Synthesis of optically active indolizidines: (-)-8a-epi-Dendroprimine and (-)-7,8-dehydro-5,6-dimethylindolizidine

Article abstract of DOI:10.1055/s-1999-3396

Indolizidinones can be employed as key intermediates in efficient asymmetric synthesis of naturally occurring indolizidine alkaloid analogues. The 5,7-dimethylindolizidine (-)-8a-epi-dendroprimine was formed by a diastereoselective methylation-reduction s

Full text of DOI:10.1055/s-1999-3396

286
PAPER
Synthesis of Optically Active Indolizidines: (Ð)-8a-epi-Dendroprimine
and (Ð)-7,8-Dehydro-5,6-dimethylindolizidine
Michel Diederich, Udo Nubbemeyer
Inst. fŸr Organische Chemie, Freie UniversitŠt Berlin, Takustr. 3, D-14195 Berlin
Fax +49(30)8385163; E-mail: udonubb@chemie.fu-berlin.de
Received 24 July 1998
The next sequence removed the hydroxyl group as well as
the phenylselenyl substituent. After activating the hydrox-
yl group as a thiocarboxylic ester 7 and radical reduction
with AIBN and tributyl stannane (BartonÐMcCombie),9
Abstract: Indolizidinones can be employed as key intermediates in
efficient asymmetric synthesis of naturally occurring indolizidine al-
kaloid analogues. The 5,7-dimethylindolizidine (Ð)-8a-epi-den-
droprimine was formed by a diastereoselective methylationÐ
reduction sequence of the lactam function. The (Ð)-5,6-dimethylin- the 7-methylindolizidinone 8 was generated in about 50%
dolizidine was generated via the same key step including an addition-
al quasi 1,2-methyl shift: an intramolecular enamine alkylation is
followed by regioselective reductive cyclopropane ring opening.
over two steps.
The second methyl group at C-5 was stereoselectively intro-
duced employing a one-pot procedure: After initial treatment
of the lactam 8 with one equivalent of methylmagnesium
Key words: indolizidinone, indolizidine, intramolecular enamine
alkylation, iminium salt, diastereoselective reduction, radical cyclo-
chloride, the in situ formed iminium salt was reduced with
NaBH4/HOAc.11 The stereoselectivity was efficiently direct-
ed by the Òopen book effectÓ, the hydride ion exclusively at-
tacks from the less hindered face parallel to the bridgehead
hydrogen. The (Ð)-8a-epi-dendroprimine 2 was isolated as
the hydrochloride in 55% yield, all spectral data were in good
agreement with those published in the literature.10
propane opening.
(Ð)-Dendroprimine 1 is an indolizidine alkaloid with un-
known biological activity isolated and characterized by LŸn-
ing from Dendrobium primulinum Lindl (Orchidaceae) in
1965.1 The correct relative configurations of the stereogenic
centers were determined after the synthesis of the racemic
compound and its diastereomers (e.g. 2) by the same group,1
the absolute configuration has been investigated in 1972 by
measuring CD-spectra of some degradation products.2 In
1979 Sonnet confirmed the results by NMR-spectroscopic
analyses.3 Until now, no synthesis of optically active den-
droprimine 1 and its epimers like 2 has been described.
Figure 1
Our synthesis started from the known indolizidinone 4
which could be generated in six steps from L-(Ð)-proline
including a stereoselective zwitterionic aza-Claisen rear-
rangement followed by a regio- and diastereoselective
transannular ring junction as the key steps; overall yield
was >50 %.4 First efforts were carried out to distinguish
the carboxylic groups: DIBALH-5 or Red-Al -reductions6
gave unselectively the amino alcohol 6 and the desired
hydroxymethyl lactam 5 in varying yields, the reaction with
NaBH4 in MeOH7 led to 5 chemoselectively in the modest (a) Li(Et)3BH, THF, 0¡C, 4 h; (b) ClC(S)OPh, pyridine, CH2Cl2,
r.t., 2 h; (c) Bu3SnH, AIBN, PhMe, 75¡C, 3 h; (d) 1. MeMgCl, Et2O,
0¡C to r.t., 1 h, 2. NaBH4, HOAc, 0¡C 1.5 h; (e) PPh3, CCl4, 77¡C,
2.5 h; (f) 1. MeMgCl, THF, 65¡C, 6 h, 2. NaBH4, HOAc, r.t., 1 h;
(g) Bu3SnH, AIBN, PhMe, 110¡C, 4 h.
yield of about 50%. The best results were achieved using
Li(Et)3BH,8 a reagent which is normally known to reduce
amides to the corresponding primary alcohols: about 81%
of the hydroxymethyl lactam 5 could be isolated, and no
reduction of the amide function was observed.
Scheme
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PAPER
Synthesis of Optically Active Indolizidines
287
1H and 13C NMR spectra were recorded on Bruker spectrometers
AC 250, AM 270 or AMX 500. IR spectra were obtained on a Nico-
let FTIR-Interferrometer 5 SXC. Mass spectra were recorded on a
Varian MAT 711. Optical rotations were measured with a Perkin
Elmer P 241 in a 1 dm cell. Elemental analyses were obtained from
a Perkin Elmer 240 Elemental Analyzer. Melting points (not cor-
rected) were determined with a BŸchi SMP 20.
Alternatively, the C-7 hydroxyl group in 5 could be acti-
vated by a chlorination following Appels procedure12 to
give the chloromethyl lactam 9 in 74% yield. With intent
to introduce the C-5 methyl group prior to the removal of
the phenylselenyl substituent, the methylmagnesium
chloride addition/NaBH4 reduction sequence was carried
out with 9 to give low amounts of the tricyclic 10 and
some side products. The yield of 10 could be significantly
increased by heating 9 in presence of the Grignard reagent
for several hours before treating the mixture with NaBH4
and HOAc. The reaction path was interpreted as follows
(Figure 2): Initially, the carbonyl group of lactam 9 was
methylated by the Grignard reagent, the in situ formed
iminium salt was deprotonated to form an enamine,13
(5R, 7S, 8aS)-5,7-Dimethylindolizidine (2) ((Ð)-8a-epi-Den-
droprimine)
Under Ar, indolizidinone 8 (60 mg, 0.39 mmol) in anhyd Et2O
(2 mL) was cooled to 0¡C. A solution of MeMgCl (0.4 mL,
1.2 mmol, 3 M in THF) was added dropwise with stirring. The cool-
ing bath was removed and the mixture was stirred at r.t. for 0.5 to
1 h (TLC control). Then, the mixture was cooled again to 0¡C and
HOAc (1.8 mL) as well as NaBH4 (30 mg, 0.78 mmol) were added
which underwent an intramolecular alkylation to generate subsequently. After stirring for a further 1.5 h, the reaction was
quenched with Et2O (20 mL), and sat. aq Na2CO3 (10 mL). The
mixture was extracted with Et2O (3 × 20 mL) the combined organic
layers were washed with brine (5 mL) and dried (MgSO4). The
MgSO4 was filtered off and concd aq HCl (0.1 mL) was added. The
the cyclopropane. Finally the resulting iminium species
was reduced stereoselectively with NaBH4 according to
the prerequisites of the open-book effect discussed above.
The removal of the phenylselenyl substituent with tributyl
solvents were evaporated and the remaining H2O was removed by
stannane and AIBN simultaneously effected the opening
of the cyclopropane to give the 7,8-dehydro-5,6-dimeth-
ylindolizidine 3 which was isolated as the hydrochloride
in 59 % yield. Obviously, the intermediately formed sec-
ondary alkyl radical adjacent to the cyclopropane under-
went ring opening with decrease of ring strain. Finally, the
methyl group was built up after H-transfer from the
Bu3SnH. The relative configurations of all stereogenic
centers of the indolizidine 3 were determined by NOE-
analysis.
distilling twice with toluene. Yield: 33 mg (0.21 mmol, 55 %) of the
hydrochloride of 2 as a pale yellow oil, which did not crystallize.
[a]D20 = Ð45.8 (c = 0.72, CHCl3).
MS (EI, 70 eV, 40¡C): m/z (%) = 153 (15, [M]+), 138 (100), 110
(13), 96 (20), 70 (9), 36 (9).
1H NMR (500 MHz, 323 K, DMSO, D2O): d = 0.92 (d, 3 H, J = 6
Hz, 7-CH3), 1.28 (d, 3 H, J = 7 Hz, 5-CH3), 1.35 (mC, 2 H, 6-H1, 8-
H1), 1.62Ð1.75 (m, 2 H, 1-H1, 7-H), 1.79 (dd, br s, 1 H, J = 11 Hz,
6-H2), 1.82Ð1.95 (m, 3 H, 2-H1, 2-H2, 8-H2), 2.08 (mC, 1 H, 1-H2),
2.88 (mC, 1 H, 3-H1), 3.09 (mC, 2 H, 5-H, 8a-H), 3.49 (mC, 1 H, 3-
H).
13C NMR (68 MHz, CDCl3): d = 17.8 (C-9), 19.4 (C-2), 20.7 (C-
10), 28.1 (C-1), 30.2 (C-7), 34.9 (C-8), 39.2 (C-6), 49.8 (C-3), 60.0
(C-5), 67.3 (C-8a).
1HÐ13C COSY (DMSO, 323 K): crosspeak dC /dH (No.) = 17.5/
0.92 (10), 19.0/1.9 (2), 21.0/1.25 (9), 27.7/1.65, 2.1 (1), 29.2/1.7
(7), 35.0/1.35, 19.5 (8), 39.0/1.35, 1.8 (6), 49.0/2.9, 3.5 (3), 58.2/
3.15 (5), 66.0/3.1 (8a).
Analysis: C10H19N (153.27) calculated: C 74.46, H 11.18. found: C
74.11, H 10.89.
(5R, 6S, 8aS)-5,6-Dimethyl-1,2,3,5,6,8a-hexahydroindolizine
Hydrochloride (3)
Figure 2
Under Ar, the cyclopropane 10 (300 mg, 1 mmol) was dissolved in
anhyd toluene (25 mL). While Ar was slowly bubbled through the
solution, Bu3SnH (580 mg, 2 mmol) and AIBN (10 mg, 0.07 mmol)
were added and the mixture was heated to 110¡C for 4 h. After cool-
ing to r.t., aq HCl (5 mL, 12.5 %) was added and the aqueous layer
was extracted with Et2O (3 × 10 mL) to remove the tin salts. Then,
In summary, indolizidine alkaloid analogues bearing alkyl
substituents at the positions 5 and 6 or 5 and 7, respective-
ly, with defined configurations, were synthesized starting
from an optically active indolizidinone. The stereogenic
center C-5 was generated by an alkylation/reduction se- the H2O was removed by distillation with toluene (3 × 10 mL).
Yield: 110 mg (0.59 mmol, 59 %) of 3 as a yellow oil, that did not
quence, the configuration was controlled by the open
book effect of the bicycle. On achieving the synthesis of
8a-epi-dendropimine (5,7-dialkylindolizidine) the func-
tional groups at C-8 and C-7-CH2 were removed by a rad-
ical reduction. The migration of the substituent of C-7 to
C-6 started with an intramolecular enamine alkylation, the
so-formed cyclopropane was regioselectively cleaved by
crystallize.[a]D20 = Ð36.8 (c = 0.78, CHCl3).
IR (KBr, Film): n = 3419, 3032, 2974, 2943, 2880, 2828, 2738,
2645, 2581, 2517, 1624, 1451, 1387, 1083 cmÐ1
.
MS (DMSO/Glyc./Xenon, CH5 DF//FAB POS): m/z (%) = 339 (10,
[M + C10H18N]+), 185 (10), 153 (26), 152 (100, [C10H18N]+), 151
(11), 150 (11), 93 (36), 75 (12), 70 (12).
a final radical reduction. Further investigations to realize 1H NMR (270 MHz, CDCl3, TMS): d = 1.05 (d, J = 7 Hz, 3 H, 6-
CH3) 1.35 (d, J = 7 Hz, 3 H, 5-CH3), 1.75 (mC, 1 H, 1-H1), 2.05 (mC,
the total synthesis of the natural dendroprimine 1 and to
2 H, 2-H), 2.30 (mC, 1 H, 1-H2), 2.65 (mC, 1 H, 6-H), 3.15 (mC, 1 H,
test scope and limitations of the alkyl shift are in
3-H1), 3.55 (mC, 1 H, 3-H2), 3.65 (mC, 1 H, 5-H), 4.30 (mC, 1 H, 8a-
progress.14
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288
M. Diederich, U. Nubbemeyer
PAPER
H), 5.55 (d, br s, J = 11 Hz, 1 H, 8-H), 5.80 (mC, 1 H, 7-H), 12.20
13C NMR (68 MHz, CDCl3): d = 21.7 (C-1), 33.9 (C-2), 34.4 (C-6),
38.0 (C-7), 45.8 (C-3), 46.0 (C-8a), 63.2 (C-8), 75.1 (C-9), 121.7,
126.5, 128.5, 129.3, 135.7 (ArC), 153.2 (OCAr), 167.0 (C=O),
194.6 (C=S).
(s, 1 H, N+-H).
NOE-analysis: irradiation at H-X
amplification at H-Y [%]: H-
3a
H-6a (8); H-3b
CH3-6b (1); H-5a
H-3a (8); CH3-5b
CH3-6b (2); CH3-6b
H-3b (6), CH3-5b (1), H-7 (1); H-7
C22H23NO3SSe (460.45) calc.: C 57.39, H 5.03. found: C 57.03, H
5.37.
CH3-6b (1).
13C NMR (68 MHz, CDCl3): d = 13.1 (CH3), 15.3 (CH3), 21.9 (C-
2), 29.9 (C-1), 30.8 (C-6), 47.1 (C-3), 54.0 (C-5), 59.3 (C-8a), 122.5
(C=C), 130.6 (C=C).
(7R, 8aS)-7-Methylindolizidin-5-one (8)
Under Ar, the thioformate 7 (1 g, 2.2 mmol) was dissolved in anhyd
toluene (80 mL). While Ar was slowly bubbled through the solution
Bu3SnH (1.54 mL, 5.4 mmol) and AIBN (130 mg, 0.8 mmol) were
added and the mixture was heated to 75¡C for 3 h. Then, the solvent
was removed (low temperature, because product might be distilled)
and the crude material was purified by column chromatography
(EtOAc/hexane, 1 : 2, Rf = 0.12) and preparative HPLC (Nucleosil
50Ð5 mm, 4 × 125 mm. UV: 220 nm. RI: Range 8. Flow: 2 ml/min.
solvent: 10% isopropanol/hexane, retention time = ~ 6.7 min
(amide 8) and 8.3 min (thioformate 7)). Yield: 270 mg (1.76 mmol,
80 %) of 8 as a colorless liquid. [a]D20 = Ð2.9 (c = 1.2, CHCl3).
C10H17N¥HCl (187.70) calc.: C 62.74, H 6.91. found: C 62.92, H 7.31.
(7R, 8R, 8aS)-7-Hydroxymethyl-8-phenylselenylindolizidin-5-
one (5)
Under Ar, the ester 4 (3.7 g, 10 mmol) was dissolved in anhyd THF
(50 mL) and cooled to 0¡C. A solution of Li(Et)3BH (21 mL,
21 mmol, 1 M in THF) was added dropwise, with stirring. After 3
to 4 h at this temperature, the reaction was detected to be complete
(TLC). Sat. aq KHSO4 (4 mL) and H2O (8 mL) were added to reach
a pH < 2. After extraction with Et2O (4 × 30 mL) the combined or-
ganic layers were washed with brine (20 mL) and dried (MgSO4).
The solvent was removed, the crude material was purified via col-
umn chromatography (EtOAc, Rf = 0.1). Yield: 2.7 g (8.1 mmol,
81%) of 5 as a white foam, mp 83¡C. [a]D20 = Ð39.1 (c = 0.85,
CHCl3).
IR (CHCl3): n = 1620 (vs).
MS (EI, 70 eV, 40¡C): m/z (%) = 153 (100, [M]+), 125 (24), 111
(45), 83 (100), 70 (90), 56 (34), 41 (39).
1H NMR (500 MHz, CDCl3, TMS): d = 1.05 (mC, 4 H, 7-H, 7-CH3),
1.40 (mC, 1 H, 1-H1), 1.70-1.80 (m, 1 H, 2-H1); 1.85Ð2.00 (m, 3 H,
2-H2, 8-H1, 8-H2), 2.00Ð2.10 (m, 2 H, 1-H2, 6-H1), 2.50 (dd, J = 15
Hz, 1 Hz, 1 H, 6-H2), 3.35Ð3.45 (m, 2 H, 3-H1, 8a-H); 3.55 (mC, 1
H, 3-H2).
13C NMR (68 MHz, CDCl3): d = 21.5 (7-CH3), 22.1 (C-2), 28.4 (C-
7), 33.2 (C-1), 37.4 (C-8), 39.6 (C-6), 44.4 (C-3), 58.9 (C-8a), 168.8
(C=O).
IR (KBr): n = 3452 (br), 1630, 1475, 1455, 1398 cmÐ1.
MS (EI; 70 eV, 100¡C): m/z = 325 (7), 323 (3), 214 (3), 169 (11),
168 (100), 158 (5), 157 (4), 150 (5), 136 (22), 108 (7), 84 (7), 83 (7),
80 (5), 70 (24).
1H NMR (270 MHz, CDCl3, TMS): d = 1.40, (mC, 1 H, 1-H1), 1.60
(mC, 1 H, 2-H1),1.75 (mC, 1 H, 2-H2), 2.00 (mC, 1 H, 1-H2), 2.40
(mC, 1 H, 7-H), 2.50 (mC, 2 H, 6-H), 2.75 (dd, J = 10 Hz, 10 Hz, 1
H, 8-H), 3.40Ð3.50 (m, 3 H, 8a-H, 3-H), 3.80 (mC, 1 H, 9-H1), 3.95
(mC, 1 H, 9-H2), 4.10 (s, 1 H, OH), 7.25 (mC, 3 H, ArH), 7.55 (mC,
2 H, ArH).
C9H15NO (153.23) calc.: C 70.55, H 9.87. found: C 71.17, H 10.24.
(7R, 8R, 8aS)-7-Chloromethyl-8-phenylselenylindolizidin-5-one
(9)
13C NMR (68 MHz, CDCl3): d = 21.7 (C-2), 33.5 (C-1), 34.0 (C-6),
39.9 (C-7), 45.5 (C-8), 45.9 (C-9), 126.8, 128.1, 130.0, 135.5 (C-
Ar), 168.8 (C=O).
Under Ar, alcohol 5 (3.2 g, 10 mmol) in anhyd CCl4 (20 mL) was
treated with PPh3 (2.6 g, 10 mmol) and the mixture was heated to
reflux for 2Ð3 h. Then, the solvent was evaporated and the crude
material was purified by column chromatography (EtOAc/MeOH,
10:1, Rf = 0.2). Yield: 2.5 g (7.4 mmol, 74%) of 9 as a white foam,
mp: 95¡C. [a]D20 = 23.2 (c = 0.76, CHCl3).
C15H19NO2Se (324.28) calc.: C 55.56, H 5.91. found: C 55.10, H
5.47.
IR (KBr): n = 1620, 1478, 1468, 1417 cmÐ1
.
(7R, 8R, 8aS)-7-(Phenyloxythiocarbonyloxymethyl)-8-
phenylselenylindolizidin-5-one (7)
MS (100¡C, EI; 70 eV): m/z = 345 (4), 343 (8), 341 (4), 188 (36),
Under Ar, alcohol 5 (1.9 g, 5.9 mmol) in anhyd CH2Cl2 (40 mL) was
treated with pyridine (1.8 mL, 21.9 mmol) and phenylchlorothiono
formate (1.2 mL, 6.5 mmol) with stirring. After 2 h the solvent was
removed and the residue was dissolved in Et2O (40 mL). The organ-
ic layer was washed with aq KHSO4 (2 × 20 mL, 0.1 M), sat. aq
NaHCO3 (2 × 20 mL) and dried (MgSO4). After removal of the sol-
vent, the crude material was purified by column chromatography
(gradient EtOAc/hexane 1: 5 to EtOAc, Rf (EtOAc) = 0.2). Yield:
1.56 g (3.4 mmol, 57%) thioformate 7 as pale yellow crystals, mp:
159¡C. [a]D20 = Ð32.0 (c = 0.87, CHCl3).
187 (13), 186 (100), 136 (16), 70 (12).
1H NMR (270 MHz, CDCl3, TMS): d = 1.50 (mC, 1 H, 1-H1) 1.75
(mC, 1 H, 2-H1), 1.90Ð2.05 (m, 1 H, 2-H2), 2.35 (mC, 1 H, 7-H),
2.45Ð2.65 (m, 3 H, 6-H1, 6-H2, 1-H2), 2.90 (dd, 1H, J= 10 Hz, 1 Hz,
8-H), 3.40Ð3.60 (m, 3 H, 3-H1, 3-H2, 8a-H), 3.80 (dd, J = 10 Hz,
3 Hz, 1 H, 9-H2), 4.20 (dd, J= 10 Hz, 5 Hz, 1 H, 9-H2), 7.35 (mC, 3
H, ArH), 7.60 (mC, 2 H, ArH).
13C NMR (68 MHz, CDCl3): d = 21.7 (ring-CH2) 33.9 (ring-CH2),
34.4 (C-6), 39.4 (C-7), 45.8 (CH2X), 46.8 (C-8), 48.3 (CH2X), 63.3
(C-9), 126.4, 128.6, 129.3, 135.8 (C-Ar), 167.2 (C=O).
IR (KBr, Film): n = 1627, 1455, 1477, 1326, 1289 cmÐ1
.
C15H18NOSe (342.73) calc.: C 48.78, H 5.63. found: C 48.97, H
5.88.
MS (EI, 70 eV, 120Ð150¡C): m/z (%) = 461 (17, [M]+), 307 (27),
305 (36), 304 (60), 230 (20), 156 (45), 151 (58), 150 (100,
[O2SC5H6]+), 149 (58), 136 (58), 122 (45), 109 (27), 108 (44), 95
(25), 91 (45), 83 (58), 70 (91), 65 (56).
1H NMR (250 MHz, CDCl3, TMS): d = 1.50 (mC, 1 H, 1-H1), 1.75
(mC, 1 H, 2-H1), 1.90 (m, 1 H, 2-H2), 2.40 (mC, 1 H, 7-H), 2.50Ð2.75
(m, 3 H, 1-H2, 6-H1, 6-H2), 2.80 (dd, J = 10Hz, 10 Hz, 1 H, 8-H),
3.40Ð3.60 (m, 3 H, 8a-H, 3-H1, 3-H2), 4.7 (dd, J = 10 Hz, 1 Hz, 1 H,
9-H1), 4.9 (dd, J = 10 Hz, 1 Hz, 1 H, 9-H2), 7.05 (mC, 2 H, ArH),
7.20Ð7.45 (m, 6 H, ArH), 7.60 (mC, 2 H, ArH).
(5R, 6S, 7S, 8R, 8aS)-6,7-Cyclopropa-8-phenylselenylindolizi-
din-5-one (10)
Under Ar, chloride 9 (3.4 g, 10 mmol) in anhyd THF (20 mL) was
treated with MeMgCl (7.2 mL, 24 mmol, 3 M in THF) with stirring.
After heating to reflux for 6 h, the mixture was cooled to r.t. and
HOAc (15 mL) and NaBH4 (380 mg, 10 mmol) were added subse-
quently. The mixture was stirred for 1 h at r.t. Then, the excess of
acid was neutralized by quenching with sat. aq NaHCO3 (20 mL)
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Synthesis of Optically Active Indolizidines
289
and the addition of solid NaHCO3 until the pH was raised to 7Ð8.
The mixture was extracted with EtOAc (5 × 20 mL), the combined
organic layers were dried (MgSO4). Finally, the crude brownish oil
was purified by column chromatography (EtOAc / hexane, 1 : 5, Rf
= 0.12). Yield: 2.2 g (7.2 mmol, 71 %) of 10 as yellow amorphous
needles, mp: 66¡C. [a]D20 = Ð12.2 (c = 0.55, CHCl3).
References
(1) LŸning, B.; Leander, K. Acta Chem. Scand. 1965, 19, 1607.
LŸning, B.; Lundin, C. Acta Chem. Scand. 1967, 21, 2136.
(2) Blomquist, L.; Leander, K.; LŸning, B.; Rosenblom, J. Acta
Chem. Scand. 1972, 26, 3203.
(3) Sonnet, P. E.; Netzel, D. A.; Mendoza, R. J. Heterocycl.
IR (KBr): n = 2962, 2924, 2865, 2789, 1580, 1481, 1430, 1369,
Chem. 1979, 16, 1041.
1155, 1075 cmÐ1
.
(4) Diederich, M.; Nubbemeyer, U. Angew. Chem. 1995, 107,
1095; Angew. Chem., Int. Ed. Engl. 1991, 34, 1026.
Diederich, M.; Nubbemeyer, U. Chem. Eur. J. 1996, 2, 896.
(5) Winterfeldt, E. Synthesis 1975, 617.
MS (100¡C, EI; 70 eV): m/z (%) = 307 (6), 238 (41), 236 (20), 157
(10), 150 (43), 134 (17), 120 (11), 97 (47), 81 (100), 80 (17), 79
(23), 78 (10), 77 (19), 70 (13), 69 (10).
(6) Capka, M.; Chvalovsky, V.; Kochloefl, K.; Kraus M. Coll.
1H NMR (270 MHz, CDCl3, TMS): d = 0.55 (mC, 1 H, 6a-H1), 0.65
(mC, 1 H, 6a-H2), 1.10 (mC, 1 H, 6-H), 1.25 (d, 3H, J = 6 Hz, 5-CH3),
1.35 (mC, 1 H, 1-H), 1.45 (mC, 2 H, 7-H), 1.60Ð1.80 (m, 3 H, 2-H1,
1-H, 2-H2), 2.05 (dd, 1 H, J = 10 Hz, 10 Hz, 3-H1), 2.1Ð2.25 (m, 1
H, 8a-H), 2.60 (mC, 1 H, 5-H), 3.25 (mC, 1 H, 3-H2, 8-H2), 7.25 (mC,
3 H, ArH), 7.60 (mC, 2 H, ArH).
13C NMR (68 MHz, CDCl3): d = 9.0 (C-6a), 18.3 (CH3), 20.2 (CH),
20.5 (C-2), 20.7 (CH), 31.2 (C-1), 45.9 (C-8), 52.9 (C-3), 56.9 (C-
5), 66.9 (C-8a), 126.7, 128.8, 129.9, 133.1 (CAr).
Czech. Chem. Commun. 1969, 34, 118.
(7) Soai, K.; Oyamada, H.; Ookawa, A. Synth. Commun. 1982,
12, 463.
Stanfield, C. F.; Parker, J. E.; Kanellis, P J. Org. Chem. 1981,
46, 4799.
(8) Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567.
(9) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. I 1975, 1574.
Robison, M. J.; Wilson, J. S.; Hansske, F. J. Am. Chem. Soc.
1983, 105, 4059.
C16H21NSe (306.31) calc.: C 62.74, H 6.91. found: C 62.92, H 7.31
(10) The spectral data in the literature (1Ð3) were published for the
racemic material. The relative configuration of the stereogenic
centers was confirmed by NOE analysis.
(11) AubŽ, J.; Rafferty, P. S.; Milligan, G. L. Heterocycles 1993,
35, 1144.
Acknowledgement
This work was supported by the DFG.
(12) Aneja, R.; Davies, A. P.; Knaggs, J. A. Tetrahedron Lett.
1974, 67.
(13) Stork, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85, 2178.
(14) An oxidation (NBS) elimination sequence with 2 led to a mix-
ture of regioisomeric iminium salts in low yields, the selective
generation of 1 failed after reduction.
Synthesis 1999, No. 2, 286–289 ISSN 0039-7881 © Thieme Stuttgart · New York