5), 57.47 ꢀd, 1C, C-6a), 48.84 ꢀt, 1C, C-8), 46.37 ꢀd, 1C, C-10a), 42.80, 36.86 ꢀeach
q, each 1C, 7- and 4-N±CH3), 32.85 ꢀd, 1C, C-5a), 30.38, 27.04 ꢀeach t, each 1C, C-9 and C-6) ppm.
ꢀ5aS,6aS,9R,10aR=5aR,6aR,9S,10aS)-4,7-Dimethyl-4,5,5a,6,6a,7,8,9,10,10a-
decahydroindolo[4,3-fg]quinolin-9-ol ꢀ15a; C16H22N2O)
Yield: 62 mg ꢀ16%); m.p.: 155ꢀC ꢀEt2O=n-hexane=CHCl3); IR ꢀ®lm): ꢃ~ ˆ 3415 ꢀOH) cmÀ 1; MS: a)
‡ ꢁ
‡ ꢁ
‡ ꢁ
CI: m=z ꢀ%) ˆ 287 ꢀM ‡ 29, 2), 259 ꢀM ‡ 1, 100), 241 ꢀM ‡ 1 ± H2O, 20); b) EI:
m=z ꢀ%) ˆ 258 ꢀM‡ ꢁ, 100), 257 ꢀM
± 1, 70), 243 ꢀM
± CH3, 30), 208 ꢀ10), 182 ꢀ15), 170
‡ ꢁ
‡ ꢁ
ꢀ30), 144 ꢀ40); 1H NMR ꢀCDCl3): ꢂ ˆ 7.06 ꢀdt, J ˆ 0.9=7.7 Hz, 2-H), 6.67, 6.35 ꢀeach d, each
J ˆ 7.7 Hz, 1-H and 3-H), 3.70±3.63 ꢀm, 9-H), 3.57 ꢀt, J ˆ 7.7 Hz, 5-H), 3.34±3.23, 3.06±3.02 ꢀeach
m, each 1H, 5a-H and 10a-H), 2.92 ꢀddd, J ˆ 2.1=4.1=10.5Hz, 8-Heq), 2.71 ꢀs, 4-N±CH3), 2.60 ꢀdd,
J ˆ 7.7=12.8Hz, 5-H), 2.61±2.53, 2.48±2.44 ꢀeach m, each 1H, 10-Hax ꢀbr) and 6a-H), 2.40 ꢀdt,
J ˆ 4.8=13.1Hz, 6-H), 2.30 ꢀs, 7-N±CH3), 2.08 ꢀbr s, OH), 2.04 ꢀdd, J ˆ 9.5=10.5Hz, 8-Hax), 1.58,
1.47 ꢀeach ddd, J ˆ 5.3=10.8=12.7 and 2.4=11.9=13.1Hz, 10-Heq and 6-H) ppm; 13C NMR ꢀCDCl3):
ꢂ ˆ 152.75, 134.85, 131.65 ꢀeach s, each 1C, C-3a, C-10c and C-10b), 127.88, 114.86, 104.98 ꢀeach d,
each 1C, C-2, C-1, and C-3), 64.82 ꢀt, 1C, C-5), 64.67 ꢀd, 1C, C-9), 63.23 ꢀt, 1C, C-8), 61.05 ꢀd, 1C,
C-6a), 43.02 ꢀq, 1C, 7-N±CH3), 37.79 ꢀd, 1C, C-10a), 36.95 ꢀq, 1C, 4-N±CH3), 36.13 ꢀt, 1C, C-10),
32.58 ꢀd, 1C, C-5a), 28.90 ꢀt, 1C, C-6) ppm.
ꢀ5aS,6aS,9S,10aR=5aR,6aR,9R,10aS)-4,7-Dimethyl-4,5,5a,6,6a,7,8,9,10,10a-
decahydroindolo[4,3-fg]quinolin-9-ol ꢀ15b; C16H22N2O)
‡ ꢁ
Yield: 28mg ꢀ7%); m.p.: 117ꢀC ꢀEt2O=n-hexane=CHCl3); MS: a) CI: m=z ꢀ%) ˆ 287 ꢀM ‡ 29, 10),
‡ ꢁ
‡ ꢁ
‡ ꢁ
± 1,
259 ꢀM ‡ 1, 100), 241 ꢀM ‡ 1 ± H2O, 20); b) EI: m=z ꢀ%) ˆ 258 ꢀM‡ ꢁ, 100), 257 ꢀM
‡ ꢁ
1
70), 243 ꢀM
± CH3, 20), 208 ꢀ10), 182 ꢀ15), 170 ꢀ25), 144 ꢀ30); H NMR ꢀCDCl3): ꢂ ˆ 7.08 ꢀdt,
J ˆ 0.9=7.7 Hz, 2-H), 6.74, 6.35 ꢀeach d, each J ˆ 7.70 Hz, 1-H and 3-H), 3.92±3.88 ꢀm, 9-H), 3.60 ꢀt,
J ˆ 7.7 Hz, 5-H), 3.48±3.38, 2.94±2.90 ꢀeach m, 5a-H and 10a-H), 2.88 ꢀddd, J ˆ 2.2=3.6=11.5Hz,
8-H), 2.72 ꢀs, 4-N±CH3), 2.62 ꢀdd, J ˆ 7.7=12.6Hz, 5-H), 2.64±2.58, 2.57±2.54 ꢀeach m, 10-H and
6a-H), 2.47 ꢀdt, J ˆ 4.7=13.3Hz, 6-H), 2.39 ꢀdd, J ˆ 1.9=11.5 Hz, 8-H), 2.34 ꢀs, 7-N±CH3), 2.15 ꢀbr s,
OH), 1.85, 1.47 ꢀeach ddd, J ˆ 3.0=6.2=14.1 and 2.4=11.9=13.3Hz, 10-H and 6-H) ppm; 13C NMR
ꢀCDCl3): ꢂ ˆ 152.82, 135.59, 131.11 ꢀeach s, each 1C, C-3a, C-10c and C-10b), 127.98, 116.33,
104.75, 66.26 ꢀeach d, each 1C, C-2, C-1, C-3, and C-9), 64.83, 62.29 ꢀeach t, each 1C, C-5 and
C-8), 61.81 ꢀd, 1C, C-6a), 42.96, 36.91 ꢀeach q, each 1C, 7-N±CH3 and 4-N±CH3), 35.66 ꢀd, 1C, C-
10a), 33.47 ꢀt, 1C, C-10), 32.41 ꢀd, 1C, C-5a), 29.92 ꢀt, 1C, C-6) ppm.
Oxoergolines 16 and 17
To a solution of 30mg ꢀ0.12 mmol) of the required hydroxy compound 14 or 15 in 5 cm3 dry CH2Cl2
Ê
Ê
100 mg grounded molecular sieves ꢀ3A=4 A) and, after stirring for 5 min, 20mg tetra-n-propylammo-
nium perruthenate were added under N2. Stirring was continued for further 20min. The reaction
mixture was puri®ed by FC: ꢀCHCl3:MeOH ˆ 19:1) without removing the solvent. After evaporation
of the eluates in vacuo the residue was crystallized by treatment with a small amount of Et2O.
ꢀ5aS,6aS,10aR=5aR,6aR,10aS)-4,7-Dimethyl-4,5,5a,6a,7,8,9,10a-
octahydro-6H-indolo[4,3-fg]quinolin-10-one ꢀ16; C16H20N2O)
Yield: 10 mg ꢀ33%); TLC ꢀeluent: see FC): Rf ˆ 0.77 ꢀeduct: Rf ˆ 0.07); IR ꢀKBr): ꢃ~ ˆ 1703 ꢀCˆO)
‡ ꢁ
‡ ꢁ
‡ ꢁ
cmÀ 1; MS: a) CI: m=z ꢀ%) ˆ 297 ꢀM ‡ 41, 2), 285 ꢀM ‡ 29, 7), 257 ꢀM ‡ 1, 100); b) EI:
m=z ꢀ%) ˆ 256 ꢀM‡ ꢁ, 100), 241 ꢀM
± CH3, 20), 213 ꢀ10), 199 ꢀ10), 170 ꢀ50), 144 ꢀ25); 1H NMR
‡ ꢁ

1030
E. Reimann et al.: C=D-cis-Con®gured Ergolines
ꢀCDCl3): ꢂ ˆ 7.02 ꢀdt, J ˆ 1.0=7.7 Hz, 2-H), 6.40, 6.39 ꢀeach d, each J ˆ 7.7 Hz, 1-H and 3-H), 3.63
ꢀt, J ˆ 7.8Hz, 5-H), 3.54±3.51, 3.46±3.36 ꢀeach m, 10a-H and 5a-H), 3.11 ꢀddd, J ˆ 2.6=6.1=11.4Hz,
8-H), 2.83±2.80 ꢀm, 6a-H), 2.79±2.70 ꢀddd, J ˆ 6.1=13.1=13.9Hz, 9-H), 2.72 ꢀs, 4-N±CH3), 2.66 ꢀdd,
J ˆ 7.8=12.8Hz, 5-H), 2.50 ꢀddd, J ˆ 2.6=11.4=13.1Hz, 8-H), 2.46 ꢀdt, J ˆ 3.3=13.5Hz, 6-H), 2.40 ꢀs,
7-N±CH3), 2.29 ꢀdq, J ˆ 2.6=13.9Hz, 9-H), 1.41 ꢀddd, J ˆ 2.0=12.3=13.5Hz, 6-H) ppm; 13C NMR
ꢀCDCl3): ꢂ ˆ 209.53 ꢀs, 1C, CˆO), 153.36, 131.00, 128.51 ꢀeach s, each 1C, C-3a, C-10c, and C-10b),
128.27, 115.34, 105.85 ꢀeach d, each 1C, C-2, C-1, and C-3), 64.74 ꢀt, 1C, C-5), 62.44 ꢀd, 1C, C-6a),
55.93 ꢀt, 1C, C-8), 53.88 ꢀd, 1C, C-10a), 42.25 ꢀq, 1C, 7-N±CH3), 39.81 ꢀt, 1C, C-9), 36.85 ꢀq, 1C,
4-N±CH3), 31.84 ꢀd, 1C, C-5a), 29.94 ꢀt, 1C, C-6) ppm.
ꢀ5aS,6aS,10aR=5aR,6aR,10aS)-4,7-Dimethyl-5,5a,6,6a,7,8,10,10a-octahydro-
4H-indolo[4,3-fg]quinolin-9-one ꢀ17; C16H20N2O)
Yield: 10 mg ꢀ33%); TLC ꢀeluent: see 16): Rf identical with that of 16; IR ꢀnujol): ꢃ~ ˆ 1714 ꢀCˆO)
‡ ꢁ
‡ ꢁ
‡ ꢁ
,
cmÀ 1; MS: a) CI: m=z ꢀ%) ˆ 285 ꢀM ‡ 29, 7), 257 ꢀM ‡ 1, 100); b) EI: m=z ꢀ%) ˆ 256 ꢀM
‡ ꢁ
100), 241 ꢀM
± CH3, 10), 227 ꢀ20), 170 ꢀ40), 145 ꢀ30), 144 ꢀ30); 1H NMR ꢀCDCl3): ꢂ ˆ 7.06 ꢀdt,
J ˆ 0.8=7.7 Hz, 2-H), 6.55, 6.36 ꢀeach d, each J ˆ 7.7Hz, 1-H and 3-H), 3.66 ꢀt, J ˆ 7.9Hz, 5-H),
3.37±3.29 ꢀm, 5a-H), 3.31 ꢀd, J ˆ 15.9Hz, 8-H), 2.97±2.93 ꢀm, 6a-H=10a-H), 2.90 ꢀd, J ˆ 15.9Hz,
8-H), 2.89 ꢀdd, J ˆ 5.0=15.5Hz, 10-H), 2.72 ꢀdd, J ˆ 0.8=15.4 Hz, 10-H, overlapped), 2.72 ꢀs, 4-N±
CH3), 2.75±2.70 ꢀm, 6a-H=10a-H), 2.66 ꢀdd, J ˆ 7.9=12.3Hz, 5-H), 2.50 ꢀdt, J ˆ 4.7=13.6Hz, 6-H),
2.41 ꢀs, 7-N±CH3), 1.60 ꢀddd, J ˆ 3.7=11.5=13.6Hz, 6-H) ppm.
References
[1] XXXV: Reimann E, Erdle W ꢀ2001) Pharmazie 56: 36

[2] Erdle W ꢀ1998) Part of PhD Thesis, LMU Munchen, Germany
[3] Forth W, Henschler D, Rummel W, Starke K ꢀ1996) Pharmakologie und Toxikologie, 6. Au¯.
Spektrum Akademischer Verlag, Heidelberg Berlin Oxford
[4] Husak M, Kratochvil B, Sedmera P, Havlicek V, Votavova H, Cvak L, Bulej P, Jegorov A ꢀ1998)
Collect Czech Chem Commun 63: 425
[5] Wachtel H, Rettig KJ, Loschmann PA, Sauer G ꢀ1991) Adv Behav Biol 39 ꢀBasal Ganglia 3):
397; see also: Sauer G, Haffer G, Wachtel H ꢀ1986) Synthesis 1007
[6] Manske RHF ꢀ1965) The Alkaloids, vol VIII. Academic Press, New York London
[7] Reimann E, Erdle W ꢀ2000) Pharmazie 55: 907
[8] Reimann E, Erdle W, Unger H ꢀ1999) Pharmazie 54: 418
[9] Dennis N, Ibrahim B, Katritzky A ꢀ1976) Synthesis 105
[10] Reimann E, Hargasser E ꢀ1988) Arch Pharm ꢀWeinheim) 321: 823
[11] Breitmaier E, Voelter W ꢀ1974) 13C-NMR-Spectroscopy. Verlag Chemie, Weinheim
[12] Mayer K, Eich E ꢀ1984) Pharmazie 39: 537
[13] Nakamara Y, Niwaguchi T, Ishii H ꢀ1977) Chem Pharm Bull 25: 1756
ꢀ
[14] Cerny A, Semansky M ꢀ1971) Pharmazie 26: 740
ꢁ
ꢁ
[15] Yoshioka T, Mohri K, Oikawa Y, Yonemitsu O ꢀ1981) J Chem Research=Mini Print 7: 2252
[16] Scholl R, Matthaiopoulos G ꢀ1896) Ber Dtsch Chem Ges 29: 1558
Received December 27, 2001. Accepted January 15, 2002