(N-tert-butanesulfinyl)imines in alkaloid synthesis: Concise formal syntheses of the dendrobate alkaloid (+)-241D and Its C-4 epimer

Article abstract of DOI:10.1055/s-0031-1289634

Concise formal syntheses of the dendrobate alkaloid (+)-241D and its C-4 epimer are described by means of a highly diastereoselective Barbier-type indium-mediated allylation strategy involving an (S)-(N-tert-butanesulfinyl) imine. Georg Thieme Verlag Stut

Full text of DOI:10.1055/s-0031-1289634

PAPER
83
(N-tert-Butanesulfinyl)imines in Alkaloid Synthesis: Concise Formal Syntheses
of the Dendrobate Alkaloid (+)-241D and Its C-4 Epimer1
(
N
-
tert-Butanesulf
o
inyl)imines
i
n
n Alkaloid
S
g
ynthesis ara Damodar, Biswanath Das*
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India
Fax +91(40)27160512; E-mail: biswanathdas@yahoo.com
Received 17 August 2011; revised 4 November 2011
Abstract: Concise formal syntheses of the dendrobate alkaloid (+)-
241D and its C-4 epimer are described by means of a highly diaste-
reoselective Barbier-type indium-mediated allylation strategy in-
volving an (S)-(N-tert-butanesulfinyl)imine.
Me(CH2)n
N
H
1
Me(CH2)n
N
H
2
n = 8, 10, 12, 14
n = 8, 10, 12, 14
Key words: (N-tert-butanesulfinyl)imine, piperidine alkaloids, al-
dol reaction, alkaloid-241D, allylation
OH
OH
O
H19C9
N
H
3
H19C9
N
H
4
H19C9
N
H
5
Nitrogen-containing compounds are essential to life and
they play a vital role in the metabolism of all living cells.
A previous report stated that more than 75% of drugs and
Figure 1 Selected examples of 2,6-disubstituted and 2,4,6-trisubsti-
drug candidates incorporate an amine functionality.2 tuted piperidine alkaloids
Among the numerous naturally occurring nitrogen-con-
taining compounds, piperidine alkaloids are widespread
in Nature and many of these are known to possess signif-
icant biological properties.3 Considering the wide spec-
trum of biological activity these compounds exhibit, it is
not surprising that between 1988 and 1998 a large number
of piperidine-derived compounds were described in clini-
cal and preclinical studies.4 In particular, simple 2,6-di-
substituted piperidines (solenopsins 1 and isosolenopsins
2, Figure 1) isolated from the venom of fire ants of the ge-
nus Solenopsis were found to display a range of biological
activity including insecticidal, antibacterial, necrotic, an-
tifungal, and anti-HIV.5 As a result, various syntheses of
piperidine-derived molecules have been reported.6
materials. Hence, the development of additional synthetic
routes to this dendrobate alkaloid are highly desirable.
(N-tert-Butanesulfinyl)imines, which can be prepared
from readily available chiral N-tert-butanesulfinamides
and an aldehyde (or ketone), exhibit unique reactivity, hy-
drolytic stability and stereoselectivity in various reactions
and have been proven to be extremely versatile chiral re-
agents.10 In continuation of our work11 on the synthesis of
natural bioactive nitrogen compounds, herein we describe
a convenient route for the concise formal synthesis of the
dendrobate alkaloid (+)-241D (3) and its C-4 epimer 4 via
a highly diastereoselective Barbier-type indium-mediated
allylation strategy involving an (S)-(N-tert-butanesulfi-
nyl)imine.
The alkaloid (+)-241D (3) is a 4-hydroxy-2,6-disubstitut-
ed piperidine alkaloid found in amphibians.7 It was isolat-
ed as a major alkaloid from Dendrobates speciosus and
occurs as a trace alkaloid in Dendrobates pumilio.8 The
synthetic racemic alkaloid-241D and the parent 4-piperi-
done 5 (Figure 1) have been found to be potent inhibitors
of the binding of perhydrohistrionicotoxin to nicotinic re-
ceptor channels of electroplax membranes.9 In addition, it
has been found that the racemic alkaloid-241D blocks the
action of acetylcholine by non-competitive blockade of
the nicotinic receptor channel complex.8 Therefore, these
compounds have become important synthetic targets due
to their scarcity in natural sources and notable physiolog-
ical effects. Several synthetic methods have been reported
for the synthesis of this alkaloid in racemic and optically
active form.9 However, many of these routes are not effi-
cient for scale-up and use non-readily available starting
Our retrosynthetic approach to alkaloid 3 is outlined in
Scheme 1. The natural product would be envisioned to
arise from d-amino-b-hydroxy ketone 11 as the key inter-
mediate. Compound 11 would be generated by aldol reac-
tion of acetone with the corresponding aldehyde, which in
turn can be obtained by ruthenium-catalysed oxidative
cleavage of the homoallyl amine 9. Compound 9 can be
generated by cleavage of the tert-butanesulfinyl group of
N-tert-butanesulfinyl homoallyl amine 8 followed by ben-
zyloxycarbonyl (Cbz) protection of the resulting free
amine. Finally, N-tert-butanesulfinyl homoallyl amine 8
would be obtained by Barbier-type indium-mediated ally-
lation of (N-tert-butanesulfinyl)imine 7, which in turn can
be produced from commercially available (S)-N-tert-bu-
tanesulfinamide and decan-1-ol (6).
The synthesis of (+)-241D (4) was initiated by oxidation
of decan-1-ol (6) with pyridinium chlorochromate (PCC)
at room temperature followed by anhydrous copper(II)
sulfate mediated condensation with (S)-N-tert-butane-
sulfinamide to produce the corresponding (S)-(N-tert-bu-
SYNTHESIS 2012, 44, 83–86
x
x.
x
x
.
2
0
1
1
Advanced online publication: 02.12.2011
DOI: 10.1055/s-0031-1289634; Art ID: Z81111SS
© Georg Thieme Verlag Stuttgart · New York

84
K. Damodar, B. Das
PAPER
OH
Cbz
NH OH
O
H19C9
N
11
H
3
S
HN
O
NHCbz
9
8
S
N
O
OH
H
7
6
Scheme 1 Retrosynthesis of the dendrobate alkaloid (+)-241D (3)
tanesulfinyl)imine 7 in 88% yield.12 In this reaction, creases the reactivity of the electrophilic centre of the
anhydrous copper(II) sulfate acts as a Lewis acid catalyst imine, while coordination of the metal to the oxygen of
as well as an effective water scavenger. The sulfinyl imine the sulfinyl group, being responsible for the allylation,
7 was then subjected to indium-mediated allylation under takes place at the re face of (S)-(N-tert-butanesulfi-
Barbier conditions.13 We previously applied this strategy nyl)imine 7. Removal of the sulfinyl group followed by
for the synthesis of (R)-coniine.11a The reaction was run protection of the resulting amine with benzyl chlorofor-
on a 5.0 mmol scale and the corresponding N-tert-butane- mate (CbzCl) afforded protected homoallyl amine 9 in a
sulfinyl homoallyl amine 8 was obtained in 86% yield moderate 67% yield. Compound 9 was obtained in excel-
with excellent diastereoselectivity (96:4 diastereomeric lent optical purity (97% ee) as determined by chiral high-
1
ratio according to H NMR spectroscopy). A six-mem- performance liquid chromatography (Chiral Pak-AD-H,
bered-ring chelation-control transition state (Figure 2) is 250 × 4.6 mm). We next subjected homoallyl amine 9 to
consistent with the high level of stereocontrol observed catalytic oxidative cleavage of the alkene using rutheni-
and with the configuration of the newly created stereogen- um(III) chloride–sodium periodate in acetonitrile–water
ic centre. Coordination of indium to the nitrogen atom in-
S
H
S
N
O
HN
O
a
b
6
7
8
NHCbz
NHCbz
c
d
+
CHO
9
10
Cbz
Cbz
NH OH
O
NH OH
O
e
11
12
OH
Cbz
NH OH
O
O
ref. 9i
ref. 9i
H19C9
N
H
3
11
OH
Cbz
NH OH
H19C9
N
H
4
12
Scheme 2 Reagents and conditions: (a) (i) PCC, CH2Cl2, r.t., 2 h, 90%; (ii) (S)-tert-butanesulfinamide, CuSO4 (anhyd), CH2Cl2, r.t., 24 h,
88%; (b) CH2=CHCH2Br, In, THF, 66 °C, 4 h, 86%; (c) (i) 4 M HCl–1,4-dioxane, MeOH, r.t., 30 min; (ii) CbzCl, sat. aq NaHCO3, 1 h, 67%
(over 2 steps); (d) RuCl3·H2O (5 mol%), NaIO4, MeCN–H2O (6:1), r.t., 2 h, 65%; (e) acetone, sat. aq NaOH, 45 min, 69%.
Synthesis 2012, 44, 83–86
© Thieme Stuttgart · New York

PAPER
(N-tert-Butanesulfinyl)imines in Alkaloid Synthesis
85
1H NMR (200 MHz, CDCl3): d = 8.01 (t, J = 5.0 Hz, 1 H), 2.49 (td,
J = 7.0, 5.0 Hz, 2 H), 1.66–1.57 (m, 2 H), 1.38–1.22 (m, 12 H), 1.17
(s, 9 H), 0.87 (t, J = 6.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 169.8, 56.4, 36.1, 31.8, 29.4, 29.3,
29.2, 25.5, 22.6, 22.3, 14.1.
ESI-MS: m/z 260 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H29NOSNa: 282.1867;
t-Bu
H
N
S
O
[In]
R
Figure 2 Chelation-control model of the indium-mediated Barbier-
type allylation of (S)-(N-tert-butylsulfinyl)imine 7 [R = C9H19]
found: 282.1878.
(6:1) to give the corresponding aldehyde 10 in 65%
yield.14
(S)-2-Methyl-N-[(S)-tridec-1-en-4-yl]propane-2-sulfinamide (8)
A mixture of In powder (0.748 g, 6.5 mmol) and 3-bromoprop-1-
ene (0.6 mL, 6.5 mmol) in THF (7 mL) was heated at 66 °C for 15
min under an N2 atm. (N-tert-Butanesulfinyl)imine (7) (1.295 g, 5.0
mmol) in THF (15 mL) was added dropwise and the mixture stirred
at the same temperature for 4 h. The progress of the reaction was
monitored by TLC. The reaction was quenched with sat. aq NH4Cl
soln, filtered through a pad of MgSO4, and rinsed thoroughly with
EtOAc. The layers were separated and the aq fraction was extracted
with EtOAc (2 × 50 mL). The combined organic layers were dried
over anhyd Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, hex-
ane–EtOAc, 3:2) to afford compound 8 (1.294 g, 86%) as a pale-
yellow liquid.
[a]D27 +44.9 (c 0.91, CHCl3).
IR (neat): 3443, 2926, 1638, 1462, 1364, 1055 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.77–5.75 (m, 1 H), 5.18–5.09 (m,
2 H), 3.30–3.26 (m, 1 H), 3.13 (d, J = 6.5 Hz, 1 H), 2.41–2.39 (m, 1
H), 2.31–2.27 (m, 1 H), 1.51–1.42 (m, 2 H), 1.36–1.22 (m, 14 H),
1.18 (s, 9 H), 0.88 (t, J = 6.5 Hz, 3 H).
Aldol reaction of aldehyde 10 with acetone using saturat-
ed aqueous sodium hydroxide solution at room tempera-
ture afforded the d-amino-b-hydroxy ketones 11 and 12 in
69% yield.15 These diastereomers were separated by flash
chromatography. The spectral data obtained for com-
pound 11 were in agreement with those reported in the lit-
erature.9i Compounds 11 and 12 could be transformed into
the desired target alkaloid (+)-241D (3) and its C-4 epimer
4 via the reported method.9i
In conclusion, we have described the concise formal syn-
theses of the dendrobate alkaloid (+)-241D (3) and its C-
4 epimer 4 by means of a highly diastereoselective
Barbier-type indium-mediated allylation strategy involv-
ing an (S)-(N-tert-butanesulfinyl)imine and an aldol reac-
tion as key steps.
Unless otherwise stated, all reactions were carried out under an inert
atmosphere by following standard syringe/septa techniques. The
solvents were dried and purified by standard techniques prior to use.
The progress of the reactions was monitored by TLC using glass
plates precoated with silica gel-60 F254 to a thickness of 0.5 mm
(Merck). The TLC plates were visualised using a UV-lamp, I2, anis-
aldehyde or ninhydrin. Column chromatography was performed on
silica gel (Merck, 60–120 or 100–200 mesh) using mixtures of
EtOAc and hexane as eluents. Yields refer to analytically pure sam-
ples. Melting points were measured on a Büchi-510 apparatus and
are uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR
spectrophotometer. 1H NMR spectra [CHCl3 (d = 7.26 ppm) or
TMS (d = 0.00 ppm) as internal standards] were recorded on Varian
Gemini 200 MHz, Bruker Avance 300 MHz, Varian Unity 400
MHz or Varian Inova 500 MHz spectrometers. Mass spectra were
obtained with a VG Micromass 7070 H (EI) or a Thermo Finnigan
ESI ion trap spectrometer.
13C NMR (50 MHz, CDCl3): d = 134.1, 118.7, 55.6, 54.8, 40.4, 34.9,
31.8, 29.4, 29.2, 25.4, 22.5, 14.0.
ESI-MS: m/z 324 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H36NOS: 302.2517; found:
302.2531.
(S)-Benzyl Tridec-1-en-4-ylcarbamate (9)
To compound 8 (1.1 g, 3.65 mmol) was added a 1:1 (v/v) mixture
of MeOH and HCl–1,4-dioxane soln (4.0 M, 2.0 equiv). The result-
ing mixture was stirred at r.t. for 30 min and then concentrated to
near dryness under reduced pressure. To the residue was added sat.
aq NaHCO3 soln (4 mL) followed by CbzCl (0.8 mL, 5.5 mmol) and
the mixture stirred for 1 h at r.t. CH2Cl2 (20 mL) and H2O (15 mL)
were added to the mixture, the two layers separated and the organic
layer washed with brine (2 × 20 mL), dried over Na2SO4 and con-
centrated under reduced pressure. The residue was purified by flash
column chromatography (silica gel, hexane–EtOAc, 19:1) to afford
protected amine 9 (0.81 g, 67%) as a white solid.
Mp 61–63 °C; [a]D27 –14.1 (c 0.86, CHCl3).
IR (KBr): 3310, 1687, 1546, 1463, 1264 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.38–7.21 (br s, 5 H), 5.73–5.71
(m, 1 H), 5.01–4.99 (m, 4 H), 4.42 (d, J = 8.0 Hz, 1 H), 3.68–3.66
(m, 1 H), 2.30–2.11 (m, 2 H), 1.50–1.19 (m, 16 H), 0.89 (t, J = 7.0
Hz, 3 H).
(S,E)-N-Decylidene-2-methylpropane-2-sulfinamide (7)
To a stirred soln of decan-1-ol (6) (1.2 g, 7.6 mmol) in anhyd
CH2Cl2 (20 mL) was added Celite (1.8 g) and PCC (2.457 g, 11.4
mmol) at 0 °C and the mixture stirred for 2 h at r.t. The mixture was
diluted with Et2O (15 mL) and then filtered through a silica gel col-
umn eluting with EtOAc–hexane (1:19) to afford the corresponding
aldehyde, decanal (2.765 g, 90%) as a colorless liquid. To a 0.5 M
soln of (S)-(N)-tert-butanesulfinamide (0.738 g, 6.1 mmol) in
CH2Cl2 was added anhyd CuSO4 (2.138 g, 13.4 mmol, 2.2 equiv)
followed by the aldehyde (0.950 g, 6.1 mmol). The mixture was
stirred at r.t. for 24 h, filtered through a pad of Celite, and the filter
cake was washed thoroughly with CH2Cl2. The residue obtained af-
ter evaporation of the filtrate was purified by column chromatogra-
phy (silica gel, hexane–EtOAc, 4:1) to afford the title compound 7
(1.388 g, 88%) as a pale-yellow liquid.
13C NMR (50 MHz, CDCl3): d = 156.1, 136.9, 134.2, 128.1, 128.0,
118.1, 66.7, 50.4, 39.2, 34.7, 31.8, 29.5, 29.0, 25.8, 22.2, 13.9.
ESI-MS: m/z 332 [M + H]+, 354 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H34NO2: 332.2589; found:
332.2594.
[a]D27 +193.6 (c 1.59, CHCl3).
IR (neat): 2926, 1622, 1461, 1364, 1087 cm–1.
(S)-Benzyl (1-Oxododecan-3-yl)carbamate (10)
An oven-dried round-bottom flask was charged with homoallylic
amine 9 (0.75 g, 2.3 mmol) and MeCN (41.5 mL) under an N2 atm.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 83–86

86
K. Damodar, B. Das
PAPER
A soln of RuCl3·H2O (0.025 g, 0.12 mmol) in H2O (6.9 mL), was
added at r.t. NaIO4 (0.98 g, 4.6 mmol) was added in one portion with
vigorous stirring and the mixture was stirred for a further 2 h at r.t.
The progress of the reaction was monitored by TLC. After complete
consumption of the starting material, the reaction was quenched
with sat. aq Na2S2O3 soln (30 mL). The phases were separated and
the aq layer was extracted with EtOAc (3 × 50 mL). The organic
portions were combined, dried over Na2SO4 and concentrated under
reduced pressure. The crude residue was subjected to column chro-
matography (silica gel, hexane–EtOAc, 17:3) to afford pure alde-
hyde 10 (0.49 g, 65%) as a colourless liquid.
ESI-MS: m/z 392 [M + H]+, 414 [M + Na]+.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors thank CSIR, New Delhi for financial assistance and are
also grateful to K. Haribabu for HPLC analysis and the NMR, Mass,
and IR divisions of IICT for recording the spectra.
[a]D27 –26.2 (c 0.58, CHCl3).
IR (neat): 3330, 1720, 1529, 1458, 1248 cm–1.
References
1H NMR (200 MHz, CDCl3): d = 9.78 (s, 1 H), 7.20–7.12 (br s, 5
H), 5.08 (s, 2 H), 4.90 (d, J = 8.0 Hz, 1 H), 4.08–4.04 (m, 1 H),
2.64–2.55 (m, 2 H), 1.51 (d, J = 7.0 Hz, 2 H), 1.39–1.20 (m, 14 H),
0.84 (t, J = 7.0 Hz, 3 H).
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66.2, 49.6, 47.1, 35.0, 31.2, 29.9, 29.8, 29.7, 25.8, 23.5, 14.7.
ESI-MS: m/z 334 [M + H]+.
Benzyl [(4R,6S)-4-Hydroxy-2-oxopentadecan-6-yl]carbamate
(11) and Benzyl [(4S,6S)-4-Hydroxy-2-oxopentadecan-6-yl]car-
bamate (12)
The aldehyde 10 (0.2 g, 0.6 mmol) was dissolved in acetone (1 mL)
and H2O (5 mL). Next, sat. aq NaOH soln (0.2 mL) was added at r.t.
The mixture was stirred at r.t. for 45 min, diluted with H2O (5 mL)
and extracted with CHCl3 (3 × 25 mL). The organic portions were
combined and dried over Na2SO4. The solvent was evaporated and
the crude residue subjected to flash column chromatography (silica
gel, hexane–EtOAc, 3:7 to 3:2) to give the pure aldol products
[0.270 g, 69%; syn (12)/anti (11) = 1:1].
Benzyl [(4R,6S)-4-Hydroxy-2-oxopentadecan-6-yl]carbamate
(7) Daly, J. W.; Garraffo, H. M.; Spande, T. F. Amphibian
Alkaloids, In The Alkaloids, Vol. 43; Cordell, G. A., Ed.;
Academic Press: New York, 1993, 185.
(11)
Pale-yellow solid; yield: 0.082 g (35%); mp 68–70 °C; [a]D27 –8.4
(c 0.85, CHCl3).
(8) Daly, J. W.; Myers, C. W.; Whittaker, N. Toxicon 1987, 25,
IR (neat): 3336, 2921, 1694, 1538, 1464, 1256 cm–1.
1023.
1H NMR (200 MHz, CDCl3): d = 7.37–7.27 (m, 5 H), 5.09 (s, 2 H),
4.82 (d, J = 9.0 Hz, 1 H), 4.10 (br s, 1 H), 3.93–3.74 (m, 2 H), 2.62
(dd, J = 12.0, 8.0 Hz, 1 H), 2.43 (dd, J = 12.0, 3.0 Hz, 1 H), 2.17 (s,
3 H), 1.64–1.51 (m, 2 H), 1.48–1.36 (m, 2 H), 1.34–1.18 (m, 14 H),
0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 208.7, 157.2, 136.3, 128.5, 128.1,
128.0, 66.9, 64.3, 50.2, 48.3, 42.7, 35.2, 31.8, 30.9, 29.6, 29.4, 29.3,
29.2, 26.1, 22.6, 14.1.
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ESI-MS: m/z 392 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C23H38NO4: 392.2800; found:
392.2806.
Benzyl [(4S,6S)-4-Hydroxy-2-oxopentadecan-6-yl]carbamate
(12)
Pale-yellow solid; yield: 0.080 g (34%); mp 67–69 °C; [a]D27 +14.5
(c 0.6, CHCl3).
IR (neat): 3336, 2921, 1694, 1538, 1464, 1256 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.33–7.26 (m, 5 H), 5.04 (s, 2 H),
4.73 (d, J = 9.0 Hz, 1 H), 4.06–4.04 (m, 1 H), 3.66–3.62 (m, 1 H),
2.73 (dd, J = 12.0, 3.0 Hz, 1 H), 2.48 (dd, J = 12.0, 8.0 Hz, 1 H),
2.14 (s, 3 H), 1.57 (t, J = 7.0 Hz, 2 H), 1.51–1.40 (m, 2 H), 1.34–
1.21 (m, 14 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 209.9, 156.3, 136.6, 128.5, 128.1,
128.0, 66.6, 65.7, 49.6, 49.1, 42.0, 35.9, 31.9, 30.7, 29.7, 29.6, 29.5,
29.3, 25.7, 22.7, 14.1.
(13) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 2004, 15,
3823.
(14) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc.
2007, 129, 15398.
(15) Raymond, J.-L.; Chen, Y. J. Org. Chem. 1995, 60, 6970.
Synthesis 2012, 44, 83–86
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