Anodic cyanation of C-4 hydroxylated piperidines: total synthesis of (±)-alkaloid 241D

Article abstract of DOI:10.1016/j.tetlet.2007.04.010

A stereospecific synthesis of dendrobates (±)-alkaloid 241D is described. Key steps in this approach involved the stepwise electrochemical synthesis of C-4 substituted α-aminonitriles and their alkylation with iodomethane and 1-bromononane, respectively.

Full text of DOI:10.1016/j.tetlet.2007.04.010

Tetrahedron Letters 48 (2007) 4097–4099
Anodic cyanation of C-4 hydroxylated piperidines:
total synthesis of ( )-alkaloid 241D
Nicolas Girard and Jean-Pierre Hurvois*
Laboratoire d’Electrochimie et Catalyse, UMR 6226, Universite´ de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France
Received 12 March 2007; revised 30 March 2007; accepted 3 April 2007
Available online 11 April 2007
Abstract—A stereospecific synthesis of dendrobates ( )-alkaloid 241D is described. Key steps in this approach involved the stepwise
electrochemical synthesis of C-4 substituted a-aminonitriles and their alkylation with iodomethane and 1-bromononane, respec-
tively. The N-aryl group was removed in the last step through a Birch dearomatization followed by the hydrolysis of the inter-
mediate dienamines.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Alkaloid 241D (1) was isolated in minute quantities in
1988 by Edwards and Daly1 from the methanolic skin
extracts of the Panamanian poison frog Dendrobates
speciosus. The structure of 1 was determined by 1H
NMR spectroscopy and was cis,cis-4-hydroxy-2-
methyl-6-nonylpiperidine. This 2,6-dialkyl substitution
pattern is found in many animal alkaloids and represen-
tative members of this family are drawn in Figure 1.
ants of the genus Solenopsis, whereas dihydropinidine
(4)3 was extracted as a minor constituent from the Mex-
ican bean beetle Epilachna varivestis. From a pharmaco-
logical standpoint, racemic alkaloid 241D proved to be a
noncompetitive blocker of acetylcholine to ganglionic
nicotinic receptor channels.4 These results were akin
to that observed with histrionicotoxin, the most widely
used blocker for nicotinic receptors. These interesting
biological properties coupled with the impossibility to
isolate more than milligram quantities from natural
sources, have incited chemists to elaborate new synthetic
schemes aimed at the synthesis of 1. The key step in these
methodologies generally involved intramolecular Man-
nich-type cyclizations,5 which led to the stereoselective
preparation of 1. In the continuation of our program
aimed at the electrochemical preparation of 2,6-dial-
kylpiperidines6 we became attracted to the synthesis of
1 as a means to develop new a-aminonitrile chemistry
that may be of more general utility. For this, we have ap-
plied a strategy delineated in Scheme 1, which is based on
the stepwise elaboration of piperidine 5. The requisite
alkyl chains should be introduced via the alkylation of
conveniently substituted a-aminonitriles, and we were
also curious to investigate what could be the influence
of the hydroxyl group (or its protected form) at C(4) con-
cerning the stereochemical outcome of our synthetic
plan. Thus, N-phenyl-piperidone 6 was selected as the
starting material as it is readily accessible from the bimo-
For example, Solenopsin A (2)2 together with its cis iso-
mer isosolenopsin A (3), were isolated from the venom of
Figure 1. 2,6-Dialkyl-piperidine alkaloids.
`
lecular Caubere condensation between bromobenzene
and commercially available 4-piperidone ethylene ketal.7
Keywords: Alkaloids; Piperidines; Anodic cyanation; Electrochemistry;
a-aminonitriles.
Corresponding author. Tel.: +33 223 236 548; fax: +33 223 235
*
The results of our synthesis of ( )-alkaloid 241D are
reported in this Letter.
967; e-mail: jean-pierre.hurvois@univ-rennes1.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.010

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N. Girard, J.-P. Hurvois / Tetrahedron Letters 48 (2007) 4097–4099
selectivity for the reduction of 9 can be understood by
the prior formation of an iminium intermediate which
is locked in a single conformation according to the pres-
ence of the O–THP group at C-4. Axial attack of the hy-
dride anion (under a stereoelectronic control)11 on this
conformer adequately accounts for the formation of 10
as the single product. For the synthesis of ( )-1, we were
faced with the stereo- and regioselective installation of
the nonyl chain at C-6. To this end, the formation of
the intermediate a-aminonitrile 11 seemed to us an obvi-
ous solution to this problem (see Scheme 2).
Scheme 1. Retrosynthetic analysis of alkaloid ( )-241D.
Indeed, several studies performed in our laboratory12
and in others13 have shown that 2-alkyl-piperidine deriv-
atives could be selectively oxidized at C(6) with a high
degree of regioselectivity. Accordingly, electrolysis of
10 was made under similar conditions than that for com-
pound 7 providing a-aminonitrile 11 (79% yield) as mix-
ture (9:1) of diastereomers, which could be easily
Acid-catalyzed deprotection of piperidone 6 followed by
the reduction of the intermediate aminoketone with an
excess of NaBH4 in EtOH at 20 ꢁC provided the amino-
alcohol, which was protected as the THP derivative 7
(84% yield from 6).
With the required amine in hand, we decided first to
introduce the methyl group at C(2) employing the
a-aminonitrile chemistry. Thus, the electrolysis
(Ep = +0.90 V/SCE, NaCN, 2.3 F/mol) of a methanolic
solution of 7 was made in a divided cell equipped with a
glassy carbon electrode as anode and a carbon rod as
cathode.8 a-Aminonitrile 8 was obtained as a mixture
(4/1) of diastereoisomers9 which could be separated by
column chromatography. On the basis of previous
investigations one can assume that the major adduct
has a (2R*,4R*) relative configuration in which the cya-
nide group is axially oriented. Reaction of a-amino-
nitrile 8 (trans/cis mixture, 4:1) with 1.2 equiv of LDA
(prepared from diisopropylamine and n-BuLi) at
À60 ꢁC, and of the resultant anion with iodomethane
at À20 ꢁC, provided adduct 9 (72% yield).10 The latter
was reduced with NaBH4 in EtOH at 20 ꢁC for 12 h,
to give the disubstituted piperidine 10 as a single diaste-
reomer (97% yield). At this stage, it was felt that 10 has a
(2R*,4R*) relative configuration. The high diastereo-
1
separated by column chromatography. The H NMR
spectrum of the major compound showed the methyl
group as a doublet (3J = 6.0 Hz) system centered at
d = 0.96 ppm. Likewise, a similar doublet system was
found at d = 1.06 ppm in the 1H NMR spectrum of
the minor diastereomer. Taken together, these observa-
tions indicate that oxidation occurred selectively at C(6).
The alkylation of 11 (cis/trans mixture = 1:9) with 1-
bromononane led to the formation of 12 in a moderate
Scheme 2. Synthesis of amine rac-10. Reagents and conditions: (1) (i)
THF–HCl 1.5 N (10:1) 65 ꢁC, 24 h; (ii) NaBH4 (4 equiv), EtOH, rt
12 h; (iii) DHP (7 equiv), PTSA (10 mol %), CH2Cl2, 40 ꢁC, 12 h; (2)
À2eÀ, –H+, MeOH, NaCN (6 equiv), LiOAc (20 g/L); (3) LDA
(1.2 equiv) THF, CH3I (1.2 equiv), À78 ꢁC to 5 ꢁC, 12 h; (4) NaBH4
(4 equiv) EtOH, rt 12 h.
Scheme 3. Completion of the synthesis of ( )-alkaloid 241D. Reagents
and conditions: (1) À2eÀ, –H+, MeOH, NaCN (7 equiv), LiOAc (20 g/
L); 2) LDA (1.2 equiv) THF, n-C9H19Br (1.2 equiv), À78 ꢁC to 5 ꢁC,
12 h; (3) NaBH4 (4 equiv) EtOH, rt 12 h; (4) (i) THF–H2SO4 1.5 N
(10:1) 65 ꢁC, 6 h; (ii) Li (100 equiv), liq. NH3–THF–EtOH (20:10:6)
À45 ꢁC, 2 h, H2SO4–H2O–EtOH (0.5:4.5:5), 60 ꢁC, 1 h.

N. Girard, J.-P. Hurvois / Tetrahedron Letters 48 (2007) 4097–4099
4099
of methanol containing 2 g of lithium acetate dihydrate
and 1.07 g (26.8 mmol, 7.0 equiv) of sodium cyanide. The
resulting solution was placed in a divided cell and oxidized
at a planar vitreous graphite electrode at (+0.9 V/SCE).
After the consumption of 870 coulomb (2.35 F/mol), the
electrolysis was stopped. The solvent was evaporated in
vacuo and the crude material was taken up with water
(100 mL) and extracted with ether (100 mL · 2). The
combined organic layers were dried over MgSO4 and
concentrated. The crude reaction mixture was purified by
silica column chromatography (diethyl ether/petroleum
ether, 1:1) to afford (2S*,4S*)-8 (0.820 g, 75%, yellow oil)
45% yield as a single stereoisomer (99% de). Several at-
tempts were made to improve the conversion yield, but
all of them remain unsuccessful. Although a single ad-
duct was detected by spectroscopic means (1H and 13C
NMR), it was not possible to univocally determine the
stereochemistry at this stage. However, one can assume
that the substituents were all in a cis configuration as
drawn in Scheme 3. Completion of the synthesis of
( )-1 was made as follows. The acidic cleavage of the
tetrahydropyranyl ether resulted in the formation of 2-
methyl-6-nonyl-1-phenyl-piperidin-4-ol whose phenyl
ring was reduced with Li (100 equiv) in a mixture of
THF and liquid ammonia in the presence of EtOH as
proton donor (Scheme 3).14 After work-up, the interme-
diate crude dienamine mixture was immediately hydro-
lyzed in aqueous acidic ethanol to produce ( )-1 (73%
yield from 13) as a white solid which melted at 97 ꢁC.
Spectral data of ( )-1 (1H, 13C NMR, and m/z) were
identical with those reported in the literature.5b
1
as the major diastereomer. H NMR (300 MHz, CDCl3):
d = 1.45–1.62 (m, 5H), 1.63–2.08 (m, 4H), 2.10–2.42 (m,
2H), 3.02–3.13 (m, 1H), 3.43–3.58 (m, 1H), 3.84–4.04
(m, 2H), 4.60–4.65 (m, 1H), 4.66–4.70 (m, 1H), 6.95–6.98
(m, 3H), 7.25–7.31 (m, 2H). 13C NMR (75 MHz, CDCl3):
d = 19.87, 25.32, 31.05, 31.08, 31.18, 32.94, 34.59, 35.80,
45.07, 45.23, 50.97, 51.02, 62.94, 69.98, 70.64, 97.41, 98.12,
118.25, 122.27, 129.34. HRMS: m/z calcd for C17H22N2O2
[M+]: 286.1681; found, 286.1665.
10. Husson, H. P.; Royer, J. Chem. Soc. Rev. 1999, 6, 383–394.
11. (a) Deslongchamps, P. In Stereoelectronic Effects in
Organic Chemistry; Baldwin, J., Ed.; Pergamon Press:
Oxford, 1983; (b) Stevens, R. V. Acc. Chem. Res. 1984, 17,
289–296.
12. Malassene, R.; Vanquelef, E.; Toupet, L.; Hurvois, J. P.;
Moinet, C. Org. Biomol. Chem. 2003, 1, 547–551.
13. For the regioselective methoxylation of 2-substituted
piperidines see: (a) Laurent, P.; Braekman, J. C.; Daloze,
D. Eur. J. Org. Chem. 2000, 2057–2062; (b) Bodmann, K.;
Bug, T.; Steinbeisser, S.; Kreuder, R.; Reiser, O. Tetrahe-
In summary, a stereoselective synthesis of ( )-alkaloid
241D has been developed. The alkylation–reduction
steps were performed stereoselectively to place the sub-
stituents in a cis relative configuration.
Acknowledgement
N.G. thanks the MENRT for a grant.
´
dron Lett. 2006, 47, 2061–2064; (c) Driessens, F.; Hootele,
C. Can. J. Chem. 1992, 70, 2722–2725.
References and notes
14. Synthesis of alkaloid ( )-241D. Compound 13 (0.36 g,
1.31 mmol) was dissolved in a THF–H2SO4 1.5 N (10:1)
mixture and stirred at +65 ꢁC for 6 h. Work-up and
purification by column chromatography (diethyl ether/
petroleum ether, 1:1) afforded 2-methyl-6-nonyl-1-phenyl-
piperidin-4-ol (0.26 g, 96%), which was dissolved in a
mixture of liquid ammonia (20 mL) THF (10 mL) and
ethanol (6 mL). Then, Li (0.55 g, 80 mmol) was added in
small pieces over a 1 h period upon which the solution
became blue. Stirring was continued for 2 h and the
solution was quenched with an excess of ethanol (5 mL)
and ammonia was allowed to evaporate under a well
ventilated hood. Water (20 mL) was added and the
resulting aqueous mixture was extracted with cyclohexane
(50 mL · 2). The combined organic layers were dried with
MgSO4 and concentrated in vacuo to afford a mixture of
crude enamines which were dissolved in a H2SO4/H2O/
EtOH (0.5:5.0:4.5) mixture. The solution was heated at
60 ꢁC for 1 h and the solvents were evaporated. The
sulfate of ( )-1 was dissolved in water and the solution
was made basic by the addition of NaOH pellets. The free
amine was extracted with diethyl ether (50 mL · 2) and the
combined organic phases were dried over MgSO4 and
concentrated. Purification by column chromatography
with diethyl ether saturated with gaseous ammonia gave
( )-1 (0.14 g, 76%) as a white solid, mp = 97 ꢁC. 1H NMR
(300 MHz, CDCl3): d = 1.47 (t, 3J = 7.10 Hz, 3H), 1.62
1. Edwards, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188–
1197.
2. For a review on the solenopsins see: Leclercq, S.; Daloze,
D.; Braekman, J. C. Org. Prep. Proced. Int. 1996, 28, 501–
503.
3. Attygale, A. B.; Xu, S. C.; McCormick, K. D.; Meinwald,
J.; Blankespoor, C. L.; Eisner, T. Tetrahedron 1993, 49,
9333–9342.
4. Edwards, M. W.; Garraffo, H. M.; Daly, J. W. Synthesis
1994, 1167–1170.
5. (a) Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503–2505; (b)
Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem.
Soc., Perkin Trans.1 2000, 353–357; (c) Davis, F. A.;
Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169–3171; (d)
Monfray, J.; Gelas-Miahle, Y.; Gramain, J.-C.; Remuson,
R. Tetrahedron: Asymmetry 2005, 16, 1025–1034.
6. Girard, N.; Gautier, C.; Malassene, R.; Hurvois, J.-P.;
Moinet, C.; Toupet, L. Synlett 2004, 2005–2009.
7. (a) Girard, N.; Hurvois, J.-P.; Moinet, C.; Toupet, L. Eur.
J. Org. Chem. 2005, 1, 2269–2280, and references cited
therein; For a recent metal-catalyzed synthesis of N-aryl
piperidones see: (b) Scho¨n, U.; Messinger, J.; Buckendahl,
M.; Prabhu, M. S.; Konda, A. Tetrahedron Lett. 2007, 48,
2519–2525.
8. For a general survey on the oxidation of nitrogen-
containing compounds see: (a) Steckan, E. In Organic
Electrochemistry; Lund, E., Hammerich, O., Eds.; Marcel
Dekker: New York, 2001; pp 545–588; (b) Shono, T.
Tetrahedron 1984, 40, 811–850.
3
3
(sext, J = 12.5 Hz, 2H), 1.80 (d, J = 6.5 Hz, 3H), 2.65–
3.20 (s, br, 2H), 1.95–1.42 (m, 16H), 1.83–1.88 (m, 2H),
2.45–2.55 (m, 1H), 2.60–2.64 (m, 1H), 3.57–3.62 (m, 1H).
13C NMR (75 MHz, CDCl3): d = 14.06, 22.43, 22.63,
26.02, 29.28, 29.52, 29.54, 29.73, 31.85, 36.77, 41.69, 43.85,
50.17, 54.87, 68.96. HRMS: m/z calcd for C15H31NO
[M+]: 240.2327; found, 240.2325.
9. Procedure for the synthesis of (2S*,4S*)-1-phenyl-4(tetra-
hydro-2H-pyran-2-yloxy)piperidine-2-carbonitrile
Compound 7 (1.0 g, 3.83 mmol) was dissolved in 100 mL
(8).