Diastereoselective synthesis of 2,5-disubstituted decahydroquinolines via ring-rearrangement metathesis and zirconium-mediated cyclization

Article abstract of DOI:10.1055/s-2004-834904

A diastereoselective approach to 2,5-substituted decahydroquinolines by zirconium-mediated cyclization of unsaturated α,α′- disubstituted piperidines II is described. The required piperidines could be obtained from secondary sulfonamides III via ruthenium-catalyzed ring-rearrangement metathesis (RRM) in high yields. Racemic trans-195A and 2-epi-trans-195A were synthesized in 8 steps starting with butyraldehyde and cyclohex-2-enol.

Full text of DOI:10.1055/s-2004-834904

PAPER
3047
Diastereoselective Synthesis of 2,5-Disubstituted Decahydroquinolines via
Ring-Rearrangement Metathesis and Zirconium-Mediated Cyclization
D
iastereos
ü
e
lective Syn
r
thesis of
g
2,5-Disubsti
e
tuted Deca
n
Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany
Fax +49(30)31423619; E-mail: blechert@chem.tu-berlin.de
Received 2 June 2004; revised 3 September 2004
first time to investigate this versatile reaction for annula-
tion of a 6,6-membered decahydroquinoline ring-system I
by conversion of adequate unsaturated a,a¢-disubstituted
piperidines II. The required piperidines II were expected
Abstract: A diastereoselective approach to 2,5-substituted decahy-
droquinolines by zirconium-mediated cyclization of unsaturated
a,a¢-disubstituted piperidines II is described. The required pipe-
ridines could be obtained from secondary sulfonamides III via ru-
thenium-catalyzed ring-rearrangement metathesis (RRM) in high to be accessible through RRM of III. RRM-processes
yields. Racemic trans-195A and 2-epi-trans-195A were synthe-
sized in 8 steps starting with butyraldehyde and cyclohex-2-enol.
have already been proven to be a powerful tool in natural
product synthesis14 and in combination with a Negishi
Key words: metathesis, ruthenium, piperidines, zirconium,
decahydroquinolines
coupling reaction the desired decahydroquinolines I
should readily be obtained in only a few steps.
Negishi
RRM
Decahydroquinolines occur in nature in skin secretions of
dendrobatid and mantelline frogs1 as well as in bufonid
toads,2 ascidians,3,4 marine flatworms4 and myrmicine
ants.5 These relatively untoxic biologically active com-
pounds have marked activity on ion channels.6 They have
proved to be noncompetitive blockers of nicotinic recep-
tor channels and are thus interesting agents for biomedical
research and molecular pharmocology.7 Both cis- and
trans-fused decahydroquinolines have been found since
discovery of the first representative cis-195A, isolated
from skin extracts of the panamanian frog dendrobatus
pumilio in 1968.8,9 Many of these compounds cannot be
obtained from their natural sources in sufficient quantities
for NMR- or X-ray-analysis and their structure and stereo-
chemistry has been only tentatively assigned.9 Synthesis
is needed to confirm their structure by comparison with
the natural material and to obtain these alkaloids, and de-
rivatives thereof, in adequate amounts for biological
screening.10
NR2
R1
N
R1
N
R1
coupling
R2
H
I
II
III
Scheme 1 Retrosynthetic analysis
Me
Me
H
H
N
Pr
N
Pr
H
H
H
H
1
2
Figure 1 Structures of the decahydroquinolines trans-195A15 and
cis-195A
To explore our strategy we started with butyraldehyde as
model compound (Scheme 2) in order to introduce a pro-
pyl chain in 2-position, which can be found in trans-195A
(1) and cis-195A (2) (Figure 1).9 Synthesis of 3 was per-
formed in 84% yield by addition of the allylboron reagent
derived from allylmagnesium bromide and triisopropoxy
borate. The reaction of the homopropargylic alcohol 3
with methanesulfonyl chloride (MsCl) gave mesylate 4 in
80% yield. After treatment with sodium azide (NaN3) 5
could be obtained in 93% yield. Subsequent LiAlH4 re-
duction and in situ protection of the resulting amine with
2-nitrobenzenesulfonyl chloride (NsCl) gave 7 in 78%
over 2 steps. The Ns-group was chosen in order to in-
crease the acidity of the N-H bond, which is advantageous
for subsequent Mitsunobu reaction.16 In addition it pre-
vents adverse interaction of the nitrogen lone pair with the
metathesis-catalyst afterwards. A better result concerning
the overall yield of 7 could be achieved in a two-step syn-
thesis using the method of Fukuyama et al. who recently
reported a concise approach to mono protected primary
amines by conversion of alcohols with N-carboalkoxy-2-
2,5-Disubstituted decahydroquinolines are the major class
with nearly 30 different representatives.11 In our work we
tried to investigate an efficient and concise approach to
these significant alkaloids. We focused on a strategy for
synthesis of the 5-methyl substituted species by means of
ring-rearrangement metathesis (RRM) and Negishi’s zir-
conium-mediated olefin-coupling12 as key steps
(Scheme 1). Application of zirconium-mediated olefin-
coupling to natural product synthesis has been succesfully
established by Mori et al. for annulation of a 5,6-mem-
bered octahydroindole ring-system and subsequent carbo-
nylation within the total synthesis of (–)-Dendrobine.13 To
the best of our knowledge an application to 6,6-membered
rings has never been performed. We have tried now for the
SYNTHESIS 2004, No. 18, pp 3047–3054
x
x.
x
x
.
2
0
0
4
Advanced online publication: 02.11.2004
DOI: 10.1055/s-2004-834904; Art ID: T06004SS
© Georg Thieme Verlag Stuttgart · New York

3048
J. Neidhöfer, S. Blechert
PAPER
nitrobenzenesulfonamides under Mitsunobu conditions
and subsequent chemoselective cleavage either of the car-
bamate or the sulfonamide moiety.17 Transformation of 3
with N-Boc-2-nitrobenzenesulfonamide, diisopropyl dia-
zodicarboxylate (DIAD) and PPh3 in THF yielded 6 in
65% and cleavage of the resulting carbamate was
achieved with 5% TFA in THF to give 7 in 98% yield.
OMs
OH
O
a
b
4 (80%)
3 (84%)
f
c
Boc
Ns
In this context we were next interested in investigating the
possibility of a kinetic resolution or a kinetic transforma-
tion by employing a diastereomeric 1:1 mixture of the
metathesis precursor to the desired RRM-process. Con-
version of 7 with cyclohex-2-enol under Mitsunobu con-
ditions gave 8a and 8b in a 1:1 ratio in 46% yield.
Attempts to synthesize 8a and 8b by replacing the amine
and alcohol functionality, employing cyclohex-2-enyl-2-
nitrobenzenesulfonamide and hept-1-en-3-ol, respective-
ly, under various conditions resulted in no conversion.
Likewise, application of palladium-mediated allylic sub-
stitution, by treatment with cyclohex-2-enyl acetate or
methylcarbonate, respectively, did not succeed. Subse-
quent metathesis was performed in CH2Cl2 under ethylene
atmosphere, using 5 mol% benzylidene-bis(tricyclohexyl-
phosphine)ruthenium dichloride (Grubbs catalyst). The
transformation resulted in complete conversion to the de-
sired tetrahydropyridine derivatives 9a and 9b, which
could be separated by chromatographic purification in an
overall yield of 96%. Employment of ethylene was essen-
tial in this reaction in order to suppress the formation of
dimeric byproducts.18 Contrary to our hopes both diaste-
reomers were converted simultaneously as indicated by
NMR-analysis of the reaction mixture.
N3
N
5 (90%)
6 (65%)
g
d,e
H
Ns
N
7 (d,e: 78%; g: 98%)
j
h
Ns
R2
R1
N
R1
R2
N
dr = 1:1
dr = 1:1
Ns
9a (48%): R1=Pr, R2=H
9b (48%): R1=H, R2=Pr
8ai (23%): R1=Pr, R2=H
8bi (23%): R1=H, R2=Pr
Scheme 2 Synthetic route to the tetrahydropyridines. Reactions and
conditions: (a) AllylMgBr, B(O-i-Pr)3, Et2O; (b) MsCl, Et3N,
CH2Cl2; (c) NaN3, DMSO; (d) LAH, Et2O; (e) NsCl, K2CO3, CH2Cl2;
(f) NsBocNH, DIAD, PPh3, THF; (g) 5% TFA, THF; (h) cyclohex-2-
enol, DIAD, PPh3, THF; (i) isolated as diastereomeric mixture (1:1)
in 46% yield; (j) 5 mol% Grubbs’ catalyst, ethylene, CH2Cl2
Me
H
b, c
R2
R1
R2
R1
N
R3
N
R3
H
11a (74%): R1=Pr, R2=H, R3=Bn
(90%): R1=Pr, R2=H, R3=H
9a:
10a (90%): R1=Pr, R2=H, R3=Bn
R1=Pr, R2=H, R3=Ns
d
e
a
a
1
14 (83%): R1=Pr, R2=H, R3=p-NO2-Bz
11b (69%): R1=H, R2=Pr, R3=Bn
15 (89%): R1=H, R2=Pr, R3=H
9b:
R1=H, R2=Pr, R3=Ns
10b (89%): R1=H, R2=Pr, R3=Bn
d
e
16 (85%): R1=H, R2=Pr, R3=p-NO2-Bz
R2
R2
R1
N
R1
N
Bn
Bn
12a: R1=Pr, R2=H, R3=Bn 13a: R1=Pr, R2=H, R3=Bn
12b: R1=H, R2=Pr, R3=Bn 13b: R1=H, R2=Pr, R3=Bn
Scheme 3 Synthetic route to the decahydroquinolines. Reactions and conditions: (a) PhSH, K2CO3, DMF, BnBr, TBAI; (b) Cp2ZrCl2, BuLi,
THF; ( HCl; (d) H2, Pd/C, MeOH; (e) p-NO2-BzCl, Et3N, CH2Cl2
Synthesis 2004, No. 18, 3047–3054 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of 2,5-Disubstituted Decahydroquinolines
3049
Whereas the cyclization of 9a with BuLi and dicyclopen- compared to 11a. In addition a less polar fraction was iso-
tadienylzirconium dichloride (Cp2ZrCl2) resulted in lated with 25% yield, which could be identified as a 2:1
dimerization by coupling of the aromatic nitro group, cy- mixture of 12b with 13b. Final hydrogenation of 11b gave
clization to the desired decahydroquinolines could be 15 in 89% yield. The configuration of 15 was established
achieved after transformation of sulfonamide 9a into the after transformation to the N-p-nitrobenzoyl derivative 16
N-benzyl derivative 10a (Scheme 3). The deprotection- and subsequent X-ray analysis (Figure 2). We presume
protection sequence was performed with thiophenol that the observed lower rate of cyclization and the in-
(PhSH) and K2CO3 in DMF and subsequent treatment creased amount of isomerized starting material by em-
with benzyl bromide (BnBr) in a one-pot procedure to ploying 10b could be caused by destabilization of the
give 10a in 90% yield. Subsequent zirconium mediated corresponding zirconacycle B due to adverse interaction
coupling afforded only decahydroquinoline 11a along of the propyl group, which is expected to be in unfavored
with isomerized starting material 12a. The ratio of 11a to axial position for 10b and in an equatorial position for 10a
12a was determined to be 7:2 by GC-analysis of the crude with the corresponding zirconacycle A (Figure 3).
product. Compound 11a could be isolated in 74% yield
H
H
and final hydrogenation with 10% palladium on charcoal
in MeOH gave 1 in 88% yield. Whereas determination of
the product configuration was not clear by NMR analysis,
structure of 1 could be established after transformation
into its well crystallizing N-p-nitro-benzoyl derivative 14
and subsequent X-ray analysis (Figure 2). The found con-
figuration was identical to the natural product trans-195A,
isolated from skin extracts of the peruvian frog epipe-
dobates bassleri.9,19
ZrCp2
ZrCp2
N
N
Pr
Bn
Bn
H
H
Pr
A
B
Figure 3 Postulated zirconacycle intermediates
In conclusion, we have presented a concise and highly
diastereoselective approach to trans-fused 2,5-disubstitut-
ed decahydroquinolines. Racemic trans-195A (1) and 2-
epi-trans-195A (15) were synthesized in 8 steps starting
with butyraldehyde and cyclohex-2-enol. Enantioselec-
tive synthesis in order to determine the absolute configu-
ration of trans-195A, which still remains unknown, is
currently under investigation in our laboratory.
1H NMR spectra (500 MHz) and 13C NMR spectra (125 MHz) were
recorded on a Bruker DRX 500 spectrometer using the indicated
solvents. NMR chemical shifts are expressed in ppm upfield, rela-
tive to the internal solvent peak. HRMS were recorded on a Finni-
gan MAT 95 SQ spectrometer. IR spectra were measured on a
Nicolet FT-IR 750 spectrometer. Melting points were determined
on a Leica Galen III heater table microscope and are uncorrected.
Elemental analyses were recorded on an Elementar Vario El Fa.
(Analytik Jena). Analytical TLC was performed on Merck silica gel
60 (0.040–0.063 mm) or Fluka alumina (type H, neutral) and pre-
parative chromatography was performed on ICN silica gel 60
(0.040–0.063 mm) or Fluka alumina (type 5016A basic, Brockmann
activity grade 3) using the indicated solvents. Anhyd Et2O, anhyd
DMSO and all chemicals were purchased from Aldrich and were
used without further purification. THF was freshly distilled under
N2 from sodium/benzophenone and CH2Cl2 was distilled from
CaH2. All reactions were carried out under N2 using flame dried
glassware with the exception of Negishi coupling which was carried
out under Ar. Metathesis reactions were performed in a Braun MB
150B-G glove box under N2.
Figure 2 X-ray structures of 14 and 1620
Taber et al. have shown that cyclozirconations are revers-
ible processes in which the stereochemistry of the prod-
ucts can be influenced by stereogenic centers in the
employed substrate, either through kinetic or thermody-
namic control.21 In our case, we assumed that the stereo-
chemistry of the propyl group of 10a could have a
Hept-1-en-4-ol (3)
A stirred solution of allylmagnesium bromide in hexane (90.0 mL,
1.0 M) was diluted with anhyd Et2O (150 mL) and cooled in an ice
remarkable influence on the high diastereoselectivity ob- bath. Triisopropoxy borate (20.8 mL, 90.0 mmol) was added drop-
wise at 0 °C over 15 min. After stirring for 2 h at r.t. n-butanal (5.41
served within the cyclization to decahydroquinoline 11a.
mL, 60.0 mmol) was added dropwise via a syringe and stirring was
To investigate the effect of a propyl group with contrary
continued for 3 h. An aq solution of NaOH (30 mL, 3 M) was added
and the mixture was refluxed for 3 h. The organic layer was washed
with water (50 mL), brine (50 mL) and dried (MgSO4). The solvent
was removed by distillation over a 10 cm Vigreux column at atmo-
spheric pressure. Fractional distillation of the crude product at re-
stereochemistry we transformed 9b into the correspond-
ing N-benzyl derivative 10b. Surprisingly, cyclization of
10b also resulted in only one diastereomer 11b, which
could be isolated with a negligible lower yield of 69%
Synthesis 2004, No. 18, 3047–3054 © Thieme Stuttgart · New York

3050
J. Neidhöfer, S. Blechert
PAPER
duced pressure yielded 3 (5.76 g, 84%) as colorless liquid; bp 67–
68 °C (24 mbar).
25.0 mmol) over 30 min. After warming to r.t. the mixture was
stirred for 72 h. The solvent was removed in vacuo and the remain-
ing oil was purified by flash chromatography on silica gel (2:1
CH2Cl2–cyclohexane) to give 6 (2.58 g, 65%) as a pale yellow oil;
Rf 0.30.
IR (film): 3453 (m), 2960 (m), 2932 (m), 1710 (s), 1435 (m), 1419
(m), 1362 (s), 1221 (s), 1018 (m), 998 (m), 912 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 5.88–5.76 (m, 1 H), 5.12 (d, J =
15.2 Hz, 1 H), 5.12 (d, J = 11.0 Hz, 1 H), 3.65 (br s, 1 H), 2.33–2.25
(m, 1 H), 2.17–2.08 (m, 1 H), 1.65 (s, 1 H), 1.56–1.40 (m, 3 H),
1.40–1.30 (m, 1 H), 0.92 (t, J = 6.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 135.0 (CH), 118.0 (CH2), 70.5
(CH), 42.0 (CH2), 39.0 (CH2), 18.9 (CH2), 14.1 (CH3).
MS (EI): m/z (%) = 97 (1) [M – OH]+, 73 (72), 71 (11), 55 (100).
HRMS: m/z [M]+ calcd for C7H14O: 114.1044; found: 114.1047.
IR (film): 2978 (w), 2961 (w), 2934 (w), 2874 (w), 1731 (s), 1546
(s), 1368 (s), 1272 (m), 1256 (m), 1178 (m), 1150 (s), 1124 (m), 772
(w), 742 (w), 734 (w), 722 (w) cm–1.
1H NMR (500 MHz, CDCl3): d = 8.34–8.28 (m, 1 H), 7.75–7.67 (m,
3 H), 5.95–5.85 (m, 1 H), 5.12 (d, J = 17.1 Hz, 1 H), 5.09 (d, J =
10.0 Hz, 1 H), 4.31 (quint, J = 7.0 Hz, 1 H), 2.73–2.60 (m, 1 H),
2.62–2.53 (m, 1 H), 1.93–1.84 (m, 1 H), 1.83–1.73 (m, 1 H), 1.53–
1.40 (m, 2 H), 1.38 (s, 9 H), 0.94 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 150.6 (Cq), 148.0 (Cq), 135.7
(CH), 134.3 (Cq), 133.8 (CH), 132.9 (CH), 131.6 (CH), 124.3 (CH),
117.7 (CH2), 84.8 (Cq), 60.0 (CH), 38.8 (CH2), 35.9 (CH2), 28.0
(CH), 20.4 (CH2), 14.2 (CH3).
MS (EI): m/z (%) = 325 (1) [M – C4H9O]+, 278 (9), 277 (24), 258
(26), 257 (100), 255 (10), 187 (10), 186 (88), 97 (12), 77 (8), 57
(96), 55 (18).
Methanesulfonic Acid 1-Propyl-but-3-enyl Ester (4)
To an ice-cold stirred solution of 3 (9.50 g, 83.2 mmol) and Et3N
(17.4 mL, 125 mmol) in CH2Cl2 (60 mL) was added dropwise MsCl
(7.73 mL, 99.8 mmol) over 15 min. The resulting mixture was al-
lowed to warm to r.t. and stirred for 3 h. After diluting with CH2Cl2
(400 mL) the reaction mixture was washed with H2O (3 × 100 mL),
brine (100 mL) and dried (MgSO4). The solvent was removed in
vacuo and the crude product was purified by flash chromatography
on silica gel (cyclohexane–MTBE, 3:1) to give 4 (12.8 g, 80%) as
pale yellow oil; Rf 0.40.
HRMS: m/z [M – C4H9O]+ calcd for C14H17N2O5S: 325.0858;
found: 325.0851.
Anal Calcd for C18H26N2O6S: C, 54.26; H, 6.58; N, 7.03. Found: C,
54.28; H, 6.54; N, 7.16.
IR (film): 2960 (m), 2925 (m), 2875 (w), 2850 (w), 1355 (m), 1336
(m), 1175 (s), 972 (w), 913 (s), 802 (w) cm–1.
2-Nitro-N-(1-propyl-3-en-1-yl)-benzenesulfonamide (7)
1H NMR (500 MHz, CDCl3): d = 5.87–5.78 (m, 1 H), 5.12 (d, J =
16.5 Hz, 1 H), 5.11 (d, J = 10.6 Hz, 1 H), 4.73 (quint, J = 6.0 Hz, 1
H), 2.98 (s, 3 H), 2.52–2.41 (m, 2 H), 1.73–1.59 (m, 2 H), 1.53–1.32
(m, 2 H), 0.92 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 132.6 (CH), 119.0 (CH2), 82.7
(CH), 39.2 (CH2), 38.8 (CH3), 36.3 (CH2), 18.4 (CH2), 13.8 (CH3).
MS (EI): m/z (%) = 191 (1) [M – 1]+, 151 (33), 105 (22), 97 (13), 96
(26), 81 (22), 79 (18), 67 (22), 55 (100), 54 (34).
HRMS: m/z [M – C3H5]+ calcd for C5H11O3S: 151.0429; found:
151.0421
From 5: To an ice-cold stirred suspension of LiAlH4 (4.68 g, 123
mmol) in Et2O (60 mL) was added dropwise 5 (8.58 g, 61.6 mmol)
in Et2O (60 mL) over 30 min. The mixture was allowed to warm to
r.t. and stirred for 3 h. After dropwise addition of NaOH (30 mL, 2.5
M) at 0 °C the resulting suspension was vigorously stirred at r.t. for
30 min. The solvent was decanted off, the remaining solid was
washed with Et2O (5 × 50 mL) and the combined extracts were
dried (MgSO4). The solvent was removed by distillation over a 10
cm Vigreux column at atmospheric pressure and the remaining liq-
uid was diluted with CH2Cl2 (40 mL). After addition of K2CO3 (17.4
g, 123 mmol) the mixture was cooled to 0 °C and NsCl (16.4 g, 74.0
mmol) was added portionwise over 15 min. The ice bath was re-
moved and the suspension was stirred at r.t. for 24 h. After diluting
with CH2Cl2 (500 mL) the mixture was washed with H2O (100 mL),
brine (100 mL) and dried (MgSO4). The solvent was evaporated and
the crude product was purified by flash chromatography on silica
gel (CH2Cl2–cyclohexane, 3:1) to give 7 (14.4 g, 78%) as pale yel-
low solid; Rf 0.38, mp 30–32 °C.
4-Azido-hept-1-ene (5)
To a stirred solution of 4 (12.8 g, 66.4 mmol) in DMSO (70 mL) at
r.t. was added NaN3 (8.68 g, 134 mmol) and the resulting suspen-
sion was stirred at 50 °C for 24 h. After cooling to r.t. and diluting
with Et2O (500 mL) the mixture was washed with H2O (3 × 100
mL), brine (100 mL) and dried (MgSO4). The solvent was removed
by distillation over a 10 cm Vigreux column at atmospheric pres-
sure to give 5 (8.58 g, 93%) as a yellowish oil, which was spectro-
scopically pure and subsequently used without further purification.
From 6: To an ice-cold stirred solution of 6 (2.00 g, 5.02 mmol) in
THF (500 mL) was added dropwise TFA (25.0 mL, 324 mmol) over
10 min. The mixture was allowed to warm to r.t., stirred for 1 h and
cooled to 0 °C. Aq sat. NaHCO3 (350 mL) was added until the aque-
ous phase showed pH 8. After separation of the organic layer, the
aqueous layer was extracted with CH2Cl2 (3 × 300 mL) and the
combined organic layers were dried (MgSO4). The solvent was re-
moved in vacuo and the remaining solid was purified by flash chro-
matography on silica gel (CH2Cl2–cyclohexane, 3:1) to give 7 as
pale yellow solid (1.47 g, 98%); Rf 0.38; mp 30–32 °C.
IR (film): 3081 (w), 2960 (s), 2935 (s), 2875 (m), 2100 (ss), 1340
(m), 1258 (s), 993 (m), 918 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 5.90–5.79 (m, 1 H), 5.15 (d, J =
16.5 Hz, 1 H), 5.12 (d, J = 9.8 Hz, 1 H), 3.34 (quint, J = 6.3 Hz, 1
H), 2.30 (t, J = 6.3 Hz, 2 H), 1.56–1.44 (m, 3 H), 1.44–1.33 (m, 1
H), 0.94 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 134.1 (CH), 118.1 (CH2), 62.1
(CH), 38.9 (CH2), 36.1 (CH2), 19.4 (CH2), 13.9 (CH3).
MS (EI): m/z (%) = 110 (1) [M – C2H5]+, 98 (12), 97 (10), 96 (8), 83
(12), 82 (12), 70 (24), 68 (26), 55 (100).
IR (film): 3338 (m), 3098 (w), 3077 (w), 2959 (m), 2931 (m), 2873
(m), 1539 (s), 1442 (m), 1413 (m), 1360 (s), 1168 (s), 1124 (m), 854
(m), 783 (m), 742 (m), 730 (m), 655 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 8.17–8.10 (m, 1 H), 7.89–7.83 (m,
1 H), 7.77–7.69 (m, 2 H), 5.63–5.53 (m, 1 H), 5.19 (d, J = 7.9 Hz, 1
H, NH), 4.93 (d, J = 16.0 Hz, 1 H), 4.93 (d, J = 11.0 Hz, 1 H), 3.58–
3.49 (m, 1 H), 2.25–2.13 (m, 2 H), 1.52–1.39 (m, 2 H), 1.39–1.29
(m, 1 H), 1.29–1.18 (m, 1 H), 0.82 (t, J = 7.2 Hz, 3 H).
HRMS: m/z [M]+ calcd for C7H13N3: 139.1109; found: 139.1124.
N-Boc-2-nitro-N-(1-propyl-but-3-enyl)-benzenesulfonamide (6)
To an ice-cold stirred solution of 3 (1.14 g, 10.0 mmol), PPh3 (7.86
g, 30.0 mmol) and N-Boc-2-nitrobenzene-sulfonamide17 (7.56 g,
25.0 mmol) in THF (30 mL) was added dropwise DIAD (4.92 mL,
Synthesis 2004, No. 18, 3047–3054 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of 2,5-Disubstituted Decahydroquinolines
3051
13C NMR (125 MHz, CDCl3): d = 147.8 (Cq), 135.4 (Cq), 133.3
(CH), 133.1 (CH), 132.9 (CH), 130.5 (CH), 125.4 (CH), 118.8
(CH2), 54.8 (CH), 39.6 (CH2), 37.0 (CH2), 18.7 (CH2), 13.8 (CH3).
MS (EI): m/z (%) = 259 (60) [M – C3H7]+, 258 (8), 257 (60), 188
(6), 187 (8), 186 (100), 92 (8).
HRMS: m/z [M – C3H5]+ calcd for C10H13N2O4S: 257.0596; found:
257.0592.
5.02 (dd, J = 17.1, 1.7 Hz, 1 H), 4.96 (dd, J = 10.1, 0.9 Hz, 1 H),
4.32–4.23 (m, 1 H), 4.06–3.97 (m, 1 H), 2.15–2.04 (m, 2 H), 2.02–
1.92 (m, 1 H), 1.89–1.79 (m, 2 H), 1.73–1.35 (m, 7 H), 0.92 (t, J =
7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 148.3 (Cq), 138.5 (CH), 134.2
(Cq), 133.2 (CH), 131.5 (CH), 130.4 (CH), 126.0 (CH), 124.1 (CH),
122.1 (CH), 114.9 (CH2), 54.1 (CH), 50.9 (CH), 37.3 (CH2), 37.2
(CH2), 33.6 (CH2), 27.1 (CH2), 26.2 (CH2), 20.1 (CH2), 13.8 (CH3).
Anal. Calcd for C13H18N2O4S: C, 52.33; H, 6.08; N, 9.38. Found: C,
52.47; H, 6.11; N, 9.24.
MS (EI): m/z (%) = 337 (3) [M – C3H7]+, 310 (14), 309 (100), 186
(56), 94 (14), 80 (23).
N-Cyclohex-2-enyl-2-nitro-N-(1-propyl-but-3-enyl)-benzene-
sulfonamide (8a with 8b)
HRMS: m/z [M – C3H5]+ calcd for C16H21N2O4S: 378.1613; found:
378.1622.
DIAD (3.41 mL, 17.3 mmol) was added dropwise over 15 min to an
ice-cold stirred solution of 7 (3.97 g, 13.3 mmol), PPh3 (5.24 g, 20.0
mmol) and cyclohex-2-en-1-ol (1.70 mL, 17.3 mmol) in THF (60
mL). The mixture was stirred at r.t. for 72 h and the solvent was re-
moved in vacuo. Flash chromatography of the remaining oil on sil-
ica gel (CH2Cl2–cyclohexane, 3:2) yielded a 1:1 diastereomeric
mixture of 8a with 8b (2.30 g, 46%) as a pale yellow oil; Rf 0.24.
Anal. Calcd for C19H26N2O4S: C, 60.30; H, 6.92; N, 7.40. Found: C,
60.09; H, 6.91; N, 7.39.
9b
Yellowish oil; Rf 0.34.
IR (film): 3077 (w), 3034 (w), 2960 (m), 2933 (m), 2872 (m), 1544
(s), 1372 (s), 1342 (s), 1335 (s), 1161 (s), 1123 (m), 852 (m), 778
(m), 743 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 8.09–7.99 (m, 1 H), 7.69–7.60 (m,
3 H), 5.75–5.68 (m, 1 H), 5.68–5.63 (m, 1 H), 5.63–5.54 (m, 1 H),
4.86 (d, J = 9.5 Hz, 1 H), 4.85 (d, J = 17.5 Hz, 1 H), 4.36 (br s, 1 H),
3.92–3.84 (m, 1 H), 2.35–2.25 (m, 1 H), 2.20–2.11 (m, 1 H), 1.90–
1.68 (m, 4 H), 1.66–1.56 (m, 1 H), 1.55–1.45 (m, 1 H), 1.41–1.23
(m, 3 H), 1.23–1.11 (m, 1 H), 4.85 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 147.9 (Cq), 138.2 (CH), 136.5
(Cq), 133.2 (CH), 131.7 (CH), 130.5 (CH), 128.2 (CH), 124.4 (CH),
124.2 (CH), 114.8 (CH2), 55.7 (CH), 55.4 (CH), 34.9 (CH2), 33.5
(CH2), 33.1 (CH2), 28.7 (CH2), 24.2 (CH2), 20.5 (CH2), 14.0 (CH3).
IR (film): 3076 (w), 3031 (w), 2958 (m), 2934 (m), 2839 (w), 1545
(s), 1373 (m), 1347 (m), 1164 (m), 1141 (m), 1126 (m), 852 (w),
772 (w), 741 (w), 728 (w) cm–1.
1H NMR (500 MHz, CDCl3): d = 8.09–8.02 (m, 2 H), 7.69–7.60 (m,
4 H), 7.56–7.47 (m, 2 H), 5.88–5.79 (m, 2 H), 5.77–5.63 (m, 2 H),
5.55 (d, J = 10.0 Hz, 2 H), 5.05 (d, J = 17.0 Hz, 1 H), 4.99 (d, J =
8.0 Hz, 1 H), 4.98 (d, J = 17.5 Hz, 1 H), 4.95 (d, J = 9.9 Hz, 1 H),
4.38 (br s, 1 H), 4.27 (br s, 1 H), 3.55 (bs, 1 H), 3.44 (br s, 1 H),
2.57–2.44 (m, 3 H), 2.43–2.34 (m, 1 H), 2.10–1.80 (m, 10 H), 1.78–
1.55 (m, 6 H), 1.41–1.18 (m, 4 H), 0.86 (t, J = 7.3 Hz, 3 H), 0.76 (t,
J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 148.7 (Cq), 148.6 (Cq), 135.8
(CH), 135.2 (Cq), 134.9 (Cq), 133.3 (CH), 133.3 (CH), 131.3 (CH),
131.2 (CH), 130.9 (CH), 130.8 (CH), 128.9 (CH), 128.7 (CH),
123.8 (CH), 123.6 (CH), 117.3 (CH2), 117.2 (CH2), 59.1 (CH), 58.9
(CH), 56.4 (CH), 55.9 (CH), 39.5 (CH2), 35.9 (CH2), 29.8 (CH2),
29.8 (CH2), 24.5 (CH2), 24.5 (CH2), 22.5 (CH2), 22.4 (CH2), 20.6
(CH2), 20.5 (CH2), 14.0 (CH3), 13.9 (CH3).
MS (EI): m/z (%) = 335 (13) [M – C3H7]+, 310 (14), 309 (100), 257
(14), 186 (40), 81 (16), 55 (8).
HRMS: m/z [M]+ calcd for C19H26N2O4S: 378.1613; found:
378.1627.
Anal. Calcd for C19H26N2O4S: C, 60.30; H, 6.92; N, 7.40. Found: C,
60.22; H, 6.88; N, 7.46.
MS (EI): m/z (%) = 337 (8) [M – C3H5]+, 257 (83), 186 (65), 81
(100), 79 (13), 55 (15).
HRMS: m/z [M – C3H5]+ calcd for C16H21N2O4S: 337.1222; found:
(rac)-(2R,6S)-1-Benzyl-6-pent-4-enyl-2-propyl-1,2,3,6-tetrahy-
dropyridine (10a)
To a stirred solution of 9a (2.88 g, 7.61 mmol) and K2CO3 (8.41 g,
60.9 mmol) in DMF (65 mL) at 80 °C was added dropwise PhSH
(0.86 mL, 8.37 mmol). The mixture was stirred at 80 °C for 2 h be-
fore TBAI (140 mg, 0.38 mmol) was added. To this solution was
added dropwise BnBr (4.51 mL, 38.0 mmol) and the resulting bright
yellow mixture was stirred for 1 h at 80 °C. After cooling to r.t. it
was diluted with MTBE (800 mL) and extracted with H2O (500
mL). The aq layer was extracted with MTBE (2 × 200 mL) and the
combined organic layers were washed with brine (200 mL). After
evaporation of the solvent the residue was dissolved in cyclohexane
(50 mL) and extracted with aq HCl (3 × 50 mL, 1 M). To the com-
bined aq layers was added MTBE (50 mL) and the mixture was sat-
urated with K2CO3 under vigorously stirring. After separation of the
organic layer, the aq layer was extracted with MTBE (2 × 50 mL)
and the combined organic layers were dried (MgSO4). Evaporation
of the solvent and flash chromatographic purification of the crude
product on alumina (cyclohexane–CH2Cl2, 10:1) gave 10a (1.94 g,
90%) as colorless oil.
337.1226.
Anal. Calcd for C19H26N2O4S: C, 60.30; H, 6.92; N, 7.40. Found: C,
60.16; H, 6.91; N, 7.41.
(rac)-(2R,6S)-1-(2-Nitro-benzenesulfonyl)-6-pent-4-enyl-2-pro-
pyl-1,2,3,6-tetrahydropyridine (9a) and (rac)-(2S,6S)-1-(2-Ni-
tro-benzenesulfonyl)-6-pent-4-enyl-2-propyl-1,2,3,6-tetra-
hydropyridine (9b)
To a stirred solution of 8a and 8b (575 mg, 1.52 mmol) in CH2Cl2
(75 mL) at r.t. was added Grubbs catalyst (63.0 mg, 0.08 mmol).
The mixture was saturated with ethylene via a syringe and stirred
for 24 h under ethylene atmosphere at 50 °C in a sealed vial. After
evaporation of the solvent and flash chromatography on silica gel
(MTBE–cyclohexane, 1:3) 9a (274 mg, 48%) and 9b (276 mg,
48%) were obtained.
9a
Pale yellow solid; mp 67–68 °C; Rf 0.27.
IR (film): 3075 (w), 3063 (w), 3024 (m), 2956 (s), 2929 (ss), 2861
(m), 2836 (m), 1640 (w), 1494 (m), 1453 (m), 909 (m), 728 (m), 697
(s) cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38 (d, J = 7.4 Hz, 2 H), 7.29 (t,
J = 7.4 Hz, 2 H), 7.20 (t, J = 7.4 Hz, 1 H), 5.80–5.61 (m, 3 H), 4.93
(dd, J = 17.3, 1.7 Hz, 1 H), 4.89 (dd, J = 11.2, 0.8 Hz, 1 H), 3.73 (d,
IR (film): 3076 (w), 3040 (w), 2957 (m), 2933 (m), 2872 (m), 1544
(s), 1373 (s), 1347 (s), 1174 (s), 1139 (m), 1126 (m), 852 (m), 776
(m), 750 (m), 744 (m), 730 (m), 711 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 7.97–7.89 (m, 1 H), 7.68–7.60 (m,
2 H), 7.60–7.53 (m, 1 H), 5.86–5.73 (m, 2 H), 5.68–5.60 (m, 1 H),
Synthesis 2004, No. 18, 3047–3054 © Thieme Stuttgart · New York

3052
J. Neidhöfer, S. Blechert
PAPER
J = 14.7 Hz, 1 H), 3.71 (d, J = 14.7 Hz, 1 H), 3.11–3.03 (m, 1 H),
2.83–2.75 (m, 1 H), 2.28–2.19 (m, 1 H), 1.95–1.87 (m, 2 H), 1.84–
1.76 (m, 1 H), 1.63–1.47 (m, 3 H), 1.47–1.22 (m, 5 H), 0.82 (t, J =
7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 142.0 (Cq), 139.1 (CH), 129.5
(CH), 128.5 (CH), 128.0 (CH), 126.4 (CH), 123.9 (CH), 114.2
(CH2), 59.6 (CH), 56.9 (CH2), 56.2 (CH), 37.0 (CH2), 34.8 (CH2),
33.9 (CH2), 26.3 (CH2), 26.1 (CH2), 20.2 (CH2), 14.3 (CH3).
MS (EI): m/z (%) = 283 (1) [M]+, 240 (15), 215 (12), 214 (100), 91
(66).
HRMS: m/z [M]+ calcd for C20H29N: 283.2300; found: 283.2301.
1H NMR (500 MHz, CDCl3): d = 7.39 (d, J = 7.4 Hz, 2 H), 7.27 (t,
J = 7.4 Hz, 2 H), 7.17 (t, J = 7.4 Hz, 1 H), 3.75 (d, J = 17.1 Hz, 1
H), 3.67 (d, J = 17.1 Hz, 1 H), 2.55–2.47 (m, 1 H), 2.29–2.23 (m, 1
H), 2.05–1.96 (m, 1 H), 1.79–1.70 (m, 1 H), 1.70–1.58 (m, 2 H),
1.58–1.48 (m, 1 H), 1.48–1.43 (m, 1 H), 1.38–1.15 (m, 5 H), 1.10–
0.90 (m, 5 H), 0.90 (d, J = 6.4 Hz, 3 H), 0.79 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 144.2 (Cq), 127.9 (CH), 127.5
(CH), 125.8 (CH), 68.3 (CH), 63.3 (CH), 51.3 (CH2), 44.1 (CH),
37.8 (CH2), 37.3 (CH), 35.6 (CH2), 32.9 (CH2), 29.5 (CH2), 28.8
(CH2), 25.4 (CH2), 19.8 (CH2), 19.6 (CH3), 14.4 (CH3).
MS (EI): m/z (%) = 285 (3) [M]+, 243 (16), 242 (100), 91 (25).
HRMS: m/z [M]+ calcd for C20H31N: 285.2456; found: 285.2455.
Anal. Calcd for C20H29N: C, 84.75; H, 10.31; N, 4.94. Found: C,
84.35; H, 9.93; N, 5.02.
Anal. Calcd for C20H31N: C, 84.15; H, 10.95; N, 4.91. Found: C,
84.15; H, 10.86; N, 4.91.
(rac)-(2S,6S)-1-Benzyl-6-pent-4-enyl-2-propyl-1,2,3,6-tetrahy-
dropyridine (10b)
The preparation of 10b was similar to the procedure described for
10a. After conversion of 9b (3.75 g, 9.91 mmol) and chromato-
graphic purification of the crude product on alumina (cyclohexane–
CH2Cl2, 10:1) 10b (2.50 g, 89%) was isolated as a colorless oil.
12a
Apolar fraction; pale yellow oil.
IR (film): 3085 (w), 3062 (w), 3024 (m), 2957 (ss), 2930 (ss), 2871
(m), 2861 (m), 1494 (m), 1453 (m), 965 (m), 728 (m), 697 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38 (d, J = 7.4 Hz, 2 H), 7.29 (t,
J = 7.4 Hz, 2 H), 7.21 (t, J = 7.4 Hz, 1 H), 5.80–5.73 (m, 1 H), 5.70–
5.63 (m, 1 H), 5.43–5.24 (m, 2 H), 3.76 (d, J = 14.7 Hz, 1 H), 3.71
(d, J = 14.7 Hz, 1 H), 3.10–3.03 (m, 1 H), 2.84–2.75 (m, 1 H), 2.30–
2.19 (m, 1 H), 2.05–1.94 (m, 2 H), 1.84–1.75 (m, 1 H), 1.65–1.52
(m, 1 H), 1.59 (d, J = 4.6 Hz, 3 H), 1.40–1.20 (m, 5 H), 0.82 (t, J =
7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 141.9 (Cq), 131.5 (CH), 129.4
(CH), 128.5 (CH), 128.0 (CH), 126.5 (CH), 124.8 (CH), 123.8
(CH), 59.0 (CH), 57.2 (CH2), 55.8 (CH), 37.0 (CH2), 35.2 (CH2),
29.8 (CH2), 22.6 (CH2), 20.2 (CH2), 18.0 (CH3), 14.3 (CH3).
IR (film): 3074 (w), 3063 (w), 3022 (m), 2655 (s), 2930 (ss), 2871
(m), 2860 (m), 2832 (m), 2804 (w), 1640 (m), 1494 (m), 1466 (m),
1454 (m), 908 (s), 739 (m), 729 (m), 697 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38 (d, J = 7.4 Hz, 2 H), 7.30 (t,
J = 7.4 Hz, 2 H), 7.23 (t, J = 7.4 Hz, 1 H), 5.85–5.79 (m, 1 H), 5.78–
5.67 (m, 1 H), 5.62–5.51 (m, 1 H), 4.91 (d, J = 17.3 Hz, 1 H), 4.89
(d, J = 9.9 Hz, 1 H), 3.78 (d, J = 13.7 Hz, 1 H), 3.34 (d, J = 13.7 Hz,
1 H), 3.07–2.99 (m, 1 H), 2.87 (br s, 1 H), 2.01–1.92 (m, 1 H), 1.90–
1.81 (m, 3 H), 1.65–1.30 (m, 7 H), 1.30–1.17 (m, 1 H), 0.95 (t, J =
7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 141.3 (Cq), 139.3 (CH), 129.8
(CH), 129.0 (CH), 128.0 (CH), 126.5 (CH), 125.5 (CH), 114.1
(CH2), 56.7 (CH), 50.6 (CH), 49.6 (CH2), 34.8 (CH2), 33.7 (CH2),
33.4 (CH2), 27.0 (CH2), 25.6 (CH2), 19.8 (CH2), 14.3 (CH3).
MS (EI): m/z (%) = 283 (1) [M]+, 240 (14), 215 (16), 214 (100), 91
(62).
HRMS: m/z [M]+ calcd for C20H29N: 283.2300; found: 283.2304.
MS (EI): m/z (%) = 283 (4) [M]+, 240 (20), 215 (16), 214 (100), 91
(57).
HRMS: m/z [M]+ calcd for C20H29N: 283.2300; found: 283.2306.
(rac)-(2S,4aS,5R,8aS)-1-Benzyl-5-methyl-2-propyl-decahydro-
quinoline (11b)
The preparation of 11b was similar to the procedure described for
11a. Conversion of 10b (500 mg, 1.76 mmol) and chromatographic
purification of the crude product on alumina (cyclohexane–CH2Cl2,
20:1) gave 11b (347 mg, 69%) as colorless oil and an inseparable
mixture of 12a with 13a (124 mg, 25%). Polar fraction (11b); apolar
fraction (12a with 13a).
Anal. Calcd for C20H29N: C, 84.75; H, 10.31; N, 4.94. Found: C,
84.84; H, 10.32; N, 4.90.
(rac)-(2R,4aS,5R,8aS)-1-Benzyl-5-methyl-2-propyl-decahydro-
quinoline (11a)
BuLi (6.17 mL, 1.6 M in hexane) was added dropwise over 10 min
to a stirred solution of Cp2ZrCl2 (1.44 g, 4.94 mmol) in THF (150
mL) at –78 °C and the mixture was stirred for 30 min. Compound
10a (1.40 g, 4.94 mmol) in THF (50 mL) was added dropwise over
15 min and stirring was continued for 1 h. The cooling bath was re-
moved and the yellow solution was allowed to warm to r.t. and
stirred for 5 h. The resulting clear bright orange solution was
quenched dropwise with aq HCl (50 mL, 1 M) and stirred for 30
min. The aqueous layer was basified and saturated with K2CO3 un-
der vigorously stirring. The organic layer was separated and the
aqueous layer was extracted with MTBE (3 × 100 mL). The com-
bined organic layers were washed with brine (50 mL) and dried
(MgSO4). Evaporation of the solvent and chromatographic purifica-
tion of the crude product on alumina (cyclohexane–CH2Cl2, 20:1)
yielded 11a (1.04 g, 74%) and 12a (279 mg, 20%).
11b
IR (film): 3084 (w), 3062 (w), 3025 (w), 2951 (s), 2926 (ss), 2868
(s), 2857 (s), 2801 (w), 2728 (w), 1493 (m), 1452 (s), 1374 (m),
1356 (m), 1161 (m), 1147 (m), 1139 (m), 1086 (m), 1072 (m), 1027
(m), 730 (s), 697 (s) cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36 (d, J = 7.4 Hz, 2 H), 7.28 (t,
J = 7.4 Hz, 2 H), 7.18 (t, J = 7.4 Hz, 1 H), 3.77 (d, J = 14.7 Hz, 1
H), 3.73 (d, J = 14.7 Hz, 1 H), 2.66–2.59 (m, 1 H), 2.62–2.48 (m, 1
H), 1.88–1.76 (m, 2 H), 1.75–1.67 (m, 2 H), 1.64–1.55 (m, 2 H),
1.45–1.28 (m, 3 H), 1.28–1.03 (m, 5 H), 1.03–0.91 (m, 2 H), 0.88
(d, J = 6.4 Hz, 3 H), 0.83 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 142.9 (Cq), 128.2 (CH), 128.0
(CH), 126.2 (CH), 58.5 (CH), 56.1 (CH), 52.7 (CH2), 44.6 (CH),
37.4 (CH), 35.7 (CH2), 32.0 (CH2), 29.6 (CH2), 25.7 (CH2), 24.8
(CH2), 24.6 (CH2), 20.4 (CH2), 19.5 (CH3), 14.4 (CH2).
MS (EI): m/z (%) = 285 (3) [M]+, 243 (16), 242 (100), 91 (25).
HRMS: m/z [M]+ calcd for C20H31N: 285.2456; found: 285.2456.
11a
Polar fraction; colorless solid; mp 29–30 °C.
IR (film): 3084 (w), 3061 (w), 3025 (w), 2954 (s), 2926 (ss), 2859
(s), 1493 (w), 1452 (m), 1440 (w), 1356 (w), 951 (w), 727 (m), 696
(m) cm–1.
Anal. Calcd for C20H31N: C, 84.15; H, 10.95; N, 4.91. Found: C,
83.99; H, 10.73; N, 4.98.
Synthesis 2004, No. 18, 3047–3054 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of 2,5-Disubstituted Decahydroquinolines
3053
12a with 13a
Anal. Calcd for C13H25N: C, 79.93; H, 12.90; N, 7.17. Found: C,
79.57; H, 12.79; N, 7.05.
13C NMR (125 MHz, CDCl3): d = 141.3 (Cq), 141.3 (Cq), 133.0
(CH), 131.1 (CH), 129.7 (CH), 129.4 (CH), 129.1 (CH), 129.0
(CH), 128.7 (CH), 128.0 (CH), 127.2 (CH), 126.5 (CH), 125.7
(CH), 125.6 (CH), 124.5 (CH), 105.4 (CH2), 57.8 (CH), 56.5 (CH),
50.8 (CH), 50.7 (CH), 49.7 (CH2), 49.6 (CH2), 37.6 (CH2), 35.1
(CH2), 34.7 (CH2), 34.5 (CH2), 29.5 (CH2), 27.1 (CH2), 25.7 (CH2),
19.9 (CH2), 19.8 (CH2), 18.0 (CH3, CH), 14.3 (CH3), 14.3 (CH),
13.8 (CH), 12.8 (CH3).
(rac)-[(2R,4aS,5R,8aS)-5-Methyl-2-propyl-octahydroquinoline-
1-yl]-(4-nitro-phenyl)-methanone (14)
p-Nitrobenzoyl chloride (114 mg, 614 mmol) was added to an ice-
cold stirred suspension of 1 (100 mg, 512 mmol) and Et3N (340 mL,
2.56 mmol) in CH2Cl2 (3 mL). The mixture was allowed to warm to
r.t. and stirred for 3 h. After diluting with MTBE (50 mL) the mix-
ture was washed with H2O (2 × 10 mL), brine (10 mL) and dried
(MgSO4). Evaporation of the solvent and flash chromatographic pu-
rification of the crude product on silica gel (EtOAc–cyclohexane,
1:4) afforded 14 (146 mg, 83%) as a pale yellow solid; Rf 0.26; mp
134–136 °C (after recrystallization from Et2O).
MS (EI): m/z (%) = 283 (4) [M]+, 240 (16), 238 (5), 215 (17), 214
(100), 91 (48).
HRMS: m/z [M]+ calcd for C20H29N: 283.2300; found: 283.2302.
(rac)-(2R,4aS,5R,8aS)-5-Methyl-2-propyl-decahydroquinoline
(1)
IR (film): 3104 (w), 3077 (w), 2954 (m), 2930 (m), 2870 (m), 1626
(ss), 1600 (m), 1522 (s), 1423 (m), 1346 (s), 862 (m), 851 (m), 705
(m) cm–1.
1H NMR (500 MHz, C6D6): d = 7.73 (d, J = 8.5 Hz, 2 H), 6.94 (d,
J = 8.5 Hz, 2 H), 3.83–3.72 (m, 1 H), 3.37 (br s, 1 H), 2.58 (br s, 1
H), 1.66–1.57 (m, 3 H), 1.55–1.40 (m, 3 H), 1.42–0.98 (m, 6 H),
0.92–0.73 (m, 3 H), 0.77 (d, J = 6.4 Hz, 3 H), 0.68 (t, J = 7.1 Hz, 3
H).
13C NMR (125 MHz, CDCl3): d = 169.6 (Cq), 147.8 (Cq), 144.5 (Cq),
127.3 (CH), 123.9 (CH), 77.3 (CH), 60.5 (CH), 44.5 (CH), 41.9
(CH2), 37.7 (CH), 35.9 (CH2), 27.6 (CH2), 25.3 (CH2), 22.3 (CH2),
20.2 (CH2), 19.4 (CH3), 14.7 (CH2), 13.9 (CH3).
Compound 11a (500 mg, 1.75 mmol) was added to a stirred suspen-
sion of palladium on charcoal (94 mg, 10% Pd/C) in MeOH (35
mL). The mixture was flushed with hydrogen and stirred under bal-
lon pressure at r.t. for 16 h. After filtration through celite and wash-
ing with MeOH (2 × 20 mL) the combined filtrates were dried
(MgSO4). The solvent was removed by distillation over a 10 cm Vi-
greux column at atmospheric pressure and the remaining liquid was
purified by bulb to bulb distillation (0.05 mbar, 150 °C) to give 1
(302 mg, 88%) as colorless solid; mp 27–28 °C.
IR (film): 3274 (w), 2954 (s), 2923 (ss), 2869 (s), 2855 (s), 2793
(m), 2729 (w), 2671 (w), 2623 (w), 1450 (s), 752 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 2.52–2.44 (m, 1 H), 2.35–0.80 (m,
1 H, NH), 2.20–2.13 (m, 1 H), 2.00–1.93 (m, 1 H), 1.74–1.72 (m, 2
H), 1.66–1.58 (m, 2 H), 1.42–1.20 (m, 6 H), 1.23–0.93 (m, 3 H),
0.93–0.83 (m, 1 H), 0.90 (t, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.3 Hz, 3
H), 0.70 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 61.4 (CH), 56.7 (CH), 48.5 (CH),
39.3 (CH2), 36.3 (CH), 35.6 (CH2), 33.8 (CH2), 32.9 (CH2), 29.0
(CH2), 24.8 (CH2), 19.2 (CH3), 14.3 (CH3).
MS (EI): m/z (%) = 196 (3) [M+ 1]+, 195 (3), 153 (15), 152 (100),
109 (5).
HRMS: m/z [M]+ calcd for C13H25N: 195.1987; found: 195.1988.
MS (EI): m/z (%) = 195 (5) [M + 1]+, 303 (20), 302 (17), 301 (100),
275 (23), 150 (67).
HRMS: m/z calcd for C20H28N2O3: 344.2100; found: 344.2098.
Anal. Calcd for C20H28N2O3: C, 69.74; H, 7.92; N, 8.19. Found: C,
69.73; H, 8.04; N, 8.21
X-ray analysis in ref.20
(rac)-[(2S,4aS,5R,8aS)-5-Methyl-2-propyl-octahydroquinoline-
1-yl]-(4-nitro-phenyl)-methanone (16)
The preparation of 16 was similar to the procedure described for 14.
Conversion of 15 (100 mg, 0.82 mmol) and purification of the crude
product by flash chromatography on silica gel (cyclohexane–
EtOAc, 1:4) gave 16 (154 mg, 87%) as a pale yellow solid; Rf 0.38,
mp 122–124 °C (after recrystallization from Et2O).
Anal. Calcd for C13H25N: C, 79.93; H, 12.90; N, 7.17. Found: C,
79.98; H, 12.92; N, 7.08.
(rac)-(2S,4aS,5R,8aS)-5-Methyl-2-propyl-decahydroquinoline
(15)
The preparation of 15 was similar to the procedure described for 1.
Conversion of 11b (235 mg, 0.82 mmol) and purification of the
crude product by bulb-to-bulb distillation (0.05 mbar, 150 °C)
yielded 15 (146 mg, 91%) as a colorless liquid.
IR (film): 3106 (w), 3077 (w), 2955 (m), 2930 (m), 1645 (ss), 1602
(m), 1522 (s), 1458 (m), 1442 (m), 1420 (m), 1341 (ss), 1312 (m),
1293 (m), 863 (m), 853 (m), 726 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 8.24 (d, J = 7.4 Hz, 2 H), 7.56 (d,
J = 7.4 Hz, 2 H), 3.69–3.58 (m, 1 H), 2.99 (dt, J = 11.3 Hz, 3.6 Hz,
1 H), 2.68–2.50 (m, 1 H), 1.99–1.88 (m, 2 H), 1.87–1.79 (m, 1 H),
1.79–1.69 (m, 1 H), 1.65–1.52 (m, 4 H), 1.50–1.40 (m, 1 H), 1.33–
1.18 (m, 4 H), 1.18–1.03 (m, 2 H), 1.26 (d, J = 6.0 Hz, 3 H), 0.90 (t,
J = 7.3 Hz, 3 H).
13C NMR (500 MHz, CDCl3): d = 171.4 (Cq), 148.2 (Cq), 145.2 (Cq),
127.8 (CH), 123.9 (CH), 58.7 (CH), 57.3 (CH), 44.9 (CH), 38.4
(CH), 34.9 (CH2), 32.2 (CH2), 30.0 (CH2), 29.4 (CH2), 26.1 (CH2),
25.3 (CH2), 20.0 (CH2), 19.4 (CH3), 14.2 (CH3).
IR (film): 3283 (w), 2952 (s), 2922 (ss), 2855 (s), 2783 (w), 2666
(w), 2636 (w), 2598 (w), 1457 (m), 1444 (m), 735 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 3.00–2.93 (m, 1 H), 2.39–2.30 (m,
1 H), 2.00–0.70 (m, 1 H, NH), 1.82–1.65 (m, 3 H), 1.65–1.48 (m, 4
H), 1.48–1.19 (m, 4 H), 1.19–0.94 (m, 4 H), 0.92 (t, J = 7.3 Hz, 3
H), 0.85 (d, J = 6.4 Hz, 3 H), 0.68 (m, 1 H).
13C NMR (125 MHz, CDCl3): d = 53.5 (CH), 52.0 (CH), 49.6 (CH),
36.2 (CH), 35.8 (CH2), 34.6 (CH2), 33.4 (CH2), 29.8 (CH2), 24.9
(CH2), 23.8 (CH2), 20.1 (CH2), 19.0 (CH3), 14.3 (CH3).
MS (EI): m/z (%) = 344 (2) [M]+, 302 (20), 301 (100), 150 (52), 104
(12), 69 (8).
MS (EI): m/z (%) = 195 (2) [M]+, 153 (14), 152 (100), 109 (5), 55
HRMS: m/z calcd for C20H28N2O3: 344.2100; found: 344.2100.
(5), 41 (5).
Anal. Calcd for C20H28N2O3: C, 69.74; H, 7.92; N, 8.19. Found: C,
69.72; H, 8.28; N, 7.97.
HRMS: m/z calcd for C13H25N: 152.1439; found: 152.1433.
X-ray analysis in ref.20
Synthesis 2004, No. 18, 3047–3054 © Thieme Stuttgart · New York

3054
J. Neidhöfer, S. Blechert
PAPER
Tokuyama, T.; Torres, J. A.; Snelling, R. R.; Jones, T. H. J.
Nat. Prod. 1999, 62, 5.
(12) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron
Lett. 1986, 27, 2829.
(13) (a) Mori, M.; Uesaka, N.; Shibasaki, M. J. Org. Chem. 1992,
57, 3519. (b) Mori, M.; Saitoh, F.; Uesaka, N.; Okamura, K.;
Date, T. J. Org. Chem. 1994, 59, 4993.
(14) (a) Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913.
(b) Zaminer, J.; Stapper, C.; Blechert, S. Tetrahedron Lett.
2002, 43, 6739. (c) Blechert, S.; Stapper, C. Eur. J. Org.
Chem. 2002, 2855. (d) Stapper, C.; Blechert, S. J. Org.
Chem. 2002, 67, 6456. (e) Buschmann, N.; Rueckert, N.;
Blechert, S. J. Org. Chem. 2002, 67, 4325. (f)Ovaa,H.;van
der Marel, G. A.; van Boom, J. H.; Stragies, R.; Blechert, S.
Chem. Commun. 2000, 1501. (g) Voigtmann, U.; Blechert,
S. Synthesis 2000, 893.
(15) Absolute configuration not known.
(16) Dodge, J. A.; Jones, S. A. Recent Res. Dev. Org. Chem.
1997, 1, 273.
(17) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301.
(18) (a) Harrity, P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda, A.
H. J. Am. Chem. Soc. 1997, 119, 1488. (b) Stragies, R.;
Blechert, S. Tetrahedron 1999, 55, 8179.
(19) Garaffo, H. M.; Simon, L. D.; Daly, J. W.; Spande, T. F.;
Jones, T. H. Tetrahedron 1994, 50, 11329.
(20) Crystallographic data for both structures have been
deposited with the Cambridge Crystallographic Data Centre
under the depository numbers.: CCDC-239791 (1), CCDC-
239792 (16).
References
(1) (a) Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards, M.
W.; Daly, J. W. Tetrahedron 1986, 42, 3453.
(b) Tokuyama, T.; Tsujita, T.; Shimada, A.; Garaffo, H. M.;
Spande, T. F.; Daly, J. W. Tetrahedron 1991, 47, 5401.
(c) Garaffo, H. M.; Caceres, J.; Daly, J. W.; Spande, T. F.;
Andriamaharavo, N. R.; Andriantsiferana, M. J. Nat. Prod.
1993, 56, 1016.
(2) Garaffo, H. M.; Spande, T. F.; Daly, J. W.; Baldessari, A.;
Gros, E. G. J. Nat. Prod. 1993, 56, 357.
(3) (a) Steffan, B. Tetrahedron 1991, 47, 8729. (b) Davis, R.
A.; Carroll, R.; Quinn, J. J. Nat. Prod. 2002, 65, 454.
(4) Kubanek, J.; Williams, D. E.; Dilip de Silva, E.; Allen, T.;
Andersen, R. J. Tetrahedron Lett. 1995, 36, 6189.
(5) (a) Daly, J. W.; Garaffo, H. M.; Jain, P.; Spande, T. F.;
Snelling, R. R.; Jaramillo, C.; Rand, A. S. J. Chem. Ecol.
2000, 26, 73. (b) Jones, T. H.; Gorman, J. S. T.; Snelling, R.
R.; Delabie, J. H. C.; Blum, M. S.; Garaffo, H. M.; Jain, P.;
Daly, J. W.; Spande, T. F. J. Chem. Ecol. 1999, 25, 1179.
(6) Daly, J. W.; Nishizawa, Y.; Edwards, M. W.; Waters, J. A.;
Aronstam, R. S. Neurochem. Res. 1991, 16, 489.
(7) Daly, J. W.; Nishizawa, Y.; Padgett, W. L.; Tokuyama, T.;
McCloskey, P. J.; Waykole, L.; Schultz, A. G.; Aronstam, R.
S. Neurochem. Res. 1991, 16, 1207.
(8) Daly, J. W.; Garaffo, M.; Spande, T. F. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press, Inc.: San Diego, 1993,
184–295.
(9) Daly, J. W.; Garaffo, H. M.; Spande, T. F. In Alkaloids, Vol.
13; Pelletier, S. W., Ed.; Pergamon: New York, 1999, 1–161.
(10) Daly, J. W. J. Med. Chem. 2003, 46, 445.
(21) Taber, D. F.; Campbell, J. P. L.; Wang, Y.; Zhang, W. Curr.
Org. Chem. 2000, 4, 809.
(11) Spande, T. F.; Jain, P.; Garaffo, H. M.; Pannell, L. K.; Yeh,
H. J. C.; Daly, J. W.; Fukumoto, S.; Imamura, K.;
Synthesis 2004, No. 18, 3047–3054 © Thieme Stuttgart · New York