Efficient synthesis of (2S,12'R)-2-(12'-aminotridecyl)pyrrolidine: A defense alkaloid of the Mexican bean beetle

Article abstract of DOI:10.1055/s-2000-6379

The synthesis of (2S,12'R)-2-(12'-aminotridecyl)pyrrolidine [(S,R)-8], a defense alkaloid of the Mexican bean beetle Epilachna varivestis starting from (R)-proline is described. The second stereogenic center is generated by nucleophilic 1,2-addition of methyllithium to an aldehyde-SAMP-hydrazone, followed by reductive N-N bond cleavage. The product is obtained in good yield and high enantiomeric and diastereomeric purity.

Full text of DOI:10.1055/s-2000-6379

510
SHORT PAPER
Efficient Synthesis of (2S,12’R)-2-(12’-Aminotridecyl)pyrrolidine: A Defense
Alkaloid of the Mexican Bean Beetle
Dieter Enders,* Christoph Thiebes
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8888127; E-mail: Enders@RWTH-Aachen.de
Received 1 December 1999; revised 22 December 1999
Because the benzyl protecting group was not essential for
Abstract: The synthesis of (2S,12’R)-2-(12’-aminotridecyl)pyr-
the next steps, conditions for the hydrogenation [Pd(OH)2/
rolidine [(S,R)-8], a defense alkaloid of the Mexican bean beetle
charcoal, 3 bar H2] were chosen to ensure its removal
Epilachna varivestis starting from (R)-proline is described. The sec-
ond stereogenic center is generated by nucleophilic 1,2-addition
along with the reduction of the double bond.8 The air sen-
of methyllithium to an aldehyde-SAMP-hydrazone, followed by re- sitive hydrazine obtained after removal of the catalyst and
ductive N-N bond cleavage. The product is obtained in good yield
the solvent was used in the final step of our synthesis with-
out purification. Treatment with excess borane-tetrahy-
drofuran complex (10 equiv) gave (S,R)-8 in 60% yield
over two steps.9 The analytical data were consistent with
those reported in the literature,3a where it has been stated
that the four stereoisomers of 8 can be distinguished by 1H
NMR after conversion into their MTPA diamides. There-
fore, we prepared the (R)-MTPA diamide of (2S,12’R)-8
with (S)-a-methoxy-a-(trifluoromethyl)phenylacety chlo-
ride. As expected, the crude 1H NMR spectrum was iden-
tical to that reported for the enantiomeric (S)-MTPA-dia-
mide of (2R,12’S)-8, and no other diastereomer could be
detected. The diastereomeric and enantiomeric excess
was therefore determined to be greater than 96%.
and high enantiomeric and diastereomeric purity.
Key words: natural products, asymmetric synthesis, alkaloids,
nucleophilic 1,2-addition, SAMP/RAMP hydrazone method, pyr-
rolidines
The Mexican bean beetle, Epilachna varivestis (Coccinel-
lidae), protects itself from predators by discharging a
blood droplet containing a variety of defense alkaloids
from its knee joints.1 Among a set of other related alka-
loids, (2S,12’R)-2-(12’-aminotridecyl)pyrrolidine [(S,R)-
8] was extracted from the bodies of adult bean beetles and
characterized.2 The determination of the absolute config-
uration and a diastereoselective synthesis by an “ex-
chiral-pool” approach was reported shortly afterwards.3
We now describe a new stereoselective synthesis of
[(S,R)-8] starting from (R)-proline in which the distant
stereogenic center at C-12’ is created by asymmetric syn-
thesis employing the diastereoselective 1,2-addition of
methyllithium to an aldehyde-SAMP-hydrazone.4
In conclusion, we have synthesised a defense alkaloid of
the Mexican bean beetle employing (R)-proline as a pyr-
rolidine building block and by 1,2-addition of methyllith-
ium to an aldehyde-SAMP-hydrazone as a key step in
good yield and excellent diastereomeric and enantiomeric
purity.
As shown in the Scheme, our synthesis starts from com-
mercially available 11-bromoundecan-1-ol (3), which
was transformed to acetal 4 by Swern-oxidation and sub-
sequent reaction with ethylene glycol.5 The bromo acetal
4 was then treated with triphenylphosphine to give a phos-
phonium bromide which was used in a Wittig olefination
with (R)-N-benzylprolinal [(R)-2], itself being obtained
from (R)-proline according to a literature procedure.6 We
have found that tert-butyllithium is necessary to ensure
complete conversion of the phosphonium bromide to the
corresponding ylide. The pyrrolidino acetal (R)-5 was ob-
tained in this way in 80% yield, while the yields were well
All reagents were of commercial quality used from freshly opened
containers. Solvents were dried and purified by conventional meth-
ods prior to use. Petroleum ether used had bp 40-60 °C. THF was
freshly distilled from sodium/lead alloy under Ar. t-BuLi (1.6 M in
hexane), MeLi (1.5 M in Et2O) were purchased from Merck, Darm-
stadt. Pd(OH)2 (20% on C) was purchased from Acros Organics.
Borane-tetrahydrofuran-complex (1 M in THF) was purchased from
Aldrich. Preparative column chromatography: Merck silica gel 60,
particle size 0.040-0.063 mm (230-400 mesh, flash). Analytical
TLC: Silica gel 60 F254 plates, Merck, Darmstadt. Optical rotation
values were measured using a Perkin-Elmer P 241 polarimeter, sol-
vents used were of Merck UVASOL quality. Microanalyses were
obtained with a Heraeus CHN-O-RAPID element analyzer. Mass
below 60% when one equivalent of butyllithium was used spectra: Varian MAT 212 (EI 70 eV) with DIE ionization. IR spec-
tra: Perkin-Elmer FT/IR 1750. 1H NMR spectra (300 and 400
as a base. Treatment of (R)-5 with 1 M hydrogen chloride
in acetone yielded the corresponding aldehyde, which was
directly trapped with (S)-1-amino-2-(methoxymeth-
MHz), 13C NMR (75 and 100 MHz): Varian VXR 300, Gemini 300
or Varian Inova 400 (solvent CDCl3, TMS as internal standard).
yl)pyrrolidine (SAMP) affording hydrazone (R,S)-6. Ad-
dition of methyllithium to the carbon-nitrogen double
bond of (R,S)-6 gave hydrazine (R,R,S)-7 as a single dia-
stereomer (de ≥ 96%).7 It was necessary to reduce the dou-
ble bond in (R,R,S)-7 by hydrogenation before the N-N
bond cleavage with the borane-tetrahydrofuran-complex.
2-(10-Bromodecyl)-1,3-dioxolane (4)
To a solution of oxalyl chloride (4.1 mL, 45 mmol) in CH2Cl2 (25
mL) at -78 ∞C was slowly added a solution of DMSO (4.4 mL, 60
mmol) in CH2Cl2 (45 mL). After stirring for 15 min at -78 ∞C, a so-
lution of 11-bromoundecan-1-ol (7.47 g, 30 mmol) in CH2Cl2 (60
mL) was added slowly and the mixture was stirred for 30 min, fol-
Synthesis 2000, No. 4, 510–512 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Efficient Synthesis of (2S,12’R)-2-(12’-Aminotridecyl)pyrrolidine
511
(2R,11Z)-1-Benzyl-2-{[11-(1,3-dioxolane)-2-yl]undec-1-
enyl}pyrrolidine [(R)-5]
a, b, c
78 %
CHO
CO2H
N
N
A solution of Ph3P (6.55 g, 25 mmol) and 4 (7.32 g, 25 mmol) in
anhyd MeCN (50 mL) was heated under reflux for 72 h. The solvent
was removed under reduced pressure and the residue was washed
with Et2O (30 mL) until it crystallized. The colourless solid phos-
phonium bromide obtained in this way (13.35 g, 98%) was used
without any further purification in the next reaction. To a suspen-
sion of the crude phosphonium bromide (8.40 g, 15.4 mmol) in an-
hyd THF (80 mL) under argon was slowly added a solution of t-
BuLi (1.6 M in hexane, 9.63 mL, 15.4 mmol) at -78 ºC. After 15
min of stirring at this temperature, the suspension was allowed to
warm to r.t. and stirred for an additional 30 min, during which the
solid disappeared. The dark red solution was cooled to -78 ºC and
a solution of 2 (1.96 g, 10.4 mmol) in THF (20 mL) was added slow-
ly. The mixture was allowed to warm to r.t. over a period of 15 h
after which it was treated with H2O (25 mL). The aqueous phase
was extracted with Et2O (3 × 100 mL) and the combined organic
phases were dried (MgSO4). After removal of the solvent under re-
duced pressure and purification of the residue by flash chromatog-
raphy (silica gel; petroleum ether/EtOAc, 4:1), 5 was obtained as a
greenish oil; yield: 3.20 g (80%); [a]D25 +37.8 (c = 1.01, CHCl3).
H
Bn
(R)-2
(R)-1
O
d, e
O
Br
OH
Br
9
9
96 %
4
3
f, g 80 %
O
O
NBn
(R)-5
h, i
98 %
N
H
N
N
HN
IR (film): n = 2925, 2854, 2785, 1454, 1141, 1126, 1030, 700 cm-1.
j
OCH3
OCH3
1H NMR (300 MHz): d = 1.25-1.48 [m, 14 H, CH=CHCH2(CH2)7],
1.48-1.96 [m, 6 H, CH2CH(OCH2CH2O), NCHHCH2CH2], 2.02-
2.14 (m, 3 H, NCHHCH=CHCH2), 2.92 (m, 1 H, NCHH), 3.03 (d,
1 H, J = 12.7 Hz, C6H5CHHN), 3.12 (m, 1 H, CHN), 3.87 (m, 4 H,
OCH2CH2O), 4.01 (d, 1 H, J = 12.7 Hz, C6H5CHHN), 4.83 [t, 1 H,
J = 4.9 Hz, CH(OCH2CH2O)], 5.34 (ddt, 1 H, J = 10.8, 8.8, 1.4 Hz,
CH=CHCH2), 5.54 (dtd, 1 H, J = 10.8, 7.2, 0.7 Hz, CH2=CHCH2),
7.17-7.31 (m, 5 H, C6H5CHHN).
13C NMR (75 MHz): d = 22.09 (NCH2CH2CH2), 24.08, 27.77,
29.30-29.87 [(CH2)7, CH2CH(OCH2CH2O), NCH2CH2], 31.39
(CH=CHCH2), 33.94 [CH2CH(OCH2CH2O)], 53.18 (NCH2), 58.36
(NCH2C6H5), 61.81 (NCHCH=CH), 64.80 (OCH2CH2O), 104.70
[CH(OCH2CH2O)], 126.69, 128.07, 129.00 (Carom), 132.25, 132.49
(CH=CH), 139.65 (Carom).
CH3
9
9
94 %
NBn
(R,S)-6
NBn
(R,R,S)-7
k, l
de ≥ 96%
61 %
NH2
CH3
N
H
de, ee ≥ 96%
(S,R)-8
Reagents and conditions: (a) BzCl/NaOH, H2O, 0∞C, 2 h;
(b) LiAlH4/THF, reflux, 16 h; (c) (COCl)2/DMSO/Et3N, -40 Æ
25 ∞C; (d) (COCl)2/DMSO/Et3N, -78 Æ 25 ∞C; (e) HOCH2CH2OH/
p-TsOH/toluene, reflux, 16 h; (f) Ph3P/MeCN, reflux, 72 h; (g) t-
BuLi/THF, -78 Æ 25 ∞C, 2 h; (R)-2/THF, -78 Æ 25 ∞C, 15 h; (h) 1
M HCl/acetone, 25 ∞C, 14 h; (i) SAMP, 0 Æ 25 ∞C, 30 min; (j) MeLi/
THF, -78 Æ 25 ∞C, 15 h; (k) H2/Pd(OH)2-C/MeOH, 25 ∞C, 6 h; (l)
BH3•THF (excess), reflux, 4h
MS: m/z (%) = 385 (M+, 43), 294 (M+ - C7H7, 11), 160 (52), 91
(100).
Anal. calcd. for C25H39NO2 (385.6): C 77.87, H 10.19, N 3.63.
Found: C 77.41, H 10.31, N 4.08.
(2R)-[(11Z)-12-(1-Benzylpyrrolidin-2-yl)dodec-11-en-1-
Scheme
ylidene]-(2S)-(2-methoxymethylpyrrolidin-1-yl)amine[(R,S)-6]
To a solution of 5 (2.89 g, 7.5 mmol) in acetone (100 mL) was add-
ed HCl (1 M, 30 mL) and the mixture was stirred for 18 h under ar-
gon. After removal of the solvent, the residue was saturated with
solid K2CO3 and extracted with Et2O (3 × 100 mL). Drying
(MgSO4) of the combined organic extracts and removal of the sol-
vent yielded a pale red oil that was used directly in the next reaction.
The crude aldehyde prepared this way was treated with SAMP (0.99
g, 7.6 mmol) under argon at 0 ºC. The reaction mixture was allowed
to warm to r.t. and stirred for 30 min, before Et2O (150 mL) was
added. The solution was dried (MgSO4) and the solvent was re-
moved under reduced pressure. Purification of the residue by flash
chromatography (silica gel; petroleum ether/EtOAc, 2:1, containing
1% Et3N) yielded 6 as a pale yellow oil; yield: 3.33 g (98%); [a]D
-18.7 (c = 1.19, CHCl3).
IR (film): n = 2924, 2875, 1605, 1454, 1197, 1120, 737, 699 cm-1.
1H NMR (400 MHz): d = 1.25-1.38 [m, 12 H, CH=CHCH2(CH2)6],
1.41-1.49 (m, 2 H, CH2CH2CH=N), 1.50-1.84 (m, 4 H,
NCHHCH2CH2), 1.85-1.98 (m, 4 H, NNCHHCH2CH2), 2.05-2.13
(m, 3 H, NCHH, CH=CHCH2), 2.20 (m, 2 H, CH2CH=N), 2.70 (m,
1 H, NNCHH), 2.92 (m, 1 H, NCHH), 3.07 (d, 1 H, J = 12.8 Hz,
lowed by addition of Et3N (12 mL). The mixture was slowly
warmed to r.t. and H2O (30 mL) was added. The organic phase was
separated and the aqueous phase was extracted three times with a to-
tal of 300 mL of CH2Cl2 and the combined organic layers were
washed with 1 M HCl, sat. of NaHCO3 and brine. After drying
(MgSO4) and evaporation of the solvent, the crude aldehyde was
obtained as a colourless oil, which was added to a solution of p-tol-
uenesulfonic acid (50 mg) and ethylene glycol (9.3 g, 150 mmol) in
anhyd toluene (150 mL) and refluxed for 16 h. Et2O (200 mL) was
added and the mixture was washed with sat. NaHCO3 and brine. Re-
moval of the solvent under reduced pressure and purification of the
residue by flash chromatography (silica gel; petroleum ether/Et2O,
10:1) afforded 4 as a colourless oil; yield: 8.4 g (96%). The analyt-
ical data were consistent with the literature data.3a
25
Synthesis 2000, No. 4, 510–512 ISSN 0039-7881 © Thieme Stuttgart · New York

512
D. Enders, C. Thiebes
H, CHN), 3.33-3.45 (m, 6 H,
SHORT PAPER
C6H5CHHN), 3.12 (m,
1
slowly and the mixture was stirred for 2 h at r.t.. The solvent was
removed under reduced pressure and the residue was extracted with
Et2O (2 × 25 mL). It was then saturated with solid K2CO3 and ex-
tracted three times with a total of 150 mL of CH2Cl2. The residue
obtained after removal of the solvent was purified by column chro-
matography (silica gel; CH2Cl2/MeOH/NH4OH, 6:4:0.3) to afford
CH3OCHHCH, NNCHH), 3.56 (dd, 1 H, J = 8.5, 3.3 Hz,
CH3OCHH), 4.01 (d, 1 H, J = 12.7 Hz, C6H5CHHN), 5.40 (m, 1 H,
CH=CHCH2), 5.55 (m, 1 H, CH=CHCH2), 6.65 (t, 1 H, J = 5.6 Hz,
CH=N), 7.18-7.32 (m, 5 H, C6H5CHHN).
13C NMR (100 MHz): d = 22.01, 22.17, 26.58, 27.77, 27.87, 29.25-
29.86 [(NCH2CH2CH2, NNCH2CH2CH2, CH=CHCH2(CH2)7],
31.32 (CH=CHCH2), 33.15 (CH2CH=N), 50.57 (NNCH2), 53.16
(NCH2), 58.34 (NCH2C6H5), 59.20 (OCH3), 61.82 (NCHCH=CH),
63.52 (NNCHCH2O), 74.88 (CH2O), 126.70, 128.10, 129.06
(Carom), 132.10, 132.60 (CH=CHCH2), 139.50 (Carom), 139.69
(CH=N).
25
the final product 8; yield: 0.49 g (61%); [a]D +8.8 (c = 2.21,
22
22
CDCl3). {Lit.3a [a]D +9.3 (c = 0.15, CDCl3); Lit.3b [a]D +9.8
(c = 0.25, CDCl3)}. MS, IR, 1H NMR and 13C NMR analyses were
consistent with those given in the literature.3a
+
HRMS: m/z calcd for C17H36N2 : 268.287849. Found: 268.287818.
The (R)-MTPA diamide of 8 was prepared by dissolving 8 (0.052g,
0.2 mmol) in anhyd CH2Cl2 (2 mL) and adding a solution of (S)-
MTPA chloride (0.101 g, 0.4 mmol) in anhyd CH2Cl2 (1 mL) at
-78ºC. The mixture was allowed to warm to r.t. and sat. NH4Cl (2
mL) was added. The aqueous phase was extracted with CH2Cl2 (2 ×
4 mL) and the combined organic phases where dried (MgSO4). The
residue obtained after removal of the solvent (120 mg) was used for
1H NMR analysis.
MS: m/z (%) = 408 (M+ - CH2OCH3, 10), 339 (52), 160 (44), 91
(C7H7 , 100).
+
Anal calcd for C29H47N3O (453.4): C 76.77, H 10.44, N 9.26.
Found: C 76.66, H 10.93, N 9.26.
(2R)-[(12Z)-13-(2R)-(1-Benzylpyrrolidin-2-yl)tridec-12-en-2-
yl]-(2S)-(2-methoxymethylpyrrolidin-1-yl)amine [(R,R,S)-7]
To a solution of MeLi (1.5 M in Et2O, 7.3 mL, 11 mmol) under ar-
gon in anhyd THF (10 mL) at -78 ºC was slowly added a solution
of 6 (2.27 g, 5 mmol) in THF (5 mL). The mixture was allowed to
warm to r.t. over a period of 15 h and quenched with sat. aq
NaHCO3 solution (20 mL). The aqueous phase was extracted with
Et2O (3 × 100 mL). The combined organic phases were washed with
H2O (20 mL) and dried (MgSO4). Removal of the solvent under re-
duced pressure and purification of the residue by flash chromatog-
raphy (silica gel; EtOAc/petroleum ether, 1:1) afforded 7 as a
colourless oil; yield: 2.20 g (94%); [a]D26 -14.6 (c = 1.03, CHCl3).
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(Leibniz Prize, Sonderforschungsbereich 380) and the Fonds der
Chemischen Industrie (Kekulé-fellowship to CT). We thank Degus-
sa-Hüls AG, BASF AG and Bayer AG for the donation of chemi-
cals.
References
IR (film): n = 2925, 2853, 1673, 1462, 1197, 1124, 755, 684 cm-1.
(1) Proksch, P.; Witte, L.; Wrag, V.; Hartmann, T. Entomol.
Gener. 1993, 18, 1.
(2) Attygalle, A. B.; Xu, S.-C.; McCormick, K. D.; Meinwald, J.;
Blankespoor, C. L.; Eisner, T. Tetrahedron 1993, 49, 9333.
(3) (a) Shi, X.; Attygalle, A. B.; Xu, S.-C.; Ahmad V. U.;
Meinwald, J. Tetrahedron 1996, 52, 6859.
(b) Shi, X.; Attygalle, A. B.; Meinwald, J. Tetrahedron Lett.
1997, 38, 6479.
(4) For examples of alkaloid syntheses employing the SAMP-
hydrazone method see:
1H NMR (400 MHz): d = 1.01 (d, 3 H, J = 6.0 Hz, NHCHCH3)
1.25-1.38 [m, 16 H, CH=CHCH2(CH2)8], 1.48-1.98 (m, 8 H,
NCHHCH2CH2, NNCHHCH2CH2), 2.03-2.19 (m, 4 H, NCHH,
NNCHH, CH=CHCH2), 2.56 (m, 1 H, NNCHH), 2.80 (m, 1 H,
CHCH3), 2.92 (m, 1 H, NCHH), 3.02 (d, 1 H, J = 12.8 Hz,
C6H5CHHN), 3.12 (m,
1 H, CHN), 3.30-3.45 (m, 5 H,
CH3OCHHCH), 3.54 (dd, 1 H, J = 9.0, 3.8 Hz, CH3OCHH), 4.01
(d, 1 H, J = 12.8 Hz, C6H5CHHN), 5.39 (m, 1 H, CH=CHCH2),
5.56 (dt, 1 H, J = 11.0, 7.4 Hz, CH=CHCH2), 7.18-7.32 (m, 5 H,
C6H5CHHN).
Enders, D.; Bartzen, D. Liebigs Ann. Chem. 1991, 569.
Enders, D; Tiebes J.; De Kimpe, N.; Keppens, M.; Skoens, C.;
Smagghe, G.; Betz, O. J. Org. Chem. 1993, 58, 4881.
Enders, D.; Tiebes, J. Liebigs Ann. Chem. 1993, 173.
Enders, D.; Bartzen, D.; Liebigs Ann./Recl. 1997, 1115.
Enders, D.; Thiebes, C. J. Ind. Chem. Soc. 1999, 76, 561.
(5) Oxidation of 11-bromoundecan-1-ol with pyridinium
chlorochromate according to Ref. 3a resulted in significantly
lower yields.
13C NMR (100 MHz): d = 20.17 (NCHCH3), 21.03, 22.03, 22.12,
26.22, 27.77, 29.30-29.91 [NCH2CH2CH2, NNCH2CH2CH2,
CH=CHCH2(CH2)7], 31.34 (CH=CHCH2), 35.90 (CH2NCHCH3),
53.18 (NCH2), 54.06 (NCHCH3), 57.56 (NNCH2), 58.36
(NCH2C6H5), 59.07 (OCH3), 61.82 (NCHCH=CH), 65.75
(NNCHCH2O), 75.07 (CH2O), 126.71, 128.10, 129.04 (Carom),
132.16, 132.57 (CH=CHCH2), 139.56 (Carom).
MS: m/z (%) = 469 (M+, 24), 424 (M+ - CH2OCH3, 100), 339 (42),
91 (36).
HRMS: m/z calcd for C30H51N3O+: 469.40321. Found: 469.40314.
(6) Deur, J.; Miller, M. W.; Hegedus, L. S. J. Org. Chem. 1996,
61, 2871.
(7) Determined by 13C NMR prior to purification by flash
chromatography.
(2S,12’R)-2-(12’-Aminotridecyl)pyrrolidine [(S,R)-8]
(8) Pearlman, W. M. Tetrahedron Lett. 1967, 8, 1663.
(9) Enders, D.; Lochtman, R.; Meiers, M.; Müller, S.; Lazny, R.
Synlett 1998, 1182.
Hydrazine 7 (1.41 g, 3 mmol) was dissolved in MeOH (30 mL) and
hydrogenated over Pd(OH)2/C (0.3 g) under 3 bar pressure for 6 h.
The residue obtained after filtration and evaporation of the solvent
from the filtrate was dissolved in anhyd THF (15 mL). After addi-
tion of borane-tetrahydrofuran complex (1 M in THF, 30 mL, 30
mmol), the mixture was stirred under reflux under argon (balloon)
for 4 h. After it had reached r.t., 10% HCl (15 mL) was added very
Article Identifier:
1437-210X,E;2000,0,04,0510,0512,ftx,en;Z08699SS.pdf
Synthesis 2000, No. 4, 510–512 ISSN 0039-7881 © Thieme Stuttgart · New York