Stereoselective synthesis of dendrobate alkaloid (+)-241D and its C-4 epimer

Article abstract of DOI:10.1016/j.tetlet.2009.12.111

An efficient stereoselective synthesis of dendrobate alkaloid (+)-241D and its C-4 epimer was achieved from the inexpensive, commercially available starting material decanal (10) in an overall yield of 21.9% and 21.1%, respectively. This synthesis utilize

Full text of DOI:10.1016/j.tetlet.2009.12.111

Tetrahedron Letters 51 (2010) 1114–1116
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Tetrahedron Letters
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Stereoselective synthesis of dendrobate alkaloid (+)-241D and its C-4 epimer
*
R. Sateesh Chandra Kumar, G. Venkateswar Reddy, G. Shankaraiah, K. Suresh Babu, J. Madhusudana Rao
Natural Products Laboratory, Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient stereoselective synthesis of dendrobate alkaloid (+)-241D and its C-4 epimer was achieved
from the inexpensive, commercially available starting material decanal (10) in an overall yield of
21.9% and 21.1%, respectively. This synthesis utilizes the key steps of Maruoka asymmetric allylation,
one-pot epoxidation followed by nucleophilic addition of an organomagnesium reagent (Forsyth’s proto-
col) and subsequent functional group transformations.
Received 2 December 2009
Revised 16 December 2009
Accepted 20 December 2009
Available online 28 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Piperidine alkaloids
Alkaloid (+)-241D
Sharpless asymmetric dihydroxylation
Wacker oxidation
Substituted piperidines are among the most ubiquitous hetero-
cyclic building blocks in both natural products and synthetic
compounds with important biological activities.1 Simple 2,6-
disubstituted piperidines (solenopsins and isosolenopsins), iso-
lated from fire ant venom, are reported to possess a broad range
of activities such as necrotic, insecticidal, antibacterial, antifungal,
and anti-HIV.2 4-hydroxy-2,6-disubstituted piperidine alkaloid,
dendrobate alkaloid 241D, isolated from methanolic skin extracts
of Panamanian poison frogs Dendrobates speciosus and Dendrobates
pumilio, possesses potent biological activity.3 Synthetic racemic
alkaloid 241D and the parent 4-piperidone 3 (Fig. 1) were found
to be potent inhibitors for binding of perhydrohistrionicotoxin to
nicotinic receptor channels of electroplax membranes.4 In addition,
it has also been found that racemic alkaloid 241D blocks the action
of acetylcholine by a non-competitive blockade of the nicotinic
receptor channel complex.5
Owing to the challenges posed by the substitution pattern and
also due to the remarkable biological properties, the synthesis of
these compounds has attracted much attention. As a consequence
of the central role played by the ring system, a number of total syn-
theses of these compounds in racemic and optically active forms
have been established.6 Despite the availability of many synthetic
methods for this class of compounds, there still exists a need to de-
velop procedures more efficient than those currently in existence.
In continuation of our ongoing studies on the synthesis of bioactive
natural products,7 we became interested in various cis-2,4,6-
trisubstituted piperidine alkaloids. In this Letter, we report a new
approach to the stereoselective synthesis of dendrobate alkaloid
(+)-241D (1) and its C-4 epimer (2) based on the route shown in
Scheme 1, which makes use of Forsyth’s, Marouka asymmetric ally-
lation as a key reaction step in the overall sequence.
In an earlier study from our laboratory we had demonstrated
the versatility of Keck allylation and Grubb’s cross metathesis reac-
tions for the synthesis of the putative 2,6-disubstituted piperidine
alkaloids,7a which were isolated from the venom of fire ants of
genus Solenopsis. Our retrosynthetic strategy for the present syn-
thesis relies on the Maruoka asymmetric allylation approach start-
ing from decanal and Forsyth’s protocol. As shown in Scheme 1,
initial disconnection of 1 revealed fragment 6, which could be sub-
jected to reductive amination and diastereoselective cyclization to
realize the target molecule. The key step in this synthesis would
utilize one-pot epoxidation followed by the nucleophilic attack of
an organomagnesium reagent (Forsyth’s protocol) onto the appro-
priately functionalized 1,2-diol 7, without being affected by its dia-
stereoselectivity. The brevity of this analysis along with the
structural simplicity of the precursors makes this route attractive
for implementation.
O
OH
OH
C9H19
N
H
3
C9H19
N
H
1
C9H19
N
H
2
C11H23
N
H
C11H23
N
H
4
5
* Corresponding author. Tel.: +91 40 27193166; fax: +91 40 27160512.
E-mail address: janaswamy@iict.res.in (J. Madhusudana Rao).
Figure 1. Representative examples of 2,6-disubstituted piperidine alkaloids.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.111

R. Sateesh Chandra Kumar et al. / Tetrahedron Letters 51 (2010) 1114–1116
1115
OH
Cbz
NH OH
O
C9H19
N
CH3
6
H
1
Cbz
NHCbz
NH OH
OH
8
7
OH
Decanal (10)
9
Scheme 1. Retrosynthetic analysis of 1.
The total synthesis based on the above-mentioned plan was ini-
tiated with decanal (10) which was subjected to an enantioselec-
tive Maruoka allylation using titanium complex (S,S)-BINOL and
allyltri-n-butyltin to furnish the homoallylic alcohol 9 in 84% yield
with an excellent enantioselectivity of 98% ee (determined by chi-
ral HPLC).8 Protection of homoallylalcohol 9 as the tosyl ester (TsCl,
pyridine, DMAP, CH2Cl2, 92% yield)9 followed by reaction with
NaN3 in DMF at 70 °C led to the azide intermediate 11 in good
yields (79%).9 The azide 11 was then reduced to an amine using
LiAlH4 followed by protection with Cbz-Cl to afford the protected
homoallylamine 8.10 Sharpless asymmetric dihydroxylation of 8
with Ad-mix-b in (1:1) aq t-BuOH at 0 °C afforded diols 7 and 12
in 80:20 ratio as an inseparable diastereomeric mixture in 87%
yield,11 whose diastereomeric ratio was determined by chiral
HPLC.12
Although homoallylic alcohols are generally prepared in a com-
mon multistep sequence from 1,2-diols (generally diol converted
to epoxide in two-step sequence followed by nucleophilic open-
ing), we found that the one-pot epoxidation and nucleophilic open-
ing sequence for 1,2-diols (Forsyth’s protocol) gave higher yields
and resulted in a cleaner overall reaction. Thus, diol mixture 7
and 12 was subjected to one-pot epoxidation followed by ring
opening with vinyl magnesium bromide (Forsyth’s protocol) to af-
ford homoallyl alcohols 13 and 14 as separable diastereomers in
OH
b,c
a
O
10
9
N3
NHCbz
e
d
11
8
Cbz
NH OH
Cbz
NH OH
OH
+
OH
12
7
Cbz
Cbz
NH OH
NH OH
f
+
13
14
OH
Cbz
NH OH
O
h
g
13
N
H
1
6
OiPr
O
O
Ti
O
Ti
O
O
PriO
(S,S)-BINOL COMPLEX
Scheme 2. Synthesis of alkaloid (+)-241D. Reagents and conditions: (a) TiCl4, TIP, Ag2O, (S,S) BINOL, allyltributyl tin, DCM, 0 °C, 24 h, 84%; (b) TsCl, pyridine–DCM (1:1), 0 °C to
rt, 6 h, 92%; (c) NaN3, DMF, 70 °C, 3 h, 79%; (d) LiAlH4, THF, 0 °C to rt, 1 h then satd NaHCO3, Cbz-Cl, 90%; (e) AD mix-b, t-BuOH–H2O (1:1), 0 °C to rt, 48 h, 87%; (f) NaH,
tosylimidazole, THF, 0 °C, 0.5 h then CuI, vinyl magnesium bromide(1 M), ꢀ20 °C, 1 h, 70%; (g) PdCl2, CuCl, O2, THF–H2O (10:1), rt for 3 h, 85%; (h) 10% Pd/C, H2, EtOAc,
overnight, 77%.

1116
R. Sateesh Chandra Kumar et al. / Tetrahedron Letters 51 (2010) 1114–1116
OH
Cbz
NH OH
O
b
a
14
N
H
15
2
Scheme 3. Synthesis of C-4 epimer of alkaloid (+)-241D. Reagents and conditions: (a) PdCl2, CuCl, O2, THF–H2O (10:1), rt for 3 h, 83%; (b) 10% Pd/C, H2, EtOAc, overnight, 76%.
70% yield.13 These diastereomers were separated by the flash chro-
matography to yield pure compounds 13 and 14. A Wacker oxida-
(b) Numata, A.; Ibuka, I. Alkaloids from Ants and Other Insects. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1987; Vol. 31, pp 193–315.
2. Leclerq, S.; Thirionet, I.; Broeders, F.; Daloze, D.; Vander Meer, R.; Braeckman, J.
tion of 13 gave the corresponding carbonyl compound 6 in 85%
yield.14 The absence of olefinic signals and the presence of a methyl
singlet at d 2.13 in 1H NMR confirmed the Wacker oxidation prod-
uct 6. Finally, reductive amination followed by diastereoselective
cyclization in the presence of 10% Pd/C in ethyl acetate under H2
atmosphere led to the title compound 1 in 77% yield (Scheme
2).15 The spectral data obtained were in good agreement with
those reported in the literature [optical rotation of 1 is +3.2° (c
0.3, MeOH)].6
Having achieved a reliable synthesis of the key homoallylic
alcohol intermediate 14, we proceeded to use this compound for
the preparation of C-4 epimer of alkaloid (+)-241D (2). Accordingly,
the double bond present in 14 was converted into ketone 15 using
Wacker oxidation protocol (PdCl2, CuCl, O2, THF–H2O (10:1), rt).
Reductive amination followed by diastereoselective cyclization of
15 with 10% Pd/C in ethyl acetate afforded 2 as a single diastereo-
mer in 76% yield and with properties consistent with literature val-
ues6 (Scheme 3). All the intermediate compounds were well
characterized by IR, NMR, and mass spectral techniques.16
In conclusion, we have developed an efficient stereoselective
protocol for the preparation of dendrobate alkaloid 1 and its C-4
epimer 2 by employing Maruoka asymmetric allylation and For-
syth’s reaction sequence as the key steps. This general synthetic
route demonstrates its versatility toward the synthesis of highly
functionalized piperidines and also paves the way for the structur-
ally related analogs. On the basis of the route described herein, fur-
ther work toward preparation of the library of 2,4,6-piperidinol
analogs for biological analysis is in progress in our laboratory.
C. Tetrahedron 1994, 50, 8465.
3. (a) Daly, J. W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25, 1023; (b) Edwards,
M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188.
4. Edwards, M. W.; Garraffo, H. M.; Daly, J. W. Synthesis 1994, 1167.
5. Daly, J. W.; Nishizawa, Y.; Edwards, M. W.; Waters, J. A.; Aaronstam, R. S.
Neurochem. Res. 1991, 16, 489.
6. Previous asymmetric synthesis of 1 and its C-4 epimer 2: (a) Chenevert, R.;
Dickmann, M. J. Org. Chem. 1996, 61, 3332; (b) Ciblat, S.; Calinaud, P.; Canet, J.-
L.; Troin, Y. J. Chem. Soc., Perkin Trans. 1 2000, 353; (c) Ma, D.; Sun, H. Org. Lett.
2000, 2, 2503; (d) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169; (e)
Monfray, J.; Gelas-Mialhe, Y.; Gramain, J.-C.; Remuson, R. Tetrahedron:
Asymmetry 2005, 16, 1025; (f) Gnamm, C.; Krauter, C. M.; Brodner, K.;
Helmchen, G. Chem. Eur. J. 2009, 15, 2050; g Previous racemic synthesis: Ref.
4.; (h) Girard, N.; Hurvois, J.-P. Tetrahedron Lett. 2007, 48, 4097.
7. (a) Kumar, R. S. C.; Sreedhar, E.; Reddy, G. V.; Babu, K. S.; Rao, J. M. Tetrahedron:
Asymmetry 2009, 20, 1160; (b) Sreedhar, E.; Kumar, R. S. C.; Reddy, G. V.;
Robinson, A.; Babu, K. S.; Rao, J. M. Tetrahedron: Asymmetry 2009, 20, 440; (c)
Reddy, G. V.; Kumar, R. S. C.; Babu, K. S.; Rao, J. M. Tetrahedron Lett. 2009, 50,
4117.
8. Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708.
9. Capaccio, C. A. I.; Varela, O. Tetrahedron: Asymmetry 2000, 11, 4945.
10. Randl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879.
11. Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 2483.
12. The diastereoselectivity was determined by HPLC [YMC silica column,
150 ꢁ 4.6 mm, 5
l, 210 nm, eluent, i-propanol/hexane, 8:92, 10 lL injection
volume, flow rate 1 mL/min retention time 9.57 & 11.05 min].
13. Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122.
14. Sabitha, G.; Sudhakar, K.; Reddy, N. M.; Kumar, M. R.; Yadav, J. S. Tetrahedron
Lett. 2005, 46, 6567.
15. Randl, S.; Blechert, S. Tetrahedron Lett. 2004, 45, 1167.
16. Spectral data for selected compounds: Compound 6: White solid, mp 95–97 °C
½
a 2D5
ꢂ
ꢀ2.8 (c 0.75, CHCl3) 1H NMR (300 MHz, CDCl3): d 7.36–7.22 (m, 5H), 5.13–
4.98 (m, 3H), 4.14–3.97 (m, 1H), 3.86–3.67 (m, 1H), 2.68–2.31 (m, 2H), 2.13 (s,
3H), 1.60–1.12 (m, 18H), 0.88 (t, 3H, J = 6.2 Hz). 13C NMR (75 MHz, CDCl3): d
207.6, 157.0, 136.6, 128.4, 128.0, 66.7, 64.4, 50.2, 48.3, 42.8, 35.4, 31.9, 30.8,
29.6, 29.5, 29.4, 26.2, 22.7, 14.2. FABMS: m/z 392 [M+1]+.
Compound 13: White solid, mp 92–94 °C ½a D25
ꢂ
+1.6 (c 1.08, CHCl3) 1H NMR
(300 MHz, CDCl3): d 7.36–7.23 (m, 5H), 5.88–5.68 (m, 1H), 5.16–4.96 (m, 4H),
4.91–4.78 (br d, 1H), 3.88–3.72 (m, 1H), 3.71–3.54 (m, 1H), 2.29–2.05 (m, 2H),
1.57–1.15 (m, 18H), 0.88 (t, 3H, J = 6.2 Hz). 13C NMR (75 MHz, CDCl3): d 157.2,
136.4, 135.2, 128.4, 128.1, 128.0, 117.0, 66.9, 66.8, 48.3, 43.4, 41.7, 35.6, 29.6,
29.5, 29.3, 26.2, 22.7, 14.2. FABMS: m/z 376 [M+1]+.
Acknowledgments
The authors gratefully acknowledge the keen interest shown by
Dr. J. S. Yadav, Director, IICT, Hyderabad. R.S.C.K. and G.V.R. thank
CSIR and UGC, New Delhi, for financial support.
Compound 8: White Solid, mp 60–62 °C ½a D25
ꢂ
ꢀ11 (c 1, CHCl3), 1H NMR
(300 MHz, CDCl3): d 7.39–7.20 (m, 5H), 5.83–5.64 (m, 1H), 5.12–4.98 (m, 2H),
4.63–4.52 (br d, 1H), 3.76–3.60 (m, 1H), 2.32–2.08 (m, 2H), 1.56–1.12 (m, 16H),
0.88 (t, 3H, J = 6.4 Hz). 13C NMR (75 MHz, CDCl3): d 155.7, 136.7, 134.2, 128.4,
128.0, 117.8, 66.4, 50.5, 39.5, 34.6, 31.9, 29.6, 29.3, 25.9, 22.7, 14.2. IR (KBr):
mmax 3312, 2920, 2851, 1686, 1348.56, 1265, 1123 cmꢀ1; FABMS: m/z 332
[M+1]+.
References and notes
1. (a) Strunz, G. M.; Findlay, J. A. Pyridine and Piperidine Alkaloids. In The
Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 26, pp 89–174;