Synthetic studies of alkaloids containing pyrrolidine and piperidine structural motifs

Article abstract of DOI:10.1002/open.201402128

Avenues to asymmetric alkaloids! Various 2-substituted pyrrolidine and piperidine chiral bioactive natural products were synthesized using a 'chiral pool' method. l-proline and l-pipecolinic acids with one chiral center served as the best precursors for the synthesis of these alkaloids. Overall, 14 total synthetic and 11 formal synthetic approaches were developed.

Full text of DOI:10.1002/open.201402128

DOI: 10.1002/open.201402128
Synthetic Studies of Alkaloids Containing
Pyrrolidine and Piperidine Structural Motifs
Chinmay Bhat*[a]
Awarding Institute: Goa University (India)
Date awarded: December, 2013
Supervisor: Prof. Santosh G. Tilve, HOD Chemistry, Goa University, Goa (India)
Synthesis of Pyrrolidine and Piperidine Alkaloids
Our molecules of interest were mainly 2-substituted pyrrolidine and piperidine alkaloids containing 1,
3-aminoketone and 1, 3-aminoalcohol units which are of special synthetic interest (Figure 1). Hygrine
and norhygrine belong to the class of tropane alkaloids. The rest of the alkaloids are isolated from
60 species of the genus Sedum and are usually referred as Sedum alkaloids which are of immense inter-
est due to their memory-enhancing properties and application as anti-Alzheimer agents. These species
have now become more important to industry due to their vast pharmaceutical applications. Our
method involves “chiral pool” strategies, wherein the starting material can easily be accessed from the
naturally available sources like amino acids. Though such a method requires a lot of synthetic maneu-
vering, it still is the best bet for chiral integrity and suitability for industrial applications.
Commercially available l-proline and l-pipecolinic acid, with one existing chiral center, were found
to be appropriate chiral sources to access these pyrrolidine and piperidine alkaloids respectively. We
developed a Henry–Nef protocol in order to synthesize the key intermediates leading to the total syn-
thesis of these natural products. The Henry–Nef protocol involves two major synthetic steps: the for-
mation of the nitro functionality from carbonyls and the successive transformation to the next carbon-
yl unit mainly by oxidative or reductive methods. Even though this method is well documented in the
literature, surprisingly, it is not well explored for synthetic applications, which got our attention. The
Figure 1. 2-Substituted pyrrolidine and piperidine alkaloids.
[a] Dr. C. Bhat
Centre for Nano and Material Sciences, Jain University, Jakkasandara Post
Kanakapura Road, Ramanagara District, Karnataka 562 112 (India)
E-mail: b.chinmay@jainuniversity.ac.in
The full thesis is available as Supporting Information on the WWW under http://dx.doi.org/10.1002/open.201402128.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which per-
mits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for
commercial purposes.
ChemistryOpen 2015, 4, 192 – 196
192
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

general synthetic route is shown in Scheme 1. The carbonyl intermediates obtained via Henry–Nef re-
action were further subjected to diastereoselective reduction to afford aminoalcohols using different
reducing agents (Scheme 2).
Scheme 1. General method of synthesis.
Scheme 2. Diastereoselective reduction. Reagents and conditions: a) Reducing agents: Li(OtBu)3AlH, NaBH4, or ZnBH4.
It was observed that, in all the cases the isomer 4 (5) was preferentially formed over 6 (7) except in
one case with pyrrolidine carbonyl and Zn(BH4)2 as a reducing agent where 6b was formed diastereo-
selectively over 4b. The synthesis of all the target natural products was then accomplished following
the synthetic Scheme 3.
Scheme 3. Total synthesis of alkaloids. Reagents and conditions: a) 1) LiAlH4, THF, reflux, 2) Dess–Martin periodinane (DMP),
CH2Cl2, rt, 95% (n=1), 60% (n=2); b) H2, Pd/C, EtOH, rt, 81% (n=1), 70% (n=3); c) H2, Pd/C, EtOH, rt, 95% (R=Me), 95%
(R=Et); d) LiAlH4, THF, reflux, 95% (n=1), 90% (n=2).
Approaches to Allokainic Acid and Kainic Acid
We next investigated novel and rapid synthetic methods for the formal synthesis of very important kai-
noids; allokainic acid and kainic acid (Figure 2). We developed two domino and one “one pot” process
for the synthesis of the pyrrolidone precursor of allokainic acid. Allokainic acid was first isolated along
with its C-4 epimer kainic acid from Japanese marine sponge Digenea simplex AG17 in 1953. Over the
ChemistryOpen 2015, 4, 192 – 196
www.chemistryopen.org
193
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

last few decades several kainoids
have interested synthetic chemists
due to their powerful neuroexcita-
tory activity in the central nervous
system (CNS). A highly functional-
ized trisubstituted pyrrolidine ring
with three contiguous stereogenic
centers and global deficiency of
these compounds are other factors
which make the synthesis of these
molecules challenging.
Figure 2. Important members of the kainoid family.
We developed two tandem methods and one ‘one-pot’ strategy for the synthesis of the key inter-
mediate of allokainic acid. The tandem strategies involved the synthesis of secondary amine 8 from p-
methoxybenzylamine (PMB) and methyl vinyl ketone (MVK). In the first strategy the secondary amine 8
was converted to the key Wittig salt 9. When all our attempts to isolate the phosphorane 10 was un-
successful, we thought of carrying out the Wittig reaction in situ. Thus it was directly condensed with
glyoxalic acid in the presence of excess Et3N by heating in toluene. We observed the formation of
cyclic acid 11 in 60% yield after spectroscopic characterization. It was subsequently transformed to
ester 13 which is a useful building block for allokainic acid (Scheme 4).
Scheme 4. Domino approaches to allokainic acid. Reagents and conditions: a) Maleic anhydride, toluene, reflux, 92% (11);
b) SOCl2, EtOH, rt, 95%; c) THF, rt; d) ClCOCH2Br, Et3N, H2O/CHCl3 (4:1), rt, 80%; e) PPh3, toluene, rt, 90%; f) CHO-COOH, Et3N,
toluene, 808C, 60% (11); g) SOCl2, EtOH, rt, 90%; h) BrPPh3CH3, n-BuLi, THF, 08C, 60%; i) (NH4)2Ce(NO3)6, EtOH, rt, 75%.
ChemistryOpen 2015, 4, 192 – 196
www.chemistryopen.org
194
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

In another route, the secondary
amine 8 was directly condensed
with maleic anhydride by refluxing
in toluene. The acid 11 was ob-
tained and converted to ester 12,
which can be converted to the key
intermediate 13 (Scheme 4).
Scheme 5. One-pot approach to allokainic acid. Reagents and conditions:
a) 1) Methyl vinyl ketone, EtOH, rt, 2) maleic anhydride, 3) SOCl2, rt, 95%.
The methodology was further
simplified by achieving the entire
sequence in a one-pot manner. The
starting materials, PMB and MVK, were mixed in ethanol and stirred for few minutes. Maleic anhydride
was then added and stirred for about 30 min followed by the addition of thionyl chloride. The inter-
mediate 12 was isolated in 95% yield and could be transformed to 13, the precursor for allokainic acid
(Scheme 5).
Diastereoselective Routes to Dexoxadrol, Epidexoxadrol, Conhydrine, and
Lentiginosine
In continuation of the asymmetric synthesis of natural products, we undertook the synthesis of a very
important N-methyl-d-aspartate (NMDA) receptor antagonist, dexoxadrol, which was first synthesized
by Hardie et al. in 1960 as an anesthetic drug along with etoxadrol. The subsequent clinical trials re-
vealed that these compounds are efficient NMDA receptor antagonists by binding with 1-(1-
phenylcyclohexyl)piperidine (PCP) cites and are found to be more efficient than the available drugs
memantine and amantadine (Figure 3). The detailed study on the biological behavior of these mole-
cules showed that the presence of a secondary amine, piperidine ring, five-membered oxygenated
ring, and the (S, S) stereochemistry altogether play a crucial role for its enhanced activity.
Our synthesis involved the classical synthetic conversion of pipecolinic acid to olefin 14a. The olefin
14a was then subjected to dihydroxylation via the Upjohn method delivering the diols 15a and 16a
in the proportion of 3:2 (Scheme 6) determined using high-performance liquid chromatography
(HPLC).
The Sharpless “binding pocket” effect for our novel monosubstituted terminal olefin attached to a pi-
peridine system was studied and found to be consistent with this effect. A better discrimination of dia-
stereoselectivity was achieved using hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2PYR)
and hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQD)2PYR).
We then proceeded with the synthetic approach to accomplish the total synthesis of dexoxadrol
(Scheme 7). Upon hydrogenolysis followed by reaction with dimethoxybenzophenone and p-toluene-
sulfonic acid (PTSA) in isopropyl alcohol held at reflux, 15a (16a) produced dexoxadrol (epidexoxa-
drol). Incidentally this is the first asymmetric synthesis of (À)-epidexoxadrol.
Figure 3. NMDA receptor antagonists.
Scheme 6. Upjohn dihydroxylation. Reagents and conditions: a) OsO4, N-methylmorpholine N-oxide, acetone/H2O (9:1), rt,
80%.
ChemistryOpen 2015, 4, 192 – 196
www.chemistryopen.org
195
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Formal approach to conhydrine
Conhydrine, whose structure was
first elucidated in 1933, is an alka-
loid of the hemlock family isolated
from the leaves and seeds of the
plant Conium Maculatum L. (+)-Con-
hydrine has attracted considerable
synthetic interest due to its potent
antitumor, antiviral, and glycosidase
inhibitory activities. The diols 16a
Scheme 7. Synthesis of dexoxadrol. Reagents and conditions: a) 1) H2, Pd/C,
EtOH, rt, 98%, 2) isopropyl alcohol, PTSA, PhC(OMe)2Ph, reflux, 60%; b) H2,
Pd/C, EtOH, rt, 98%, 2) isopropyl alcohol, PTSA, PhC(OMe)2Ph, reflux, 56%.
and 15a were efficiently transformed to 17a and 17b respectively to complete the formal synthesis of
conhydrine (Scheme 8).
Scheme 8. Formal approach to conhydrine. Reagents and conditions: a) TsCl, 4-dimethylaminopyridine, Et3N, CH2Cl2, 08C to rt,
2 h, crude; b) K2CO3, MeOH, rt, 58% (for 17a), 60% (for 17b).
Formal approach to (+)-lentiginosine
The recent synthetic report by Vankar and co-workers describes a total synthesis of (+)-lentiginosine
from diol 15a prepared by synthetic maneuvering of d-mannitol. (+)-Lentiginosine is a naturally occur-
ring isomer first isolated from Astragalus lentiginosus in 1990. Being a hydroxylated alkaloid, it serves
as a sugar mimic and acts as a potent selective inhibitor of a-glucosidase and amyloglucosidase. Inci-
dentally during our synthetic ma-
neuvering of dexoxadrol, the same
diol 15a was obtained from anoth-
er chiral source (À)-pipecolic acid.
Thus the synthesis of diol 15a pro-
vides a straightforward formal syn-
thetic approach to (+)-lentiginosine
(Scheme 9).
Scheme 9. Formal approach to lentiginosine.
Keywords: alkaloids · asymmetric synthesis · natural products · piperidines · pyrrolidines
Publications arising from this work:
*
C. Bhat, S. G. Tilve, Tetrahedron Lett. 2011, 52, 6566.
*
C. Bhat, S. G. Tilve, Tetrahedron Lett. 2013, 54, 245.
*
C. Bhat, S. G. Tilve, Tetrahedron 2013, 69, 6129.
*
C. Bhat, S. G. Tilve, Tetrahedron 2013, 69, 10876.
*
C. Bhat, S. G. Tilve, RSC Adv. 2014, 4, 5405.
Received: November 25, 2014
Published online on January 16, 2015
ChemistryOpen 2015, 4, 192 – 196
www.chemistryopen.org
196
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim