An efficient access to novel enantiomerically pure steroidal δ-amino acids

Article abstract of DOI:10.1002/chem.200601076

A highly chemoselective sequence of Stille and Heck couplings on the heterocyclic bromoenol triflates 2a-c with the bicycloalkenylstannanes cis-3 and trans-3 furnished the intermediate bromobutadienes 4a-c in good yields ranging from 73-94%. A modified He

Full text of DOI:10.1002/chem.200601076

DOI: 10.1002/chem.200601076
An Efficient Access to Novel Enantiomerically Pure Steroidal
d-Amino Acids
Hans Wolf Sünnemann,[a] Anja Hofmeister,[b] Jçrg Magull,[b] and Armin de Meijere*[a]
Abstract: A highly chemoselective se-
quence of Stille and Heckcouplings on
the heterocyclic bromoenol triflates
2a–c with the bicycloalkenylstannanes
cis-3 and trans-3 furnished the inter-
mediate bromobutadienes 4a–c in
good yields ranging from 73–94%. A
modified Heckcoupling protocol em-
ploying the palladacycle 8 and an addi-
tional bidentate ligand such as 1,4-bis(-
diphenylphosphinyl)butane allowed a
significant reduction in catalyst loading
while still obtaining the heterocyclic
1,3,5-hexatrienes 5a–c in good yields
(71–94%). The unsymmetrically substi-
tuted 1,3,5-hexatrienes 5a–c in solution
underwent 6p-electrocyclizations fol-
lowing an optimized microwave-heat-
ing protocol to yield the steroidal tetra-
cycles cis-7a–c and trans-7b (59–69%).
Tetracycles cis-7a–c are the products of
a subsequent 1,5-hydrogen shift to the
thermodynamically more stable, more
highly substituted diene units. Removal
of the tert-butyl groups provided the
novel steroidal d-amino acid 9a and
the d-amino acid derivatives 9b,c in
good yields (76–86%).
Keywords: amino acids · catalysis ·
cross-coupling
·
electrocyclic
reactions · palladium · steroids
Introduction
well as for foldamers, since d-amino acids demonstrated ex-
ceptional capabilities in inducing stable secondary structures
in oligopeptides.[6] Considering our previously reported se-
lective Stille–Heckcross-coupling sequence to build up dif-
ferentially substituted 1,3,5-hexatrienes as precursors to cy-
clohexadienes,[7] we envisaged the possibility of assembling
novel conformationally restrained d-amino acids with a ster-
oidal skeleton and set out to prepare them.
Bioactive peptides are frequently being considered as candi-
dates for new therapeutic drugs, but often limitations have
been encountered due to severe pharmacological problems
such as rapid metabolism, poor absorption, and low bioa-
vailability upon oral administration.[1] Thus, considerable at-
tention has been paid to the development of peptidomimet-
ics, which exhibit peptide-like activity and resistance to-
wards proteases.[2] In this context, non-natural amino acids
are of great interest as new building blocks, especially if
they lead to highly ordered structures[3] and, like amino acid
homologues, introduce additional elements of diversity for
new generations of drug candidates.[4] Among such homo-
logues, d-amino acids have attracted considerable interest in
the design of peptidomimetics.[5] Furthermore, d-amino
acids have gained importance as building blocks for back-
bone generation of peptide nucleic acid (PNA) structures as
Results and Discussion
Starting with the Stille coupling of the enantiomerically
pure hexahydroindenylstannanes cis-3 and trans-3 with the
new heterocyclic bromoenol triflates 2a–c, prepared in good
yields (56–80%, see Table 1) from the bromopiperidinones
1a–c,[8] the heterocyclic bromobutadienes cis-4a–c and
trans-4b were assembled. Under the optimized conditions
the enol triflates 2a,b were formed with high regioselectivi-
ties, yet the enol triflate 2c was accompanied by a minor
[a] Dr. H. W. Sünnemann, Prof. Dr. A. de Meijere
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
Fax : (+49)551-399-475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
Table 1. Synthesis of the heterocyclic bromoenol triflates.
Starting compound
Product
Yield (%)[a]
1a
1b
1c
2a
2b
2c
74
80
56
[b] Dipl.-Chem. A. Hofmeister, Prof. Dr. J. Magull
Institut für Anorganische Chemie
Georg-August-Universität Gçttingen
Tammannstrasse 4, 37077 Gçttingen (Germany)
[a] Yield of isolated product.
8336
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8336 – 8344

FULL PAPER
for example, the hexatriene cis-
5b was obtained in only 68%
yield even with 10 mol% of the
precatalyst 8. The application
of 8 with a co-ligand for stabili-
zation to avoid premature de-
composition of the catalytically
active species has not been re-
ported before and allows for a
significant reduction of the
amount of precatalyst 8 neces-
sary for complete conversion of
the reactants. This protocol can
be a convenient alternative to
Figure 1. Structure of the bromoenol triflate 2b in the crystal.[10]
amount of the undesired regioisomer,[9] which had to be re-
moved by column chromatography. The crystal structure of
2b was proved by X-ray diffraction (Figure 1).[10]
Table 2. Chemoselective Stille–Heckcoupling sequences of the 2-bromo-
4-azacyclohexenyl triflates leading to tricyclic 1,3,5-hexatrienes (see
Scheme 1).
Starting compound
Alkene
Product
Yield (%)[a]
The Stille coupling worked best with a catalyst cocktail
consisting of [Pd
2(dba)3][11] and a copper(i) cocatalyst using
G
2a
2b
2c
2b
cis-3
cis-3
cis-3
trans-3
cis-4a
cis-4b
cis-4c
85
94
73
90
freshly distilled N-methylpyrrolidone (NMP) as solvent to
provide the products cis-4a–c and trans-4b in yields between
73–94% (Scheme 1; Table 2).[12]
trans-4b
cis-4a
cis-4b
cis-4b
cis-4c
cis-5a
cis-5b
cis-5b
cis-5c
83
92
68[b]
71
trans-4b
trans-5b
85
[a] Yields of isolated products. [b] Reaction was performed with
10 mol% of palladacycle 8 without addition of a co-ligand.
particularly tuned ligands which are either expensive or
time consuming when specifically prepared. High yields
were achieved (71–92%), by using a solvent mixture consist-
ing of DMF and water.[15]
The heterocyclic 1,3,4,5,6-pentasubstituted hexatrienes
cis-5a–c and trans-5b are reasonably well set up for an addi-
tional ring closure by a thermally induced 6p-electrocycliza-
tion (Scheme 1),[16] and this was achieved best by heating a
solution in toluene or in a mixture of toluene and DMF in a
microwave oven following a special temperature profile.
After 45 min at 1708C, the hexatrienes cis-5a–c had been
completely converted into a mixture of the expected 6p-
electrocyclization product cis-6a–c and cis-7a–c (see also
Table 3), arising from subsequent 1,5-hydrogen shifts. The
Scheme 1. A) Tf2O, NEt3, CH2Cl2, ꢀ78!208C, 20 h; B) [Pd2-
A
658C, 10 h; C) 8 (3.0 mol%), dppb (3.0 mol%), tert-butyl acrylate (5.0–
10.0 equiv), NEt3 (3.0–4.0 equiv), DMF/H2O 10:1, 1058C, 8 h; D) micro-
wave heating 170 (45 min) ! 2008C (2 min), toluene/DMF 10:1.
The tricyclic bromodienes cis-4a–c and trans-4b were im-
mediately subjected to subsequent Heckreactions with tert-
butyl acrylate to form the unsymmetrically substituted tricy-
clic 1,3,5-hexatrienes cis-5a–c and trans-5b, respectively.
The best results for this step were obtained with the pallada-
cycle 8[13] and dppb[14] as co-ligand in the presence of trie-
thylamine as a base. These conditions were significantly su-
perior to the sole application of palladacycle 8 upon which,
Table 3. Thermal 6p-electrocyclizations of heterocyclic 1,3,4,5,6-penta-
substituted 1,3,5-hexatrienes.
Starting compound
Product
Yield (%)[a]
cis-5a
cis-5b
cis-5c
cis-7a
cis-7b
cis-7c
60
69
59
55
trans-5b
trans-7b
[a] Yield of isolated product.
Chem. Eur. J. 2006, 12, 8336 – 8344
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8337

A. de Meijere et al.
Table 4. Deprotection of steroidal amino acids.
latter apparently are the thermodynamically more stable iso-
mers, as upon extended heating at 2008C for 2 min they
were the sole products.
Starting compound
Product
Yield (%)[a]
[a]2D0 [b] [8]
cis-7a
cis-7b
cis-7c
cis-9a
cis-9b
cis-9c
76
86
79
ꢀ34.3 (0.530)
+8.2 (0.45)[c]
ꢀ3.3 (0.86)
The heterotetracyclic compounds cis-7a–c were obtained
as single diastereomers in yields ranging from 59–69%.
However, simply heating solutions of the unsymmetrically
substituted hexatrienes cis-5a–c above 2008C for 30 min led
to increased decomposition and provided the tetracycles cis-
7a–c only in 30–40% yields. The structure of the steroidal
d-amino acid cis-7b was rigorously confirmed by X-ray crys-
tallography (Figure 2). Thus, the sequence provides interest-
[a] Yield of isolated product. [b] Concentrations c [mgmLꢀ1] in methanol
in parentheses. [c] Methyl acetate instead of methanol as a solvent.
Heating the isomer trans-5b with a trans-configured CD-
ring junction at 1708C for 30 min in a microwave oven led
to the primary electrocyclization product trans-6b and
traces of a substance which is suggested to be the product
trans-7b of a [1,5]-hydrogen shift (Scheme 3). The steroidal
amino acid trans-6b shows a trans relationship of the hydro-
gens on C8 and C14 and a trans CD-ring junction which is
typical for the majority of naturally occurring steroids.[19]
Figure 2. Structure of the steroidal d-amino acid cis-7b in the crystal.[20]
Scheme 3. A) Toluene, microwave heating at 1708C, 30 min.
ing new steroidal d-amino acids with a cis CD-ring junction
as it is found in a pharmacologically important class of natu-
ral steroids such as cardenolides and bufadienolides.[17]
Deprotection of the hydroxy, the amino and the carboxyl
functionality in cis-7a could be achieved in one step using
boron trifluoride etherate (Scheme 2)[18] to provide, the free
steroidal d-amino acid cis-9a in good yield (76%).
It is noteworthy that the 6p-electrocyclizations occur with
a high degree of disrotational selectivity, as the tetracycles
cis-7a–c and trans-6b were all isolated as single diastereom-
ers.
Interestingly, the cyclization of the cis-configured hexa-
trienes cis-5a–c occurred with inward rotational selectivity
whereas the trans-configured hexatriene trans-5b cyclized
with outward rotational selectivity.[21] These steroidal amino
acids ought to be enantiomerically pure as well, since the bi-
cyclic alkenylstannanes cis-3 and trans-3 were enantiomeri-
cally pure starting materials, and any racematization along
the route would not be probable.
Conclusion
The Stille–Hecksequence of heterocyclic bromoenol tri-
flates with the bicycloalkenylstannanes and tert-butyl acryl-
ates as used in this study, provided unsymmetrically substi-
tuted (E)-1,3,5-hexatrienes, which were converted by highly
diastereoselective thermally induced 6p-electrocyclizations
to new tetracyclic dienes. Removal of the tert-butyl groups
provided the new enantiomerically pure steroidal d-amino
acids and amino acid derivatives which are interesting to be
tested as novel heterocyclic steroid analogues and as d-amio
acids to be incorporated into peptidomimetics. The descri-
bed methodology constitutes an efficient sequence by which
a remarkable increase of molecular complexicity is achieved.
With this process, by variation of the starting materials, a va-
Scheme 2. A) BF3·OEt2, toluene, 208C, 4 h.
Under the same conditions, only the tert-butoxy groups
were removed in derivatives cis-7b,c to furnish the amino
acid derivatives cis-9b and cis-9c in yields ranging from 79–
86% (Table 4). An attempted removal of the N-benzyl
group from the tetracycle cis-9c by catalytic hydrogenation
over palladium on charcoal to provide the amino acid cis-9a
was not successful.
8338
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8336 – 8344

Steroidal d-Amino Acids
FULL PAPER
and brine (15 mL) yielded the a-bromopiperidinone (1a) as a yellow oil
(0.948 g, 72%). Rf =0.50 (pentane/diethyl ether 2:1). The analytical data
were consistent with the ones reported previously.[23]
riety of different structurally rigid amino acids with a steroi-
dal skeleton should be accessible.
1-Benzenesulfonyl-3-bromopiperidine-4-one (1b): According to GP 1, 1-
benzenesulfonyl-4-trimethylsilanyloxy-1,2,3,6-tetrahydropyridine (2.21 g,
7.39 mmol), NBS (1.70 g, 11.1 mmol) and NaOAc (60.6 mg, 0.739 mmol)
in THF/water (60 mL) after 1 h and work-up with diethyl ether (2”
70 mL), satd. NaHCO3 solution (35 mL), water (35 mL) and (brine
20 mL) yielded the a-bromopiperidinone (1b) as a colorless oil (1.55 g,
Experimental Section
General remarks: 1H NMR: Bruker AM 250 (250 MHz). Chemical shifts
in CDCl3 are reported as d values relative to chloroform (d=7.26) and
benzene (d=7.20) as internal reference. 13C NMR: Bruker AW 250
(62.9 MHz). Chemical shifts in CDCl3 are reported as d values relative to
chloroform (d=77.0) and benzene (d=128); the multiplicity of the sig-
nals was determined by the DEPT (62.9 MHz) technique and quoted as
(+) for CH3 and CH groups, (ꢀ) for CH2 groups and (Cquat) for quaterna-
ry carbon atoms. IR spectra: Bruker IFS 66. Low-resolution EI mass
spectra: Finnigan MAT 95, ionizing voltage 70 eV. High-resolution mass
spectra: Finnigan MAT 95; preselected ion peakmatching at R~10000 to
be within ꢁ2 ppm of the exact masses. Elemental analyses: Mikroanaly-
tisches Labor des Instituts für Organische und Biomolekulare Chemie
der Universität Gçttingen, Germany. Melting points are uncorrected. Sol-
vents for extraction and chromatography were of technical grade and dis-
tilled before use. Flash column chromatography (CC) was performed
using MerckKieselgel 60 (200–400 mesh). Aluminum oxide (ICN Alumi-
na N, Super I) was obtained from ICN Biomedicals. Unless otherwise
specified, aluminum oxide was deactivated with 5% water. TLC analyses
were performed using Machery-Nagel precoated plates, 0.25 mm, Alu-
1
68%). Rf =0.45 (pentane/diethyl ether 2:1); H NMR (250 MHz, CDCl3):
d=2.51–2.68 (m, 1H, CH2), 2.80–3.07 (m, 1H, CH2), 3.18–3.47 (m, 2H,
3
CH2), 3.50–3.63 (m, 1H, CH2), 3.80–3.99 (m, 1H, CH2), 4.45 (dd, J=9.1,
3J=6.1 Hz, 1H, 3-H), 7.40–7.64 (m, 3H, Ar-H), 7.69–7.81 (m, 2H, Ar-H);
13C NMR (62.9 MHz, CDCl3, DEPT): d=38.43 (ꢀ, CH2), 45.59 (ꢀ, CH2),
49.31 (ꢀ, CH2), 52.81 (+, CH3, C-3), 133.25 (+, CH, Ar), 127.09 (+, 2C,
CH, Ar), 129.26 (+, 2C, CH, Ar), 136.25 (Cquat, Ar), 200.51 (Cquat, C-4);
IR (film): n˜ = 3064, 2918 (C-H), 2857, 1734, 1700, 1684, 1653, 1465,
1447, 1358, 1339, 1311, 1288, 1215, 1169, 1095, 1074, 988, 934, 801, 743,
691, 657, 577 cmꢀ1; MS (70 eV, EI): m/z (%): 318/316 (4/4), 276 (1), 238
(3), 196 (6), 177 (2), 169 (3), 140 (22), 132 (8), 97 (5), 77 (100), 55 (9), 51
(22), 42 (24); HRMS: m/z: calcd for C11H12O3NSBr+H+ (319.2):
317.97937 (correct HRMS).
1-Benzyl-3-bromopiperidine-4-one (1c): According to GP 1, 1-benzyl-4-
trimethylsilanyloxy-1,2,3,6-tetrahydropyridine (2.60 g, 9.92 mmol), NBS
(2.27 g, 14.9 mmol) and sodium acetate (81.3 mg, 0.992 mmol) in THF/
water (45 mL) after 1 h and work-up with diethyl ether (2”75 mL), sat.
NaHCO3 solution (40 mL), water (40 mL) and brine (20 mL) yielded the
a-bromopiperidinone (1c) as a colorless oil (0.80 g, 31%). Rf =0.25 (pen-
tane/diethyl ether 2:1). The analytical data were consistent with the ones
reported previously.[24]
gram Sil G/UV254 (I) and Merckprecoated silica gel 60 F
aluminium
254
sheets (II). All reactions were carried out under an atmosphere of dry ni-
trogen or argon in oven- and/or flame-dried glassware. Unless otherwise
specified, solutions of NH4Cl, NaCl, Na2SO3 and NaHCO3 are saturated
aqueous solutions. Benzene, decalin, toluene, THF and diethyl ether
were distilled from sodium/benzophenone. Dichloromethane was distilled
from CaH2.
tert-Butyl 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylate,[22]
1-benzyl-4-trimethylsilanyloxy-1,2,3,6-tetrahydropyridine,[22] were pre-
pared as described in literature.
General procedure for the synthesis of bromoenol triflates (GP 2): To a
solution of the a-a-bromopiperidinone (1.00 equiv) and triethylamine
(3.00–5.00 equiv) in dichloromethane was added dropwise at ꢀ788C tri-
fluoromethansulfonic acid anhydride (1.05–1.30 equiv) in dichlorome-
thane. The reaction mixture was slowly warmed to ambient temperature
and stirred for a total of 20–24 h. After treatment with satd. NaHCO3 sol-
ution, the aqueous phase was extracted with diethyl ether. Then the com-
bined organic layers were washed with water and brine. After concentra-
tion in vacuo the residue was purified by CC on silica gel.
1-Benzenesulfonyl-4-trimethylsilanyloxy-1,2,3,6-tetrahydropyridine: Tri-
fluoromethanesulfonic acid trimethylsilyl ester (3.43 g, 15.4 mmol) in di-
chloromethane (20 mL) was added at ꢀ208C within 20 min to a solution
of 1-benzenesulfonylpiperidine-4-one (5.00 g, 21.0 mmol) and triethyl-
amine (6.60 g, 65.2 mmol) in dichloromethane (100 mL). After stirring
for 1.0 h at ꢀ208C, the reaction mixture was treated with satd. NaHCO3
solution (30 mL) and washed with water (30 mL). The organic phase was
dried over MgSO4 and concentrated in vacuo. The residue was purified
by CC on silica gel (55 g, pentane/diethyl ether 1:1) to obtain the product
tert-Butyl 5-bromo-4-trifluoromethanesulfonyl-3,6-dihydro-2H-pyridine-
1-carboxylate (2a): According to GP 2 a-bromopiperidinone (1a) (1.20 g,
4.31 mmol) and triethylamine (1.30 g, 12.9 mmol) in dichloromethane
(20 mL) were treated with trifluoromethanesulfonic acid anhydride
(1.46 g, 5.18 mmol) in dichloromethane (5 mL). Workup with diethyl
ether (35 mL) und satd. NaHCO3 solution (15 mL), extraction of the
aqueous phases with diethyl ether (2”5 mL) yielded after purification by
CC on silica gel (25 g, pentane/diethyl ether 1:1) the bromoenol triflate
1a as colorless oil (1.31 g, 74%). Rf =0.61; 1H NMR (250 MHz, CDCl3):
d=1.50 (s, 9H, tBu), 2.48–2.61 (m, 2H, 2-H), 3.69 (t, 3J=6.3 Hz, 2H, 3-
H), 4.25 (brs, 2H, 6-H); 13C NMR (75.6 MHz, CDCl3, APT): d=28.2 [+,
as colorless oil (6.41 g, 98%). Rf =0.43; 1H NMR (250 MHz, CDCl3): d=
3
0.16 [s, 9H, CH3, Si
(CH3)3], 2.19 (m, 2H, 5-H), 3.06 (t, J=7.2 Hz, 2H, 6-
H), 3.40 (m, 2H, 5-H), 4.71–4.79 (m, 1H, 2-H), 7.49–7.62 (m, 3H, Ar-H),
7.77–7.83 (m, 2H, Ar-H); 13C NMR (62.9 MHz, CDCl3, DEPT): d=0.17
[+, 3C, CH3, Si
(CH3)3], 29.85 (ꢀ, CH2), 43.18 (ꢀ, CH2), 43.74 (ꢀ, CH2),
99.17 (+, CH, C-2), 127.55 (+, 2C, CH, Ar), 129.01 (+, 2C, CH, Ar),
132.72 (+, CH, Ar), 136.56 (Cquat, Ar), 148.68 (Cquat, C-4).
3C, CH3, C
N
G
(ꢀ, Cquat, C-4), 153.8 (ꢀ, Cquat, C=O); IR (film): n˜ = 2979 (C-H), 2935,
1705, 1653, 1635, 1591, 1457, 1420, 1368, 1337, 1296, 1246, 1215, 1163,
1140, 1116, 1077, 1043, 998, 868, 814, 768, 698, 668, 622 cmꢀ1; MS (70 eV,
EI): m/z (%): 355/353 (2/2), 338/336 (3/3), 309/307 (1/1), 273 (1), 221/219
(5/5), 176 (1), 132 (2), 96 (2), 69 (4) [CF3+], 57 (100).
General procedure for the synthesis of the a-bromopiperidinones (GP
1): To a solution of N-bromosuccinimide (1.30–1.50 equiv) and sodium
acetate (0.100 equiv) in THF/water 1:1 at 08C was added dropwise the
corresponding trimethylsilylenol ether (1.00 equiv). The reaction mixture
was warmed to ambient temperature and stirred for the stated time. It
was treated with aqueous sodium sulfite solution (10%) until it decolor-
ized. The reaction mixture was extracted with two portions of diethyl
ether. After washing the combined organic phases with satd. sodium hy-
drogencarbonate, water and brine, it was dried over MgSO4. After con-
centration in vacuo the crude material was used without further purifica-
tion. Otherwise it was purified by CC on silica gel.
1-Benzenesulfonyl-5-bromo-4-trifluoromethanesulfonyl-1,2,3,6-tetrahy-
dropyridine (2b): According to GP 2, a-bromopiperidinone 1b (312 mg,
0.981 mmol) and triethylamine (297 mg, 2.94 mmol) in dichloromethane
(10 mL) were treated with trifluoromethanesulfonic acid anhydride
(414 mg, 1.47 mmol) in dichloromethane (4 mL). Workup with diethyl
ether (20 mL) and sat. NaHCO3 solution (10 mL), extraction of the aque-
ous phase with diethyl ether (2”20 mL) yielded, after purification on
silica gel (15 g, pentane/diethyl ether 1:1), the bromoenol triflate 2b as a
colorless oil (352 mg, 80%). Good quality crystals for X-ray diffraction
were grown from pentane/diethyl ether 1:1 by slow evaporation of sol-
vents at 238C. Rf =0.43; 1H NMR (250 MHz, CDCl3): d=2.44–2.66 (m,
tert-Butyl 3-bromo-4-oxopiperidine-1-carboxylate (1a): According to GP
1, tert-butyl 4-trimethylsilanyloxy-3,6-dihydro-2H-pyridine-1-carboxylate
(1.00 g, 4.76 mmol), NBS (1.27 g, 8.25 mmol) and sodium acetate
(39.1 mg, 0.476 mmol) in THF/water (45 mL) after 1 h and work-up with
diethyl ether (2”50 mL), satd. NaHCO3 solution (20 mL), water (20 mL)
Chem. Eur. J. 2006, 12, 8336 – 8344
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8339

A. de Meijere et al.
2H, 2-H), 3.47 (t, 3J=7.2 Hz, 2H, 3-H), 3.47 (t, 3J=0.83 Hz, 2H, 6-H),
7.49–7.71 (m, 3H, Ar-H), 7.73–7.84 (m, 2H, Ar-H); 13C NMR (75.5 MHz,
CDCl3, APT): d=29.11 (ꢀ, CH2), 42.64 (ꢀ, CH2), 50.35 (ꢀ, CH2), 110.21
(ꢀ, Cquat, C-3), 118.22 (ꢀ, q, 1J=321 Hz, Cquat, CF3), 127.33 (+, 2C, CH,
Ar), 129.53 (+, 2C, CH, Ar), 133.52 (+, CH, Ar), 136.48 (ꢀ, Cquat, Ar),
143.34 (ꢀ, Cquat, C-4); IR (film): n˜ = 3065, 2920, 2863, 1684, 1447, 1422,
1357, 1340, 1250, 1214, 1171, 1138, 1101, 1085, 1024, 999, 967, 951, 915,
866, 815, 748, 739, 715, 690, 677, 624 cmꢀ1; MS (70 eV, EI): m/z (%): 450/
448 (3/2), 369 (11), 309/307 (17/18), 275 (1), 236 (3), 227 (2), 176/174 (9/
9), 140 (40), 96 (1), 77 (100), 51 (22), 42 (6).
H), 2953 (C-H), 2871 (C-H), 2843 (C-H), 1474, 1465, 1457, 1388, 1376,
1361, 1255, 1226, 1199, 1125, 1091, 1071, 1047, 1025, 992, 907, 893, 873,
743 cmꢀ1; MS (70 eV): m/z (%): 469/467 (1/1) [M +], 428/426 (1/1), 412/
410 (37/35) [M +ꢀC4H9], 357/355 (43/56), 339 (23), 312 (8), 276 (32), 258
(28), 232 (79), 231 (25), 220 (6), 174 (4), 131 (5), 91 (8), 57 (100) [C4H9+],
41 (14); DCI-MS (NH3): m/z (%): 487/485 (50/50) [M+NH4+], 446 (100),
431/429 (52/54), 407 (36), 346 (45), 288 (17), 254 (24), 232 (22), 175 (4),
138 (10).
(1S,3aR,7aS)-1-Benzolsulfonyl-5-bromo-4-(1’-tert-butoxy-7a’-methyl-
2’,3’,3a’,6’,7’,7a’-hexahydro-1’H-indene-5’-yl)-1,2,3,6-tetrahydropyridine
(cis-4b): According to GP 3, the bromoenol triflate 2b (1.41 g,
3.13 mmol) in NMP (10.0 mL) and bicycloalkenylstannane cis-3 (1.79 g,
1-Benzyl-5-bromo-4-trifluoromethanesulfonyl-1,2,3,6-tetrahydropyridine
(2c): According to GP 2, a-bromopiperidinone 1c (3.80 g, 14.2 mmol)
and triethylamine (5.74 g, 56.8 mmol) in dichloromethane (60 mL) were
treated with trifluoromethanesulfonic acid anhydride (6.01 g, 21.3 mmol)
in dichloromethane (15 mL). Work-up according to GP 2 with diethyl
ether (50 mL) and satd. NaHCO3 solution (25 mL), extraction of the
aqueous phases with diethyl ether (2”40 mL) yielded after purification
on silica gel (35 g, pentane/diethyl ether 3:1) the bromoenoltriflate 2c as
a colorless oil (3.19 g, 56%). Rf =0.53; 1H NMR (250 MHz, CDCl3): d=
2.50–2.62 (m, 2H, 5-H), 2.86 (t, 3J=6.1 Hz, 2H, 6-H), 3.39 (t, 3J=
0.76 Hz, 2H, 2-H), 3.67 (s, 2H, PhCH2), 7.28–7.47 (m, 5H, Ar); 13C NMR
(75.6 MHz, CDCl3, APT): d=28.93 (ꢀ, CH2), 42.65 (ꢀ, CH2), 48.64 (ꢀ,
CH2), 60.17 (ꢀ, CH2, PhCH2), 112.35 (ꢀ, Cquat, C-4), 118.53 (ꢀ, q, 1J=
318 Hz, Cquat, CF3), 127.61 (+, CH, Ar), 128.52 (+, CH, 2C, Ar), 128.89
(+, CH, 2C, Ar), 137.06 (ꢀ, Cquat, Ar), 143.75 (ꢀ, Cquat, C-3); IR (film):
n˜ = 3064, 3029, 2976, 2865, 1685, 1495, 1434, 1418, 1383, 1367, 1347,
1250, 1231, 1202, 1146, 1136, 1084, 1075, 1054, 1028, 1012, 997, 976, 919,
880, 858, 820, 768, 739, 698, 630, 604 cmꢀ1; MS (70 eV, EI): m/z (%): 401/
399 (2/2), 320 (2), 310/308 (1/1), 268 (1), 187 (3), 159 (1), 119 (2), 91
(100), 65 (12); HRMS: m/z: calcd for C13H13O3NBrF3S (400.2): 398.9752
(correct HRMS).
3.61 mmol), after treatment with [Pd2(dba)3] (86.3 mg, 94.2 mmol), LiCl
C
(400 mg, 9.44 mmol), CuI (17.9 mg, 94.0 mmol), work-up with diethyl
ether (100 mL), NH3 solution (2”40 mL, 5%), water (40 mL), backex-
traction with diethyl ether (2”55 mL) treatment with satd. KF solution
(75 mL) and CC on silica gel (70 g, pentane/diethyl ether 5:1) gave the
bromobutadiene cis-4b as a colorless oil which quickly turned yellow at
1
RT (1.50 g, 94%). Rf =0.43; H NMR (300 MHz, CDCl3): d=0.85 (s, 3H,
CH3), 1.14 [s, 9H, C(CH3)3], 1.27–1.58 (m, 4H), 1.85–2.13 (m, 5H), 2.25
N
(m, 2H), 3.28 (q, 3J=6.6 Hz, 2H, 2-H), 3.60 (t, 3J=7.2 Hz, 1H, 1’-H),
3.87 (m, 2H, 6-H), 5.23 (m, 1H, 4’-H), 7.47–7.63 (m, 3H, ArH), 7.75–7.83
(m, 2H, ArH); 13C NMR (75.5 MHz, CDCl3, APT): d=20.94 (+, CH3),
23.22 (ꢀ, CH2), 28.22 (ꢀ, CH2), 28.72 [+, 3C, CH3, C
CH2), 30.90 (ꢀ, CH2), 32.56 (ꢀ, CH2), 41.49 (ꢀ, CH2), 42.87 (ꢀ, Cquat, C-
7a’), 43.75 (+, CH, C-3a’), 51.34 (ꢀ, CH2, C-2), 72.47 [ꢀ, Cquat, C(CH3)3],
A
ACHTREUNG
76.10 (+, CH, C-1’), 111.08 (ꢀ, Cquat), 127.52 (+, 2C, CH, Ph), 128.94 (+,
2C, CH, Ph), 130.37 (+, CH, Ph), 132.96 (+, CH, C-4’), 135.30 (ꢀ, Cquat),
136.69 (ꢀ, Cquat), 138.15 (ꢀ, Cquat); IR (film): n˜ = 2970 (C-H), 2871 (C-
H), 1669 (C=C), 1616, 1587, 1559, 1506, 1458, 1446, 1388, 1356, 1309,
1197, 1170, 1093, 1018, 967, 910, 865, 808 cmꢀ1; EI-MS (70 eV): m/z (%):
372 (18), 354 (6), 316 (3), 288 (3), 278 (9), 231/229 (15/13), 212 (4), 169
(8), 140 (13), 91 (11), 83 (18), 77 (48), 57 (100), 40 (31); DCI-MS (NH3):
m/z (%): 795/793 (5/5), 621 (3), 571 (3), 544/542 (26/24) [M+NH3+NH4+],
527/525 (38/36) [M+NH4+], 520 (5), 385 (3), 370 (14), 353 (9), 303 (28),
286 (100), 254 (6), 192 (4), 136 (3).
General procedure for Stille couplings of heterocyclic 2-bromocyclohex-
1-enyl triflates (GP 3): In a Pyrex bottle containing a magnetic stirring
bar were placed NMP (5 mL), the bromoenol triflate (1.00–1.20 equiv)
and the stannane (1.00 equiv). The bottle was sealed with a septum and
the contained solution was purged with argon in an ultrasonic bath for
5 min. Then [Pd
A
(3S,3aS,7aR)-1-Benzyl-5-bromo-4-(1-tert-butoxy-7a-methyl-2,3,3a,6,7,7a-
hexahydro-1H-indene-5-yl)-1,2,3,6-tetrahydropyridine (cis-4c): According
to GP 3, to bromoenol triflate (2c) (400 mg, 1.00 mmol) in NMP
(4.00 mL) with bicycloalkenylstannane (cis-3) (522 mg, 1.05 mmol), after
mol%) followed, and the suspension was purged with argon for another
5 min. After removal of the septum, the bottle was sealed with a screw
cap, and then heated with vigorous stirring at the stated temperature for
the stated time. When the reaction had ceased, the mixture was poured
into diethyl ether and aqueous NH3 solution (5%). The organic layer
was washed with water and the combined aqueous layers were extracted
backwith diethyl ether (2”30 mL). The combined organic layers were
treated with satd. KF solution, dried over MgSO4, concentrated in vacuo,
and the residue was purified by column chromatography (CC) on silica
gel.
treatment with [Pd2(dba)3]·CHCl3 (36.3 mg, 35.1 mmol), LiCl (128 mg,
A
3.02 mmol) and CuI (6.71 mg, 35.2 mmol), work-up with diethyl ether
(80 mL), NH3 solution (2”30 mL, 5%), water (30 mL), extraction with
diethyl ether (2”30 mL), treatment with sat. KF solution (60 mL) and
CC on silica gel (50 g, pentane/diethyl ether 5:1) gave the bromobuta-
diene cis-4c as a colorless oil, which quickly turned yellow at RT
(334 mg, 73%). Rf =0.33; 1H NMR (250 MHz, CDCl3): d=0.95 (s, 3H,
CH3), 1.18 [s, 9H, C(CH3)3], 1.31–1.68 (m, 6H), 1.93–2.22 (m, 5H), 2.60-
C
(1’S,3a’S,7a’R)-tert-Butyl
5-bromo-4-(1’-tert-butoxy-7a’-methyl-
2’,3’,3a’,6’,7’,7a’-hexahydro-1’H-indene-5’-yl)-3,6-dihydro-2H-pyridine-1-
carboxylate (cis-4a): According to GP 3, bromoenol triflate 2a (615 mg,
1.50 mmol) in NMP (5 mL) and bicycloalkenylstannane cis-3 (845 mg,
CH2), 28.26 (ꢀ, CH2), 28.74 [+, 3C, C(CH3)3], 30.00 (ꢀ, CH2), 31.53 (ꢀ,
G
1.70 mmol), after treatment with [Pd2(dba)3]·CHCl3 (39 mg, 38 mmol),
A
CH2), 32.56 (ꢀ, CH2), 41.52 (Cquat, C-3a), 43.84 (+, CH, C-7a), 49.21 (ꢀ,
CH2, C-2’), 60.12 (ꢀ, CH2, C-3’), 61.45 (ꢀ, CH2, PhCH2), 72.41 [Cquat, C-
LiCl (191 mg, 4.50 mmol) CuI (6.8 mg, 36 mmol) at 658C for 12 h and
work-up with diethyl ether (100 mL), NH3 solution (2”35 mL, 5%),
water (35 mL), backextraction of the combined aqueous phases with di-
ethyl ether (2”40 mL) treatment with satd. KF solution (75 mL) and CC
on silica gel (35 g, pentane/diethyl ether 5:1) gave the bromobutadiene
cis-4a as a colorless oil which quickly turned yellow at RT (597 mg,
85%). Rf =0.38; 1H NMR (250 MHz, CDCl3): d=0.91 (s, 3H, CH3), 1.16
A
(+, 2C, CH, Ar), 129.07 (+, 2C, CH, Ar), 129.71 (+, CH, C-7), 136.03
(Cquat), 137.67 (Cquat); IR (film): n˜ = 3063, 2976 (C-H), 2963, 2871 (C-H),
2842, 1692 (C=C), 1424, 1416, 1375, 1341, 1304, 1249, 1197, 1144, 1070,
1041, 1017, 983, 952, 883, 858, 819 cmꢀ1; MS (70 eV): m/z (%): 459/457
(10/9) [M +], 386/384 (3/2), 325 (1), 312 (18), 308 (100), 300 (4), 226 (3),
209 (11), 135 (6).
[s, 9H, C
A
R
1.62 (m, 3H), 1.93–2.32 (m, 7H), 3.54 (m, 1H), 3.71 (t, 3J=8.0 Hz, 1H,
4’-H), 4.11 (m, 2H, 6’-H), 5.39 (m, 1H, 1’-H); 13C NMR (62.9 MHz,
CDCl3 additional APT): d=21.1 (+, CH3), 23.4 (ꢀ, CH2), 28.3 (ꢀ, CH2),
General procedure for Heck couplings of functionalized bromodienes
with acrylates (GP 4): In a Pyrex bottle containing a magnetic stirring
bar was charged with DMF/H2O (10:1) and the respective bromodiene
(1.00 equiv). The bottle was sealed with a septum, and the contained sol-
ution was purged with argon in an ultrasonic bath for 5 min. Then trans-
28.4 [+, 3C, C
A
A
(ꢀ, CH2), 32.6 (ꢀ, CH2), 41.6 (ꢀ, CH2), 42.7 (ꢀ, CH2), 43.9 (+, CH, C-
3’a), 50.2 (ꢀ, Cquat, C-7’a), 72.5 [ꢀ, Cquat, C(CH3)3], 76.1 [ꢀ, Cquat, COOC-
(CH3)3], 80.2 (+, CH, C-1’), 113.1 (ꢀ, Cquat), 130.1 (+, CH, C-4’), 135.9
(ꢀ, Cquat), 138.3 (ꢀ, Cquat), 154.1 (ꢀ, Cquat, C=0); IR (film): n˜ =2976 (C-
AHCTREUNG
E
di(m-acetato)bis[o-(di-o-tolylphosphanyl)benzyl]dipalladium(ii)
(8)
(3 mol%), 1,4-bis(diphenylphosphinyl)butane (3 mol%), triethylamine
8340
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8336 – 8344

Steroidal d-Amino Acids
FULL PAPER
(3.00–4.00 equiv) and tert-butyl acrylate (5.00–10.0 equiv) were added.
The reaction mixture was purged with argon for another 2 min. The
septum was removed, the Pyrex bottle was sealed with a screw cap and
heated with vigorous stirring at the stated temperature for the stated
time. After the reaction mixture had cooled down to RT, it was poured
into diethyl ether (40 mL) and 5% aqueous NH3 solution (10 mL). The
organic layer was washed with 5% aqueous NH3 solution (10 mL), and
the combined aqueous layers were extracted backwith Et 2O (2”25 mL).
The combined organic layers were dried over MgSO4, concentrated in
vacuo and the residue was purified by column chromatography (CC) on
silica gel.
(26) [M +ꢀ2”C4H8], 442 (34) [M +ꢀC4H9ꢀC4H8], 398 (24), 358 (22), 314
(5), 302 (64), 284 (33), 256 (26), 209 (10), 184 (6), 141 (10), 83 (7), 77
(20), 57 (100) [C4H9+], 41 (24); HRMS: m/z: calcd for C32H45O5SN+H+
(556.8): 556.30909 (correct HRMS).
(E)-(1’’S,3a’’R,7a’’S)-tert-Butyl 3-[1’-benzyl-4’-(1’’-tert-butoxy-7a’’-methyl-
2’’,3’’,3a’’,6’’,7’’,7a’’-hexahydro-1’’H-indene-5’’-yl)-1’,2’,5’,6’-tetrahydropyri-
dine-3’-yl]acrylate (cis-5c): According to GP 4, to a solution of the bro-
mobutadiene cis-4c (301 mg, 656 mmol) in DMF/H2O 10:1 (2.0 mL), 1,4-
bis(diphenylphosphinyl)butane (14.0 mg, 32.8 mmol), palladacycle
8
(30.7 mg, 32.7 mmol), triethylamine (199 mg, 1.97 mmol) and tert-butyl
acrylate (0.400 mL, 0.350 g, 2.73 mmol)were added. The resulting mixture
was heated at 1058C for 8 h. Work-up with diethyl ether (60 mL), water
(2”15 mL), backextraction with diethyl ether (2”20 mL), brine (15 mL)
yielded after CC (30 g silica gel, pentane/diethyl ether 5:1) the hexatriene
cis-5c as a colorless oil (235 mg, 71%). Rf =0.30; 1H NMR (250 MHz,
(E)-(1’’S,3a’’R,7a’’S)-tert-Butyl 5’-(2-tert-butoxycarbonylethenyl)-4’-(1’’-
tert-butoxy-7a’’-methyl-2’’,3’’,3a’’,6’’,7’’,7a’’-hexahydro-1’’H-inden-5’’-yl)-
3’,6’-dihydro-2’H-pyridine-1’-carboxylate (cis-5a): According to GP 4, to
a solution of the bromodiene cis-4a (1.50 g, 3.21 mmol) in DMF/H2O
10:1 (11 mL), 1,4-bis(diphenylphosphanyl)butane (41 mg, 96 mmol), palla-
dacycle 8 (90 mg, 96 mmol), triethylamine (1.31 g, 12.9 mmol) and tert-
butyl acrylate (3.50 g, 27.3 mmol) were added. The resulting mixture was
heated at 1058C for 8 h. After CC (30 g silica gel, pentane/diethyl ether
5:1) the hexatriene cis-5a was obtained as a colorless oil (1.38 g, 83%).
C6D6): d=1.06 (s, 3H, CH3), 1.10 [s, 9H, C
A
1.46 [s, 9H, CO2C(CH3)3], 1.52–1.78 (m, 3H), 1.93–2.10 (m, 3H), 2.13–
AHCTREUNG
2.29 (m, 3H), 2.34–2.42 (m, 1H), 3.16 (m, 2H), 3.22 (m, 2H, CH2Ph),
3.69 (t, 3J=6.9 Hz, 1H, 1’’-H), 5.42–5.49 (m, 1H, 5’’-H), 5.89 (d, 3J=
15.9 Hz, 1H, 1-H), 7.11–7.23 (m, 3H, Ph), 7.31–7.42 (m, 2H, Ph), 8.04 (d,
3J=15.9 Hz, 1H, 3-H); 13C NMR (62.9 MHz, CDCl3, DEPT): d=21.48
1
Rf =0.35; H NMR (300 MHz, CDCl3): d=0.90 (s, 3H, CH3), 1.13 [s, 9H,
C
N
N
(+, CH3), 25.13 (ꢀ, CH2), 28.24 [+, 3C, C
(CH3)3], 29.07 (ꢀ, CH2), 30.44 (ꢀ, CH2), 31.08 (ꢀ, CH2), 32.84 (ꢀ, CH2),
34.39 (ꢀ, CH2), 42.05 (Cquat, C-7a’’), 44.45 (+, CH, C-3a’’), 49.38 (ꢀ,
CH2), 62.78 (ꢀ, CH2, CH2Ph), 72.50 [Cquat, C(CH3)3], 76.65 (+, CH, C-
1’’), 79.30 [Cquat, CO2C(CH3)3], 116.74 (+, CH, C-1), 126.89 (Cquat), 127.38
A
(m, 3H), 2.14–2.24 (m, 2H), 2.29 (m, 2H), 3.38–3.51 (m, 2H), 3.56 (t,
3J=8.1 Hz, 1H, 1’’-H), 4.01 (m, 2H), 5.37–5.43 (m, 1H, 5’’-H), 5.63 (d,
3J=16.4 Hz, 1H, 1-H), 7.51 (d, 3J=16.4 Hz, 1H, 3-H); 13C NMR
(75.5 MHz, CDCl3, additional APT): d=20.9 (+, CH3), 24.8 (ꢀ, CH2),
AHCTREUNG
AHCTREUNG
AHCTREUNG
28.2 [+, 3C, C
N
N
(+, CH, Ar), 128.39 (+, 2C, CH, Ar), 129.13 (+, 2C, CH, Ar), 132.33
(Cquat), 134.99 (+, CH), 139.06 (Cquat), 141.81 (+, CH), 147.82 (Cquat, Ar),
166.74 (Cquat, C=O); IR (film): n˜ = 3063, 2951 (C-H), 2915 (C-H)), 2843,
2839, 1711 (C=O), 1680, 1658, 1650, 1621 (C=C), 1564, 1503, 1478, 1469,
1450, 1366, 1158, 1144, 1111, 1025, 1018, 850, 767, 731, 672 cmꢀ1; MS
(70 eV): m/z (%): 505 (43) [M +], 448 (100) [M +ꢀC4H9], 432 (8), 404
(34), 392 (30) [M +ꢀC4H8ꢀC4H9], 355 (4), 298 (12), 257 (4), 242 (8), 208
(2), 171 (1), 131 (3), 120 (8), 91 (85) [Bn+], 57 (34) [C4H9+], 41 (6);
HRMS: m/z: calcd for C33H47O3N+H+ (506.7): 506.36306 (correct
HRMS).
ACHTREUNG
A
ACHTREUNG
ACHTREUNG
134.4 (ꢀ, Cquat), 140.5 (+, CH), 148.1 (ꢀ, Cquat), 154.7 (ꢀ, Cquat, NC=O),
166.7 (ꢀ, Cquat, OC=O); IR (film): n˜ = 2977, 2958 (C-H), 2933 (C-H)),
1701 (C=O), 1685, 1617 (C=C), 1559, 1507, 1478, 1457, 1393, 1368, 1338,
1319, 1285, 1253, 1197, 1171, 1149, 1043, 1025, 987, 908, 849, 744, 729,
704, 648 cmꢀ1; MS (70 eV): m/z (%): 515 (2) [M +], 459 (8) [M +ꢀC4H8],
441 (63), 403 (38) [M +ꢀ2”C4H8], 402 (30) [M +ꢀC4H8ꢀC4H9], 385 (64),
+
346 (62), 328 (52), 302 (76), 284 (72), 258 (73), 240 (38), 57 (100) [C4H9
(E)-(1’’S,3a’’S,7a’’S)-tert-Butyl
3-[1’-benzenesulfonyl-4’-(1’’-tert-butoxy-
], 41 (29); DCI-MS (NH3): m/z (%): 644 (5), 549 (4), 533 (100)
[M+NH4+], 516 (51) [M+H+], 477 (58), 416 (25), 383 (50), 327 (66), 271
(11), 208 (3); HRMS: m/z: calcd for C31H49NO5: 515.3611 (correct
HRMS).
7a’’-methyl-2’’,3’’,3a’’,6’’,7’’,7a’’-hexahydro-1’’H-indene-5’’-yl)-1’,2’,5’,6’-tet-
rahydropyridine-3’-yl]acrylate (trans-5b): According to GP 4, to a solu-
tion of the bromobutadiene trans-4b (633 mg, 1.24 mmol) in DMF/
CH3CN/H2O 5:5:1 (5 mL), 1,4-bis(diphenylphosphanyl)butane (15.9 mg,
37.3 mmol), palladacycle 8 (34.8 mg, 86.5 mmol) triethylamine (314 mg,
3.10 mmol) and tert-butyl acrylate (1.59 g, 12.4 mmol) were added. The
resulting mixture was heated at 1058C for 8.5 h. Work-up with diethyl
ether (55 mL), water (2”20 mL), backextraction with diethyl ether (2”
25 mL), brine (30 mL) yielded after CC (40 g silica gel, pentane/diethyl
ether 3:1) the hexatriene trans-5b as a colorless oil (586 g, 85%). Rf =
0.42; 1H NMR (300 MHz, CDCl3): d=0.72 (s, 3H, CH3), 1.13 [s, 9H, C-
(E)-(1’’S,3a’’R,7a’’S)-tert-Butyl 3-[1’-benzenesulfonyl-4’-(1’’-tert-butoxy-
7a’’-methyl-2’’,3’’,3a’’,6’’,7’’,7a’’-hexahydro-1’’H-indene-5’’-yl)-1’,2’,5’,6’-tet-
rahydropyridine-3’-yl]-acrylate (cis-5b): According to GP 4, to a solution
of the bromobutadiene cis-4b (1.10 g, 2.16 mmol) in DMF/CH3CN/H2O
5:5:1 (10 mL), 1,4-bis(diphenylphosphanyl)butane (36.9 mg, 86.5 mmol),
palladacycle 8 (81.0 mg, 86.4 mmol), triethylamine (437 mg, 4.32 mmol)
and tert-butyl acrylate (3.16 mL, 2.77 g, 21.6 mmol) were added. The re-
sulting mixture was heated at 1058C for 8.5 h. Work-up with diethyl
ether (120 mL), water (2”35 mL), backextraction with diethyl ether (2”
55 mL), brine (35 mL) yielded after CC (50 g silica gel, pentane/diethyl
ether 3:1) the hexatriene cis-5b as a colorless oil (1.10 g, 92%). Rf =0.50;
A
N
3
3H), 1.77–2.16 (m, 5H), 2.38 (m, 2H), 3.20 (t, J=7.3 Hz, 2H, 4’-H), 3.44
(dd, 3J=8.8, 3J=8.3 Hz, 1H, 1’’-H), 3.73 (m, 2H), 5.32 (m, 1H, 1’’-H),
3
5.58 (d, J=15.7 Hz, 1H, 2-H), 7.40–7.62 (m, 3H, Ph, 3-H), 7.76–7.82 (m,
1H NMR (250 MHz, CDCl3): d=0.88 (s, 3H, CH3), 1.12 [s, 9H, C
1.15–1.42 (m, 2H), 1.46 [s, 9H, CO2C(CH3)3], 1.48–1.58 (m, 3H), 1.77–
(CH3)3],
2H, Ph); 13C NMR (75.6 MHz, CDCl3, APT): d=11.21 (+, CH3), 24.32
AHCTREUNG
(ꢀ, CH2), 26.53 (ꢀ, CH2), 28.13 [+, 3C, C
(CH3)3], 29.88 (ꢀ, CH2), 31.48 (ꢀ, CH2), 33.62 (ꢀ, CH2), 41.63 (ꢀ, Cquat
C-7a’’), 42.59 (ꢀ, CH2), 43.64 (+, CH, C-3a’’), 44.66 (ꢀ, CH2), 72.30 [ꢀ,
quat, C (CH3)3],
A
3
2.09 (m, 4H), 2.15 (m, 2H), 2.36 (m, 2H), 3.53 (t, J=7.5 Hz, 1H, 1’’-H),
3.72 (m, 2H), 5.30-5.34 (m, 1H, 1’’-H), 5.59 (d, 3J=15.6 Hz, 1H, 2-H),
7.43 (d, 3J=15.6 Hz, 1H, 3-H), 7.49–7.63 (m, 3H, Ph), 7.76–7.82 (m, 2H,
Ph); 13C NMR (75.6 MHz, CDCl3, APT): d=20.80 (+, CH3), 24.72 (ꢀ,
A
,
C
C
ACHTREUNG
117.35 (+, CH, C-2), 123.90 (ꢀ, Cquat), 127.59 (+, 2C, Ph), 129.12 (+,
CH2), 28.04 [+, 3C, C
(CH3)3], 28.16 [+, 3C, CO2C
(CH3)3], 28.65 (ꢀ,
2C, Ph), 129.58 (+, CH), 132.88 (+, CH), 136.07 (ꢀ, Cquat), 136.18 (ꢀ,
CH2), 29.11 (ꢀ, CH2), 29.63 (ꢀ, CH2), 32.94 (ꢀ, CH2), 41.40 (ꢀ, CH2),
C
42.59 (ꢀ, Cquat, C-7a’’), 44.26 (+, CH, C-3a’’), 44.68 (ꢀ, CH2), 72.61 [ꢀ,
(film): n˜ =3069, 2973 (C-H), 2938 (C-H)), 1960, 1911, 1817, 1716 (C=O),
1652, 1619 (C=C), 1446, 1436, 1360, 1263, 1203, 1035, 891, 850 cmꢀ1; MS
(70 eV): m/z (%): 555 (3) [M +], 499 (20) [M +ꢀC4H8], 454 (7), 442 (17)
[M +ꢀC4H9ꢀC4H8], 380 (9), 358 (21), 314 (9), 302 (25), 284 (18), 256
(17), 209 (11), 170 (5), 141 (8), 117 (2), 77 (29), 57 (100) [C4H9+], 41
(29); HRMS: m/z: calcd for C32H45O5SNꢀH+ (556.8): 556.30912 (correct
HRMS).
Cquat, C
(CH3)3], 77.29 (+, CH, C-1’’), 80.19 [ꢀ, Cquat, CO2C
(CH3)3],
117.30 (+, CH, C-2), 123.59 (ꢀ, Cquat), 127.62 (+, 2C, Ph), 129.14 (+,
2C, Ph), 132.74 (+, CH), 132.86 (+, CH), 133.82 (ꢀ, Cquat), 136.24 (ꢀ,
Cquat), 139.95 (+, CH), 146.82 (ꢀ, Cquat), 166.31 (ꢀ, Cquat, C=O); IR
(film): n˜ = 3063, 2977 (C-H), 2932 (C-H)), 1968, 1902, 1817, 1712 (C=
O), 1654, 1615 (C=C), 1446, 1361, 1293, 1233, 1001, 896, 854, 749 cmꢀ1
;
MS (70 eV): m/z (%): 555 (5) [M +], 499 (26) [M +ꢀC4H8], 481 (8), 443
Chem. Eur. J. 2006, 12, 8336 – 8344
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8341

A. de Meijere et al.
General procedure for the 6p-electrocyclization of the 1,3,5-hexatrienes
cis-5a–c and trans-5b (GP 5): In a thick-walled Pyrex test tube, contain-
ing a magnetic stirring bar was charged with the respective hexatriene
(1.00 equiv) in toluene/DMF 10:1. The test tube was sealed with a
septum, and the solution was purged with argon in an ultrasonic bath for
10 min. The septum was replaced with a screw cap, and the solution was
heated in a microwave oven at the stated temperature for the stated
time. After the reaction mixture had cooled down to ambient tempera-
ture, it was concentrated (258C, 5 mbar), and the product purified by
column chromatography (CC) on silica gel.
3H), 1.87–2.38 (m, 8H), 2.72–2.92 (m, 3H), 3.00-3.15 (m, 1H), 3.47 (dd,
3J1 =5.7 Hz, 3J2 =5.3 Hz, 1H, 7-H), 3.58 (d, 3J=7.6 Hz, 2H, CH2Ph),
7.22–7.40 (m, 5H, Ph); 13C NMR (75.6 MHz, CDCl3, additional APT):
d=19.74 (+, CH3), 22.05 (ꢀ, CH2), 25.50 (ꢀ, CH2), 28.04 [+, 3C, C-
(CH3)3], 28.60 [+, 3C, CO2C
U
30.43 (ꢀ, CH2), 33.56 (ꢀ, CH2), 42.19 (ꢀ, Cquat, C-6a), 43.00 (+, CH, C-
10), 47.31 (+, CH, C-9a), 50.31 (ꢀ, CH2), 56.75 (ꢀ, CH2), 62.72 (ꢀ, CH2,
CH2Ph), 72.62 [ꢀ, Cquat, C
C
,
CO2C
A
127.22 (ꢀ, Cquat), 128.18 (+, CH, 2C, Ph), 129.17 (+, CH, 2C, Ph),
129.26 (ꢀ, Cquat), 130.01 (+, CH, Ph), 173.37 (ꢀ, Cquat, C=O); IR (film):
n˜ =3062 (C-H), 3029, 2972 (C-H), 2928, 2871 (C-H), 1718 (C=O), 1653,
1636, 1617, 1472, 1456, 1389, 1366, 1265, 1251, 1229, 1198, 1152, 1095,
1055, 1027, 944, 911, 850, 735, 699 cmꢀ1; MS (70 eV): m/z (%): 505 (100)
[M +], 503 (5), 448 (94) [M +ꢀC4H9], 402 (19), 392 (38) [M +
ꢀC4H8ꢀC4H9], 346 (3), 334 (12), 288 (2), 248 (2), 229 (1), 169 (2), 134
(4), 120 (9), 91 (55) [Bn+], 84 (4), 57 (12) [C4H9+], 41 (2); HRMS: m/z:
calcd for C33H47O3N: 505.3555 (correct HRMS).
(6aS,7S,9aR,10S)-7-tert-Butoxy-6a-methyl-1,3,4,5,6,6a,7,8,9,9a,10,11-do-
decahydro-1H-indeno[5,4-f]isoquinoline-2,10-dicarboxylic acid di-tert-
A
butyl ester (cis-7a): According to GP 5, the hexatriene cis-5a (1.00 g,
1.94 mmol) was heated in toluene/DMF 10:1 (10 mL) at 1708C for
45 min and at 2008C for 2 min. Column chromatography on silica gel
(40 g, pentane/Et2O 5:1) afforded the steroid cis-7a as a colorless wax
(595 mg, 60%). Rf =0.37; 1H NMR (300 MHz, CDCl3): d=0.95 (s, 3H,
CH3), 1.13 [s, 9H, C
ACHTREUNG
A
U
(6aS,7S,9aS,10S)-tert-Butyl
2,3,4,5,6,6a,7,8,9,9a,9b,10-dodecahydro-1H-indeno
2-benzenesulfonyl-7-tert-butoxy-6a-methyl-
[5,4-f]isoquinoline-10-
6H), 2.72–2.80 (m, 1H), 3.11 (m, 1H), 3.48 (t, 3J=5.4 Hz, 1H, 7-H),
3.56–3.78 (m, 2H), 3.80–3.89 (m, 2H), 3.92–4.11 (m, 2H); 13C NMR
(75.5 MHz, CDCl3, additional APT): d=19.6 (+, CH3), 22.3 (ꢀ, CH2),
ACHTREUNG
carboxylate (trans-7b): According to GP 5, the hexatriene trans-5b
(305 mg, 0.549 mmol) was heated in toluene (5.00 mL) at 1708C for
45 min and at 2008C for 1.0 min. Column chromatography (30 g silica
gel, pentane/diethyl ether 3:1) afforded the steroid trans-7b as a colorless
wax (168 mg, 55%). Rf =0.21; 1H NMR (300 MHz, CDCl3): d=0.63 (s,
28.0 (ꢀ, CH2), 28.0 [+, 3C, C
[+, 3C, NCO2C
(ꢀ, CH2), 30.5 (ꢀ, CH2), 33.6 (ꢀ, CH2), 42.2 (ꢀ, Cquat, C-6a), 42.9 (+,
CH, C-10), 47.4 (+, CH, C-9a), 72.7 [ꢀ, Cquat, C(CH3)3], 79.4 [ꢀ, Cquat
NCO2C (CH3)3], 124.0
(CH3)3], 79.8 (+, CH, C-7), 80.2 [ꢀ, Cquat, CO2C
G
G
(CH3)3], 29.0 (ꢀ, CH2), 30.4
A
,
3H, CH3), 1.12 [s, 9H, C
A
A
G
G
(m, 4H), 1.75–2.40 (m, 8H), 2.69 (m, 1H), 2.82 (m, 1H), 3.23 (d, 3J=
16.8 Hz, 1H), 3.47 (t, 3J=5.9 Hz, 1H, 7-H), 3.51–3.59 (m, 1H), 3.67 (d,
3J=16.8 Hz, 1H), 5.55 (m, 1H, 11-H), 7.45–7.60 (m, 3H, Ph), 7.75–7.80
(m, 2H, Ph); 13C NMR (75.6 MHz, CDCl3, APT): d=11.45 (+, CH3),
(ꢀ, Cquat), 126.9 (ꢀ, 2C, Cquat), 130.8 (ꢀ, Cquat), 154.9 (ꢀ, Cquat, NC=O),
172.9 (ꢀ, Cquat, C=O); IR (film): n˜ =2975 (C-H), 2932 (C-H), 2871 (C-H),
1700 (C=O), 1457, 1392, 1367, 1281, 1249, 1151, 1029, 995, 914, 881, 850,
772 cmꢀ1; MS (70 eV): m/z (%): 515 (1) [M +], 459 (1) [M +ꢀC4H8], 402
(2) [M +ꢀC4H8ꢀC4H9], 347 (2), 298 (1), 254 (1), 197 (1), 169 (1), 110 (1),
81 (1), 57 (100) [C4H9+], 41 (24); HRMS: m/z: calcd for C31H49NO5:
515.3611 (correct HRMS).
23.90 (ꢀ, CH2), 24.83 (ꢀ, CH2), 27.98 [+, 3C, C
CO2C
(CH3)3], 31.07 (ꢀ, CH2), 31.21 (ꢀ, CH2), 38.99 (ꢀ, CH2), 40.36 (+,
CH, C-9a), 40.50 (+, CH, C-9b), 41.54 (ꢀ, Cquat, C-6a), 43.18 (+, CH, C-
10), 43.40 (ꢀ, CH2), 48.54 (ꢀ, CH2), 72.24 [ꢀ, Cquat, C(CH3)3], 80.12 (+,
CH, C-7), 80.53 [ꢀ, Cquat, CO2C(CH3)3], 120.45 (+, CH, C-10), 124.35 (ꢀ,
A
AHCTREUNG
AHCTREUNG
AHCTREUNG
(6aS,7S,9aR,10R)-tert-Butyl 2-benzenesulfonyl-7-tert-butoxy-6a-methyl-
2,3,4,5,6,6a,7,8,9,9a,10,11-dodecahydro-1H-indeno[5,4-f]isoquinoline-10-
C
quat), 125.72 (ꢀ, Cquat), 127.70 (+, CH, 2C, Ph), 128.94 (+, CH, 2C, Ph),
H
133.69 (ꢀ, Cquat), 132.84 (+, CH, Ph), 136.06 (ꢀ, Cquat, Ph), 172.44 (ꢀ,
Cquat, C=O); IR (film): n˜ =3070, 3035, 2952 (C-H), 2901, 2883 (C-H),
1729 (C=O), 1672, 1620, 1579, 1564, 1554, 1547, 1461, 1441, 1434, 1394,
carboxylate (cis-7b): According to GP 5, the hexatriene cis-5b (250 mg,
0.450 mmol) was heated in toluene (5.00 mL) at 1708C for 45 min and at
2008C for 1.0 min. Column chromatography (20 g silica gel, pentane/di-
ethyl ether 3:1) afforded the steroid cis-7b as a colorless wax (172 mg,
69%). Rf =0.27; 1H NMR (300 MHz, CDCl3): d=0.86 (s, 3H, CH3), 1.13
1109, 1059, 878, 754 cmꢀ1
; ESI-MS (MeOH): m/z (%): 1128 (100)
[2M+NH4+], 1126 (45), 968 (8), 573 (21), 500 (7); HRMS: m/z: calcd for
C32H45O5NS+NH4+: 573.33557 (correct HRMS).
[s, 9H, C
A
C
(m, 3H), 1.83–2.42 (m, 8H), 2.63–2.76 (m, 2H), 3.24–3.36 (m, 1H), 3.45
General procedure for the deprotection of steroids cis-7a–c (GP 6): In a
Schlenkflasksealed with a septum containing a magnetic stirring bar,
was placed the respective steroid (1.00 equiv) in toluene. The resulting
solution was treated with borontrifluoride etherate (3.00–3.50 equiv) at
08C for 1 h and at 228C for 3 h. When the reaction had ceased, the mix-
ture was poured into methanol/water 5:1 (2 mL), concentrated in vacuo,
and the product purified by column chromatography (CC) on reverse
phase silica gel.
3
(t, J=5.6 Hz, 1H, 7-H), 3.59–3.67 (m, 1H), 3.69–3.79 (m, 1H), 7.46–7.60
(m, 3H, Ph), 7.74–7.82 (m, 2H, Ph); 13C NMR (75.6 MHz, C6D6, addi-
tional APT): d=19.55 (+, CH3), 22.13 (ꢀ, CH2), 24.48 (ꢀ, CH2), 27.93
[+, 3C, C
G
G
CH2), 30.44 (ꢀ, CH2), 33.50 (ꢀ, CH2), 42.20 (ꢀ, Cquat, C-6a), 42.56 (+,
CH, C-10), 43.31 (ꢀ, CH2), 47.20 (+, CH, C-9a), 47.89 (ꢀ, CH2), 72.68
[ꢀ, Cquat, C
122.33 (ꢀ, Cquat), 126.34 (ꢀ, Cquat), 126.43 (ꢀ, Cquat), 127.62 (+, CH, 2C,
Ph), 128.98 (+, CH, 2C, Ph), 131.17 (ꢀ, Cquat), 132.66 (+, CH, Ph),
136.29 (ꢀ, Cquat, Ph), 172.55 (ꢀ, Cquat, C=O); IR (film): n˜ =3078, 3032,
2956 (C-H), 2909, 2884 (C-H), 1734 (C=O), 1669, 1623, 1576, 1559, 1533,
1465, 1437, 1394, 1339, 1103, 1069, 874, 832, 754 cmꢀ1; MS (70 eV): m/z
(%): 555 (14) [M +], 499 (62) [M +ꢀC4H8], 498 (54) [M +ꢀC4H9], 454
(56), 443 (72) [M +ꢀ2”C4H8], 442 (72) [M +ꢀC4H8ꢀC4H9], 424 (28), 398
(18), 358 (61), 349 (9), 302 (79), 256 (24), 209 (26), 169 (11), 141 (9), 77
(21) [Ph+], 57 (100) [C4H9+], 41 (24); HRMS: m/z: calcd for
(ꢀ)-(6aS,9bR,7S,10S)-7-Hydroxy-6a-methyl-2,3,4,5,6,6a,7,8,9,9a,10,11-do-
decahydro-1H-indeno[5,4-f]isoquinoline-10-carboxylic acid (cis-9a): Ac-
A
cording to GP 6, the steroid cis-7a (146 mg, 0.283 mmol) was treated
with borontrifluoride etherate (133 mg, 0.936 mmol) in toluene (5 mL).
CC on reverse phase silica gel (20 g, methanol/H2O 1:1) afforded the free
steroidal amino acid cis-9a as a colorless solid (65.3 mg, 76%). Rf =0.42;
m.p. 186–1888C; [a]2D0 =ꢀ34.3 (c=0.53, MeOH); 1H NMR (300 MHz,
D2O): d=0.98 (s, 3H, CH3), 1.34–1.50 (m, 3H), 1.56–1.71 (m, 1H), 2.04–
2.67 (m, 9H), 3.03–3.11 (m, 1H, 10-H), 3.29–3.51 (m, 2H, 3-H), 3.73 (m,
2H, 1-H), 3.84 (dd, 3J=5.6, 3J=4.4 Hz, 1H, 7-H); 1H NMR (600 MHz,
D2O): d=0.97 (s, 3H, CH3), 1.36–1.46 (m, 3H), 1.59–1.68 (m, 1H), 2.07–
2.16 (m, 1H), 2.19–2.34 (m, 4H), 2.36–2.48 (m, 3H), 2.53–2.63 (m, 1H),
3.02–3.08 (m, 1H, 10-H), 3.30–3.39 (m, 1H, 3-H), 3.42–3.48 (m, 1H, 3-
H), 3.72 (q, 3J=18.7, 2H, 1-H), 3.84 (dd, 3J=5.9, 3J=4.1 Hz, 1H, 7-H);
13C NMR (75.5 MHz, D2O, additional APT): d=18.1 (+, CH3), 21.1 (ꢀ,
CH2), 21.6 (ꢀ, CH2), 29.2 (ꢀ, CH2), 29.5 (ꢀ, CH2), 29.8 (ꢀ, CH2), 31.5
(ꢀ, CH2), 41.6 (ꢀ, CH2), 42.8 (ꢀ, Cquat, C-6a), 44.3 (+, CH, C-9a), 44.7
(ꢀ, CH2, C-1), 46.7 (+, CH, C-10), 80.9 (+, CH, C-7), 118.9 (ꢀ, Cquat),
+
C32H45O5NS+NH4 (573.7): 573.33572 (correct HRMS).
(6aS,7S,9aR,10R)-tert-Butyl
2,3,4,5,6,6a,7,8,9,9a,10,11-dodecahydro-1H-indeno
2-benzyl-7-tert-butoxy-6a-methyl-
[5,4-f]isoquinoline-10-
AHCTREUNG
carboxylate (cis-7c): According to GP 5, the hexatriene cis-5c (400 mg,
0.791 mmol) was heated in toluene (10.0 mL) at 1708C for 45 min and at
2008C for 1 min. Column chromatography (20 g silica gel, pentane/dieth-
yl ether 3:1) afforded the steroid cis-7c as colorless wax (237 mg, 59%).
1
Rf =0.33; H NMR (250 MHz, CDCl3): d=0.91 (s, 3H, CH3), 1.18 [s, 9H,
C
N
N
8342
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8336 – 8344

Steroidal d-Amino Acids
FULL PAPER
125.6 (ꢀ, Cquat), 126.7 (ꢀ, Cquat), 134.0 (ꢀ, Cquat), 181.31 (ꢀ, Cquat, C=O);
IR (film): n˜ =3302 (OH), 3041, 2956 (C-H), 2904, 2861 (C-H), 2529,
2337, 1684 (C=O), 1663, 1646, 1569, 1554, 1521, 1472, 1457, 1382, 1362,
1289, 1146, 1027, 901, 832, 807, 721 cmꢀ1; MS (70 eV): m/z (%): 303 (3)
[M +], 259 (2), 225 (1), 184 (1), 158 (1), 123 (2), 105 (1), 95 (5), 77 (3), 75
(4), 56 (16), 44 (100), 41 (14); ESI-MS (MeOH): m/z (%): 1186 (10), 800
(8), 695 (29), 414 (9), 304 (100) [M+H+], 243 (20); HRMS: m/z: calcd
for C18H25NO3 (303.4): 303.1834 (correct HRMS).
[1] E. Danieli, A. Trabocchi, G. Menchi, A. Guarna, Eur. J. Org. Chem.
2005, 4372–4381.
[2] a) J. Gante, Angew. Chem. 1994, 106, 1780–1802; Angew. Chem. Int.
Ed. Engl. 1994, 33, 1699–1720; b) A. Giannis, T. Kolter, Angew.
Chem. 1993, 105, 1303–1326; Angew. Chem. Int. Ed. Engl. 1993, 32,
1244–1267.
[3] a) A. E. Pojitkov, E. N. Efremenko, S. D. Varfolomeev, J. Mol. Catal.
B 2000, 10, 47–55; b) B. Ayers, U. K. Blaschke, J. A. Camarero, G. J.
Cotton, M. Holford, T. W. Muir, Biopolymers 1999, 51, 343–354.
[4] D. Seebach, Peptides: The Wave of the Future (Eds.: M. Lebl, R. A.
Houghten), American Peptide Society 2001, pp. 569–571.
[5] a) A. Trabocchi, F. Guarna, A. Guarna, Curr. Org. Chem. 2005, 9,
1127–1153; b) H.-D. Arndt, A. Knoll, U. Koert, Angew. Chem.
2001, 113, 2137–2140; Angew. Chem. Int. Ed. 2001, 40, 2076–2078.
[6] a) L. Szabo, B. L. Smith, K. D. McReynolds, A. L. Parill, E. R.
Morris, J. Gervay, J. Org. Chem. 1998, 63, 1074–1078; b) S. Hannes-
sian, X. Luo, R. Schaum, S. Michnick, J. Am. Chem. Soc. 1998, 120,
8569–8570; c) T. Hintermann, K. Gademann, B. Jaun, D. Seebach,
Helv. Chim. Acta 1998, 81, 983–1002; d) C. Baldauf, R. Günther,
H.-J. Hofmann, J. Org. Chem. 2004, 69, 6214–6220; e) M. Kuwa-
hara, M. Arimitsu, M. Sisido, Tetrahedron 1999, 55, 10067–10078.
[7] a) P. v. Zezschwitz, F. Petry, A. de Meijere, Chem. Eur. J. 2001, 7,
4035–4046; b) H. W. Sünnemann, A. de Meijere, Angew. Chem.
2004, 116, 913–915; Angew. Chem. Int. Ed. 2004, 43, 895–897.
[8] The bromoenol triflates were assembled from the N-substituted 4-
piperidones, to the corresponding trimethylsilyl enol ethers via the
a-bromopiperidinones 1a–c using very economical conditions based
on trifluoromethanesulfonic acid anhydride and triethylamine: a) A.
Boumendjel, J. C. Roberts, P. E. Hu, J. Org. Chem. 1996, 61, 4434–
4438; b) J. Castro, I. Collins, M. G. N. Russell, A. P. Watt, B. Sohal,
J. Med. Chem. 1998, 41, 2667–2670; c) W. J. Kerr, M. Mc Laughlin,
A. J. Morrison, P. L. Pauson, Org. Lett. 2001, 3, 2945–2948; d) K. A.
Parker, H. J. Kim, J. Org. Chem. 1992, 57, 752–755; e) K. Ritter,
Synthesis 1993, 735–762.
(+)-(6aS,7S,9aS,10S)-2-Benzenesulfonyl-7-hydroxy-6a-methyl-
2,3,4,5,6,6a,7,8,9,9a,10,11-dodecahydro-1H-indeno[5,4-f]isoquinoline-10-
A
carboxylic acid (cis-9b): According to GP 6, the steroid cis-7b (100 mg,
0.180 mmol) was treated with borontrifluoride etherate (66.4 mg, 75.0 ml,
0.468 mmol) in toluene (4.0 mL). CC (23 g silica gel, CHCl3/EtOAc/
MeOH 10:10:2) afforded the steroidal sulfonamide cis-9b as colorless
solid (68.7 mg, 86%). Rf =0.35; m.p. 197–1988C; [a]2D0 =+8.2 (c=0.45,
MeOH); 1H NMR (300 MHz, CDCl3): d=0.88 (s, 3H, CH3), 1.07–1.22
(m, 2H), 1.30–1.71 (m, 1H), 1.83–2.52 (m, 9H), 2.77 (m, 1H), 2.82–2.93
(m, 1H), 3.32–3.41 (m, 1H), 3.58 (m, 1H), 3.61–3.80 (m, 3H), 5.23 (brs,
1H, 7-OH), 7.40–7.64 (m, 3H, Ph), 7.69–7.84 (m, 2H, Ph), 13C NMR
(75.5 MHz, CDCl3, additional APT): d=17.29 (+, CH3), 22.04 (ꢀ, CH2),
24.66 (ꢀ, CH2), 28.18 (ꢀ, CH2), 28.73 (ꢀ, CH2), 30.44 (ꢀ, CH2), 32.19 (ꢀ,
CH2), 41.47 (+, CH, C-9a), 43.13 (ꢀ, CH2), 43.60 (ꢀ, Cquat, C-6a), 45.93
(+, CH, C-10), 47.69 (ꢀ, CH2, C-1), 81.67 (+, CH, C-7), 122.57 (ꢀ,
Cquat), 126.35 (ꢀ, Cquat), 126.95 (ꢀ, Cquat), 127.60 (+, 2C, CH, Ph), 129.04
(+, 2C, CH, Ph), 129.52 (ꢀ, Cquat), 132.75 (+, CH, Ph), 136.34 (ꢀ, Cquat
,
Ph), 177.56 (ꢀ, Cquat, C=O); IR (film): n˜ =3260 (OH), 3056, 2948 (C-H),
1700 (C=O), 1695, 1646, 1456, 1387, 1362, 1253, 1192, 1034, 993, 911, 882,
848, 773 cmꢀ1; MS (70 eV): m/z (%): 441 (2), 413 (1), 396 (6), 364 (2),
347 (6), 334 (8), 299 (18), 272 (12), 255 (100), 253 (38), 222 (12), 209 (17),
194 (42), 180 (30), 168 (20), 143 (14), 91 (10), 77 (48), 44 (17), 42 (10);
HRMS: m/z: calcd for C24H29O5NS+H+ (444.1): 444.18424 (correct
HRMS).
(ꢀ)-(6aS,7S,9aS,10S)-2-Benzyl-7-hydroxy-6a-methyl-
2,3,4,5,6,6a,7,8,9,9a,10,11-dodecahydro-1H-indeno[5,4-f]isoquinoline-10-
A
carboxylic acid (cis-9c): According to GP 6 the steroid cis-7c (240 mg,
0.475 mmol) was treated with boron trifluoride etherate (177 mg,
0.200 mL, 1.25 mmol) in toluene (10 mL). CC on reverse phase silica
(20 g, methanol/water 1:1) afforded the steroidal amino acid cis-9c as col-
orless solid (148 mg, 79%). Rf =0.35; m.p. 179–1818C; [a]2D0 =ꢀ3.3 (c=
0.86, MeOH); 1H NMR (300 MHz, d4-MeOH): d=0.97 (s, 3H, CH3),
1.28–1.45 (m, 2H), 1.52–1.70 (m, 1H), 1.97–2.49 (m, 9H), 2.52–2.71 (m,
3H), 2.98 (m, 1H), 3.58–3.75 (m, 3H), 4.37 (s, 2H, PhCH2), 7.40–7.61 (m,
5H, Ar); 13C NMR (75.6 MHz, d4-MeOH, additional APT): d=18.47 (+,
CH3), 22.94 (ꢀ, CH2), 23.00 (ꢀ, CH2), 29.08 (ꢀ, CH2), 30.55 (ꢀ, CH2),
31.25 (ꢀ, CH2), 33.00 (ꢀ, CH2), 42.74 (+, CH, C-9a), 44.41 (ꢀ, Cquat, C-
6a), 47.75 (+, CH, C-10), 50.31 (ꢀ, CH2), 53.77 (ꢀ, CH2, C-1), 60.48 (ꢀ,
CH2, PhCH2), 81.68 (+, CH, C-7), 120.37 (ꢀ, Cquat), 127.07 (ꢀ, Cquat),
127.85 (ꢀ, Cquat), 130.43 (+, 2C, CH, Ph), 130.58 (ꢀ, Cquat), 131.25 (+,
[9] The use of different amide bases such as NaHMDS or LiHMDS for
an improved regioselectivity during the enolate formation in a-bro-
mopiperidinone 1b,c led to complete decomposition of the sub-
strates.
[10] CCDC-605599 (2b) contains the supplementary crystallographic
data for compound 2b. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif/
[11] The addition of rate enhancing ligands such as AsPh3 and (2-
furyl)3P in significant amounts to the catalytic cocktail led to an in-
creased formation of side products.
[12] For reviews on the Stille reaction see: a) T. N. Mitchell, in Metal-
CatalyzedCross-Coupling Reactions (Eds.: A. de Meijere, F. Dieder-
ich), Wiley-VCH, Weinheim, 2004, pp. 167–202; b) V. Farina, V.
Krishnamurthy, W. J. Scott, Organic Reactions, Vol. 50 (Ed.: L. A.
Paquette), Wiley, New York, 1997; c) T. N. Mitchell, Synthesis 1992,
803–815; d) M. Kosugi, K. Fugami, in Handbook of Organopalladi-
um Chemistry for Organic Synthesis (Eds.: E. Negishi, A. de Mei-
jere), Wiley, New York, 2002, pp. 263–284.
CH, Ph), 132.24 (+, 2C, CH, Ph), 134.35 (ꢀ, Cquat, Ph), 176.55 (ꢀ, Cquat
,
C=O); IR (film): n˜ =3262 (OH), 3091, 3064, 2952 (C-H), 2926, 2873 (C-
H), 1739, 1701 (C=O), 1653, 1597, 1572, 1495, 1447, 1388, 1370, 1347,
1248, 1205, 1167, 1082, 1048, 981, 960, 924, 891, 845, 790, 747 cmꢀ1; DCI-
MS (NH3): m/z (%): 394 (14) [M+H+], 348 (100), 289 (3), 272 (9), 256
(20), 254 (10), 198 (1), 134 (2), 106 (4), 91 (1) [Bn+]; HRMS: m/z: calcd
for C25H31O3N+H+ (394.5): 394.23674 (correct HRMS).
[13] The palladacycle was prepared from Pd(OAc)2 and (oTol)3P:
N
a) W. A. Herrmann, C. Brossmer, K. Öfele, C.-P. Reisinger, T. Prier-
meier, M. Beller, H. Fischer, Angew. Chem. 1995, 107, 1989–1992;
Angew. Chem. Int. Ed. Engl. 1995, 34, 1844–1848; b) W. A. Herr-
mann, C. Brossmer, K. Öfele, C.-P. Reisinger, T. Priermeier, M.
Beller, Chem. Eur. J. 1997, 3, 1357–1364; for reviews on the applica-
tion of palladacycles in Heckcouplings see: c) J. Dupont, C. S. Con-
sorti, J. Spencer, Chem. Rev. 2005, 105, 2527–2571; d) W. A. Herr-
mann, V. P. W. Bçhm, C.-P. Reisinger, J. Organomet. Chem. 1999,
576, 23–41; e) V. Farina, Adv. Synth. Catal. 2004, 346, 1553–1582.
Acknowledgements
This workwas supported by the State of Niedersachsen as well as the
companies BASF AG, Schering AG and Chemetall GmbH (Chemicals).
H.W.S. is indebted to the German Merit Foundation (Studienstiftung des
Deutschen Volkes) for a graduate student fellowship. The authors are
grateful to Dr. Burkhard Knieriem, Gçttingen, for his careful proof-read-
ing of the final manuscript.
[14] (oTol)3P as co-ligand also allows for a decreased loading of the pre-
A
catalyst necessary for the full consumption of bromobutadienes cis-
4a–c and trans-4b in Heckreactions providing higher yields for hex-
atrienes cis-5a–c and trans-5b at the same time.
Chem. Eur. J. 2006, 12, 8336 – 8344
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8343

A. de Meijere et al.
[15] a) L. Botella, C. Nµjera, Tetrahedron 2004, 60, 5563–5570; b) F.
Ozawa, A. Kubo, T. Hayaschi, Chem. Lett. 1992, 2177–2180; c) S.
Lemaire-Audoire, M. Savignac, C. Dupuis, J.-P. GenÞt, Tetrahedron
Lett. 1996, 37, 2003–2006; d) F. Y. Zhao, M. Shirai, M. Arai, J. Mol.
Catal. A 2000, 154, 39–44; e) L. F. Tietze, T. Nçbel, M. Spescha,
Angew. Chem. 1996, 108, 2385–2386; Angew. Chem. Int. Ed. Engl.
1996, 35, 2259–2261.
[16] a) T. L. Gilchrist, R. J. Summersell, J. Chem. Soc. Perkin Trans. 1
1988, 2595–2601; b) R. von Essen, D. Frank, H. W. Sünnemann, D.
Vidovic, J. Magull, A. de Meijere, Chem. Eur. J. 2005, 11, 6583–
6592.
tons of the methyl group at C13 and the proton at C8 as well as be-
tween the proton at C7 and the proton at C8 were observed.
[20] CCDC-605600 (7b) contains the supplementary crystallographic
data for compound 7b. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif/
[21] a) B. M. Trost, P. G. Mc Dougal, J. Org. Chem. 1984, 49, 458–468;
this rotational selectivity has also been termed torquoselectivity. Cf.
b) E. A. Kallel, Y. Wang, D. C. Spellmeyer, K. N. Houk, J. Am.
Chem. Soc. 1990, 112, 6759–6763; c) J. D. Evanseck, B. E. Thomas
IV, D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1995, 60, 7134–
7141.
[22] J. Castro, I Collins, M. G. N. Russell, A. P. Watt, B. Sohal, J. Med.
Chem. 1998, 41, 2667–2670.
[23] A. Gangjee, E. Elzein, S. F. Queener, J. J. McGuire, J. Med. Chem.
1998, 41, 1409–1416.
[24] A. Boumendjel, J. C. Roberts, P. E. Hu, J. Org. Chem. 1996, 61,
4434–4438.
[17] Another remarkable feature of certain 3-azasteroids is their ability
to act as inhibitors of 5a-reductase which converts testosterone to
5a-dihydrotestosterone in androgen sensitive cells: a) A. J. Robin-
son, I. DeLucca, S. Drummond, G. A. Boswell, Tetrahedron Lett.
2003, 44, 4801–4804; b) G. H. Rasmusson, G. F. Reynolds, T. Utne,
R. B. Jobson, L. Raymond, J. Med. Chem. 1984, 27, 1690–1701.
[18] a) M. Baumgarth, K. Irmscher, Tetrahedron 1975, 31, 3109–3118;
b) M. D. Ferreira, J. I. Fernando, J. I. Moral, S. Arseniyadis, Tetrahe-
dron: Asymmetry 1999, 10, 1527–1537.
1
[19] The structure of the d-amino acid trans-6b was confirmed by H–1H
Received: July 25, 2006
NOESY NMR experiments in which interactions beween the pro-
Published online: September 22, 2006
8344
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8336 – 8344