Synthesis of (+)-dumetorine and congeners by using flow chemistry technologies

Article abstract of DOI:10.1002/chem.201100300

An efficient total synthesis of the natural alkaloid (+)-dumetorine by using flow technology is described. The process entailed five separate steps starting from the enantiopure (S)-2- (piperidin-2-yl)ethanol 4 with 29 % overall yield. Most of the reactio

Full text of DOI:10.1002/chem.201100300

FULL PAPER
DOI: 10.1002/chem.201100300
Synthesis of (+)-Dumetorine and Congeners by Using Flow Chemistry
Technologies
Elena Riva,[b] Anna Rencurosi,[a] Stefania Gagliardi,[a] Daniele Passarella,[b] and
Marisa Martinelli*[a]
Abstract: An efficient total synthesis of
the natural alkaloid (+)-dumetorine by
using flow technology is described. The
process entailed five separate steps
starting from the enantiopure (S)-2-
engers to minimize handling. New pro-
tocols for performing classical reactions
under continuous flow are disclosed:
the ring-closing metathesis reaction
with a novel polyethylene glycol-sup-
ported Hoveyda catalyst and the un-
precedented flow deprotection/Esch-
weiler–Clarke methylation sequence.
The new protocols developed for the
synthesis of (+)-dumetorine were ap-
plied to the synthesis of its simplified
natural congeners (À)-sedamine and
(+)-sedridine.
(piperidin-2-yl)ethanol
4 with 29%
overall yield. Most of the reactions
were carried out by exploiting solvent
superheating and by using packed col-
umns of immobilized reagents or scav-
Keywords: alkaloids · flow chemis-
try · metathesis · microreactors ·
total synthesis
Introduction
in African folk medicine.[3] (À)-Sedamine and (+)-sedridine
isolated from Sedum Acre[4] have been shown to exhibit in-
teresting and potentially useful biological activity.[5] To the
best of our knowledge, besides our work, only two total syn-
theses of (+)-dumetorine have been published by Blechert[6]
and Hassner,[7] whereas numerous syntheses of both racemic
and optically active Sedum alkaloids have been reported to
In natural products and pharmaceuticals, the piperidine core
is a common structural motif and has been recognized as a
privileged structure in medicinal chemistry.[1] In particular,
2-piperidinyl alkaloids are an interesting family of natural
products and we have previously reported the total synthesis
of some of these biologically
important compounds.[2] (+)-
Dumetorine[2a] (1) and its sim-
plified natural congeners (À)-
sedamine[2b] (2a) and (+)-sedri-
dine[2b] (2b) were synthesised
by exploiting aldehyde 3 as a
common chiral electrophilic
coupling partner useful for fur-
ther
functionalization
(Scheme 1).
(+)-Dumetorine
was isolated in 1985 from the
tubers of Discorea dumetorum
Scheme 1. Synthetic plan for dumetorine and congeners.
Pax,
a yam the extracts of
which have found extensive use
date, making them popular molecules for the demonstration
of synthetic methods.[8]
Our recent interest in the application of flow chemistry
technology in organic synthesis[9] stimulated our attention to
devise an efficient flow approach to 1 to improve the syn-
thesis outlined previously.[2a] Flow chemistry represents an
attractive solution for multi-step synthesis not only for its
established advantages[10] but also for the possibility of car-
rying out two or more reactions with no or minimal workup
and purification. To date a large number of single-step reac-
tions have been transferred to continuous-flow systems.[11]
Nevertheless, the potential of flow chemistry for multi-step
synthesis,[12] especially of natural compounds, has hardly
[a] Dr. A. Rencurosi, Dr. S. Gagliardi, Dr. M. Martinelli
Department of Medicinal Chemistry
NiKem Research Srl, Via Zambeletti, 25
20021 Baranzate (Italy)
Fax : (+39)02356947606
E-mail: marisa.martinelli@nikemresearch.com
[b] Dr. E. Riva, Prof. D. Passarella
Dipartimento di Chimica Organica e Industriale
Universitꢀ degli Studi di Milano
Via Venezian 21, 20133 Milano (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100300.
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6221

been exploited with few examples reported in the litera-
ture.[13] The flow synthesis of (+)-dumetorine made use of
our batch-mode approach based on ring-closing metathesis
(RCM) reactions for the formation of the dihydropyranone
ring.
lyzed preparation,[2b] was converted into the corresponding
aldehyde 3 by continuously cycling the flow stream through
a PL-IBX amide[15] pre-packed column[16] until complete
conversion was achieved. Long reaction times were intrinsi-
cally related to the use of supported reagents[17] and to ac-
celerate the reaction rate, the column containing the resin
was heated to 458C. Higher temperatures, described as pos-
sible in the literature,[18] in our hands gave degradation of
the supported oxidant. After 8 h, the pure product was re-
covered in 91% yield by simple solvent evaporation.
The second step of Grignard addition to aldehyde 3 had
been achieved in batch-mode in 58% yield (diastereoiso-
meric mixture) working at À788C and by using two equiva-
lents of 2-methyl-allylmagnesium bromide. Under flow con-
ditions, this reaction was successfully performed by exploit-
ing the protocol recently developed by our group.[9b] The
solutions of 3 and the Grignard reagent were simultaneously
pumped in the flow apparatus and put into contact through
a T-junction. Thanks to the efficient mixing and heat disper-
sion typical of the flow techniques, cryogenic conditions
were avoided and the reaction took place at RT with a slight
excess of Grignard reagent. The recovered crude was then
directly passed through a short column containing polymer-
supported benzaldehyde to scavenge the excess Grignard re-
agent. The reactor output was then concentrated in vacuum
and directly purified on a silica gel cartridge to give the de-
sired diastereoisomer 5 in 43% yield (90% yield for the dia-
stereoisomeric mixture). Notably this separation of diaste-
reoisomers 5 and 6 was the only chromatography required
in the whole reaction sequence.
Results and Discussion
The flow strategy comprised the combination of five sepa-
rate synthetic steps (Scheme 2). Packed columns containing
appropriate immobilized reagents or scavenger materials
Acylation of alcohol 5 with acryloyl chloride was accom-
plished by flowing the reagents through the reactor at 908C
in CH2Cl2 by using pyridine as a base.[19] A back-pressure
regulator connected in-line at the end of the reactor, al-
lowed solvent heating well above its usual boiling point.
Two in-line scavengers were inserted: PS-trisamine, to trap
excess acyl chloride and MP-bicarbonate, for the neutraliza-
tion of the pyridine hydrochloride formed during the reac-
tion. This product cleanup method provided, after solvent
evaporation, the pure ester 7 in 88% yield.
The key RCM step was improved under flow conditions
relative to the batch protocol (2 h, CH2Cl2, 458C, 75%
yield). Complete conversion was achieved by simply flowing
the ester 7 for 20 min at RT in the presence of either 1st or
2nd-generation Grubbs catalyst. However, despite this
result, we thought that the use of columns with packed im-
mobilised catalysts[20] could be a more convenient approach
to minimise the post-reaction manipulations. Numerous sup-
ported Grubbs/Hoveyda catalysts for RCM are reported in
the literature[21] although only a few of them have been ap-
plied in flow chemistry. In particular, Trapp[21c] prepared mi-
crocapillaries coated with a film of dimethylpolysiloxane
soaked with Grubbs 2nd-generation catalyst. A monolithic
metathesis catalyst was prepared by Kirschning[21d] to be
used in a PASS-flow reactor though, being a ꢂboomerangꢃ
catalyst, it was affected by partial leaching under flow condi-
tions. Therefore, we turned our attention to a polystyrene-
Scheme 2. Five-step continuous-flow synthesis of (+)-dumetorine.
were used to minimize handling, workup and purification
and to ensure the quality of the final product. All the reac-
tions were conducted by using a commercially available
meso-flow apparatus.[14]
In the first step, (S)-2-(piperidin-2-yl)ethanol 4, obtained
on the gram scale with high enantiopurity by enzyme-cata-
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Chem. Eur. J. 2011, 17, 6221 – 6226

Synthesis of (+)-Dumetorine and Congeners
FULL PAPER
supported 2nd-generation Grubbs catalyst, prepared as de-
scribed by Buchmeiser.[22] The RCM reaction was then per-
formed by flowing the starting material through the pre-
packed column. Unfortunately poor conversion (less than
20%) was obtained even after 48 h possibly due to the limit-
ed surface contact between the solution and the catalyst
beads.
To overcome this problem, we considered the use of a
PEG-supported Ru catalyst. In this case, the RCM reaction
would benefit from the homogeneous conditions ensured by
the solubility of the catalyst in CH2Cl2, maintaining the pos-
sibility of simple catalyst recovery by solvent-promoted pre-
cipitation and filtration. Therefore, a newly synthesized
PEG-supported Hoveyda catalyst, an analogue of a PEG-
immobilised Ru catalyst described in the literature,[23] was
easily recovered by solvent evaporation in high purity and
in 95% yield. An efficient protocol for RCM under continu-
ous flow conditions was thus developed and we seek to
apply this methodology to further examples.
In the original batch synthesis, the two final steps were af-
fected by low yields. In particular, the acid-catalyzed cleav-
age of the tert-butoxycarbonyl (Boc) protecting group result-
ed in the isolation of a small amount of the desired product
14 (10% yield) along with the tricyclic byproduct 15 (60%
yield) from Michael addition of the secondary amine to the
a,b-unsaturated lactone ring (Scheme 4). Furthermore, the
inherent instability of 14 significantly reduced the yield of
the final reductive amination.
readily prepared from
a
salicylaldehyde derivative
(Scheme 3). The obtained catalyst 13 (loading 0.2 mmolgÀ1
Scheme 4. Deprotection and reductive amination in batch. a) TFA,
CH2Cl2, RT, 3 h, 10%; b) 14, CH2O, NaBH3CN, RT, 1.5 h, 35%. TFA=
trifluoroacetic acid.
We believed that the formation of the undesired 1,4 addi-
tion byproduct could be avoided if the N-deprotection and
N-methylation occurred simultaneously. In line with this
concept, the methylation of secondary amines by treatment
with formaldehyde in the presence of formic acid at high
temperature (Eschweiler–Clarke reaction)[25] appeared as an
optimal solution to block the formation of the undesired
1,4-addition byproduct. This reaction has, to the best of our
knowledge, never been reported under flow conditions and
the use of a protected amine constitutes an additional ele-
ment of novelty. The optimal reaction conditions were rap-
idly found by quickly screening the reaction solvent, resi-
dence times and temperature. The best results were ob-
tained when the solution containing 8, dissolved in acetoni-
trile, was combined with the stream of formaldehyde and
formic acid in acetonitrile in a pre-heated PTFE reactor.
The Boc removal and the reductive amination occurred at
1408C in 15 min giving complete conversion of the starting
material to (+)-dumetorine. Flash heating is known to im-
prove the overall yield and purity in many different chemi-
cal transformations and, also in our case, a rapid warming to
1408C gave a clean product. An additional advantage of the
flow protocol is the use of acetonitrile in place of DMSO,
Scheme 3. Synthesis of PEG-supported Hoveyda Ru catalyst: a) iso-
Propyl iodide, Cs2CO3, K2CO3, DMF, RT, 7 h, quantitative yield;
b) Ph3PCH3Br, KHDMS, toluene, À788C–RT, 3 h, 85%; c) LiAlH4, THF,
08C–RT, 1 h, 93%; d) succinic anhydride, DMAP, CH2Cl2, RT, 16 h,
60%; e) pivaloyl chloride, Et3N, Et2O, 0 8C–RT, 1 h, quantitative yield;
f) PEG 5000, trioctylamine, DMAP, CH2Cl2, RT, 21 h, 99%; g) Grubbs
2nd-generation catalyst, CuCl, CH2Cl2, 408C, 1 h, 99%. DMAP=4-dime-
thylaminopyridine; KHMDS=potassium hexamethyl disilazide.
1
determined by H NMR spectroscopy), stable at room tem-
perature for more than six months, showed excellent perfor-
mance in RCM reactions and ensured a simple and quanti-
tative catalyst recovery. Moreover, it was efficiently recycled
in a model reaction up to six times before a slight decrease
in reactivity was observed.[24] The streams containing 7 and
the catalyst (13, 6% moles Ru) dissolved in dry CH2Cl2
were pumped into a poly(tetrafluoroethylene) (PTFE) loop
reactor warmed at 708C (residence time 50 min). The reac-
tion output was collected into a vial containing an appropri-
ate volume of diethyl ether to quantitatively precipitate the
PEG-bound catalyst. The catalyst was filtered off with a
solid/liquid phase separator cartridge and the product 8 was
which is often employed as
a good solvent for the
Eschweiler–Clarke reaction especially when performed
under microwave conditions.[26] Finally, the flow stream con-
taining the newly formed 1 was directly purified in-line
through a column containing silica-supported sulfonic acid
(SCX). A brief washing sequence was used to elute any resi-
due prior to release of the product by passage of a metha-
nolic ammonia solution. After this ꢂcatch and releaseꢃ purifi-
cation, the solvent was finally evaporated in vacuum afford-
ing pure (+)-dumetorine in 92% yield (>98% purity by
Chem. Eur. J. 2011, 17, 6221 – 6226
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6223

M. Martinelli et al.
demonstration of the advantag-
es of flow processing in the as-
sembly of synthetically chal-
lenging molecules as natural
products.
Experimental Section
Procedures for the synthesis of (+)-
dumetorine (1)
Oxidation reaction procedure (synthe-
sis of 3): One flow stream driven at
100 mLminÀ1 by the Vapourtec R4/
R2+containing a CH2Cl2 solution of
Scheme 5. Synthesis of (À)-sedamine and (+)-sedridine in flow.
the alcohol
4 (800 mg, 3.49 mmol,
1 equiv) was directed through a re-
agent column (150 mm, 10 mm bore) containing PL-IBX (loading
1.09 mmolgÀ1, 5 g) heated to 458C. The reaction was performed by con-
tinuously cycling the stream through the column until complete conver-
sion of the alcohol 4 into 3. A 100 psi back pressure regulator (BPR) en-
sured the system was pressurized, before eluting into a reaction flask. Fi-
LC/MS and NMR spectroscopic analysis).[27] The overall
yield for the entire sequence was slightly less than 30%
(65% for the diastereoisomeric mixture) compared with
about 1% of the batch mode. Once optimized, 227 mg of
(+)-dumetorine were produced from 800 mg of 3.
nally, the solvent was concentrated in vacuo to give
3.19 mmol, 91% yield).
3 (725 mg,
The new protocols developed for the synthesis of (+)-
dumetorine, allowed for the rapid and efficient preparation
of its congeners (À)-sedamine (2a) and (+)-sedridine (2b)
(Scheme 5). By using the optimised protocol previously de-
scribed, compounds 16 and 17 were obtained by reaction of
synthon 3 with phenyl and methyl magnesium bromide, re-
spectively. The synthesis of (À)-sedamine from the protected
amine 16 was efficiently accomplished in 89% yield with
formaldehyde and formic acid in acetonitrile under flow
conditions for 10 min at 1808C. To complete the synthesis of
(+)-sedridine, the Boc protecting group was quantitatively
removed at high temperature in acidic conditions: two ace-
tonitrile solutions, the first containing 17 and the second
HCl in dioxane solution were simultaneously pumped into
the PTFE flow reactor for 15 min at 708C.[28] After in-line
purification, compounds 2a and 2b were obtained in 42 and
48% overall yield, respectively. While only two examples
were fully examined here, we believe this approach to be
fairly general and easily applicable to the preparation of ad-
ditional 2-piperidinyl-alkaloids.
Grignard addition reaction procedure (synthesis of 5): Two flow streams
driven by the Vapourtec R4/R2+; stream 1 containing a solution of 3
(725 mg, 3.19 mmol, 1 equiv) in THF (10 mL) and stream 2 containing (2-
methylallyl)magnesium chloride (0.5m THF solution, 7.6 mL, 3.80 mmol,
1.2 equiv) dissolved in THF (10 mL in total). These were pumped at a
flow rate of 75 mLminÀ1 each and mixed at a T-piece before entering the
convection flow coil (CFC) (volume 10 mL) maintained at RT for
33 min. The stream was then directed through
a reagent column
(150 mm, 10 mm bore) filled with PS-benzaldehyde (loading
1.09 mmolgÀ1; 3.5 g). A 100 psi BPR ensured the system was pressurized.
The output of the reactor was concentrated in vacuo directly onto a silica
samplet cartridge and eluted (eluent: petroleum ether/EtOAc 10:1) by
using a Biotage purification system to give (380 mg, 1.34 mmol, 43%
yield) 5 (S)-tert-butyl 2-[(R)-2-hydroxy-4-methylpent-4-enyl]piperidine-1-
carboxylate and (432 mg, 1.52 mmol, 47% yield) 6 (S)-tert-butyl 2-[(S)-2-
hydroxy-4-methylpent-4-enyl]piperidine-1-carboxylate (90% total yield
as diastereoisomeric mixture).
Acylation reaction procedure (synthesis of 7): Two flow streams driven by
the Vapourtec R4/R2+; stream 1 containing a solution of 5 (380 mg,
1.34 mmol, 1 equiv) and pyridine (0.325 mL, 4.02 mmol, 3 equiv) in
CH2Cl2 (10 mL in total) and stream 2 containing acryloyl chloride
(0.217 mL, 2.68 mmol, 2 equiv) in CH2Cl2 (10 mL in total). These were
pumped at a flow rate of 66 mLminÀ1 each and mixed at a T-piece before
entering the CFC (total volume 12 mL) for 90 min at 908C. The stream
was then directed through a series of reagent columns (150 mm, 10 mm
bore) containing PS-trisamine (loading 4.11 mmolgÀ1, 1 g) and then MP-
HCO3 (loading 1.8 mmolgÀ1, 3 g). A 100 psi BPR ensured the system was
pressurized, before eluting into a reaction flask. Finally, the solvent was
concentrated in vacuo to give 7 (398 mg, 1.179 mmol, 88% yield).
Conclusion
In summary, we have developed a flow-based total synthesis
of (+)-dumetorine and its congeners. Significant improve-
ments over the existing batch protocols were obtained. The
main advantages were the precise control of reaction condi-
tions that results in the dramatic improvement of the overall
yield, the reduction in reaction time, minimized handling of
intermediates and the avoidance of extensive purification
and workup procedures. New protocols were developed for
performing classical reactions under continuous flow, such
as the RCM with novel PEG-supported Hoveyda catalyst
and the unprecedented flow deprotection/Eschweiler–
Clarke methylation sequence. This work represents a further
RCM procedure (synthesis of 8): Two flow streams driven by the Vapour-
tec R4/R2+; stream 1 containing a solution of the ester 7 (398 mg,
1.179 mmol, 1 equiv) in CH2Cl2 (5 mL) and stream 2 containing PEG-
Hoveyda supported catalyst 13 (loading 0.2 mmolgÀ1; 353 mg; 0.070 mol;
6 mol% Ru) in CH2Cl2 (5 mL). These were pumped at a flow rate of
100 mLminÀ1 each and mixed at a T-piece before entering the CFC
(volume 10 mL) for 50 min at 708C. A 100 psi BPR ensured the system
was pressurized, before eluting into a reaction flask. Diethyl ether was
added; PEG-supported catalyst was precipitated and was filtered. Finally,
the solvent was removed in vacuo to give lactone 8 (347 mg, 1.1 mmol,
95% yield).
Deprotection and Eschweiler–Clarke reaction procedure (synthesis of 1):
Two flow streams driven by the Vapourtec R4/R2+; stream 1 containing
6224
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Chem. Eur. J. 2011, 17, 6221 – 6226

Synthesis of (+)-Dumetorine and Congeners
FULL PAPER
a solution of the lactone 8 (347 mg, 1.1 mmol, 1 equiv) in acetonitrile
(5 mL) and stream 2 containing formaldehyde (aq. solution 36%)
(343 mL, 4.49 mmol, 4 equiv) and formic acid (172 mL, 4.49 mmol,
4 equiv) in acetonitrile (5 mL in total). These were pumped at a flow rate
of 330 mLminÀ1 each and mixed at a T-piece before entering the CFC
(volume 10 mL) for 15 min at 1408C. The flow stream was then directed
into a column (150 mm, 10 mm bore) containing silica-supported sulfonic
acid (SCX; loading 0.6 mmolgÀ1, 2.5 g) to perform a catch and release
purification with any unreacted reagents simply passing through to waste.
A brief washing sequence (MeOH, 0.4 mLminÀ1) was used to elute any
residues prior to release the product by passage of NH3 in MeOH (3%
NH4OH solution, 0.1 mLminÀ1). The product stream was so eluted into a
reaction flask. Finally, the solvent was removed in vacuo to give (+)-
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dumetorine
1
(227 mg, 1.01 mmol, 91% yield). [a]2D5 =+38 (c=1 in
CHCl3) (lit.: [a]2D5 =+37 (c=1 in CHCl3)); 1H NMR (300 MHz,
[D1]CHCl3): d=5.82 (s, 1H), 4.24–4.79 (m, 1H), 2.87–3.06 (m, 1H), 2.42–
2.56 (m, 1H), 2.40 (s, 3H), 2.15- 2.39 (m, 5H), 2.00 (s, 3H), 1.57–1.94 (m,
4H), 1.29–1.55 ppm (m, 2H); 13C NMR (75 MHz, [D1]CHCl3): d=164.89
(s, 1C) 157.12 (s, 1C) 116.47 (s, 1C) 73.91 (s, 1C) 59.89 (s, 1C) 56.87 (s,
1C) 42.46 (s, 1C) 37.62 (s, 1C) 35.48 (s, 1C) 29.93 (s, 1C) 24.95 (s, 1C)
23.56 (s, 1C) 22.92 ppm (s, 1C).
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Acknowledgements
We thank Prof. M. Benaglia (Universitꢀ degli Studi di Milano) and Dr.
A. Caselli (Universitꢀ degli Studi di Milano) for assistance with the syn-
thesis of PEG-supported Hoveyda catalyst, Dr. S. Riva (ICRM, C.N.R.)
for the enzyme-catalyzed preparation of (S)-2-(piperidin-2-yl)ethanol and
Dr. D. Vigo (NiKem Research Srl) for precious collaboration.
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Conversion [%]
100
100
100
98
94
91
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Received: January 27, 2011
Published online: April 19, 2011
6226
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Chem. Eur. J. 2011, 17, 6221 – 6226