Tetrahedron Letters
A stereoselective approach for the total synthesis
of (À)-tadanalactam from acetonide-D-glucose
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Saidulu Konda, Bhaskar Kurva, Lingaiah Nagarapu , Akkewar M. Dattatray
Organic Chemistry Division-II (CPC), Indian Institute of Chemical Technology (CSIR), Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective and realistic approach for the total synthesis of naturally occurring d-lactam (À)-tadan-
Received 12 November 2014
Revised 17 December 2014
Accepted 21 December 2014
Available online 29 December 2014
alactam, has been accomplished from the commercially existing acetonide-D-glucose involving Birch
reduction, Pinnick oxidation, Staudinger reaction, and hydroboration reactions. Finally benzyl ether
deprotection and subsequent oxirane formation using Birch reduction completed the total synthesis of
(À)-tadanalactam.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Birch reduction
Pinnick oxidation
Staudinger reaction
2-Piperidone
Tadanalactam
Substituted 2-piperidones (d-lactam), exhibiting interesting
biological activities, are present in numerous natural products such
as alkaloids and drugs. Therefore, efficient stereoselective synthe-
ses of functionalized 2-piperidone derivatives are of importance
in medicinal chemistry. 2-Piperidone moiety (Fig. 1) is found in
Cardellina et al.8 In 2007, Lago et al.9 reported the isolation and
characterization of (À)-tadanalactam from the leaves of Piper crass-
inervium (piperaceae). In 2009 Tilve and co-workers10 reported the
total synthesis and stereochemistry of (À)-tadanalactam (1) and
(+)-tadanalactam (2) by following a synthetic route with tandem
Oxidation-Wittig reaction and Sharpless asymmetric dihydroxyla-
tion as the key steps. In continuation of our research program
focused toward the total synthesis of bioactive molecules from
inexpensive and readily accessible starting materials,11 we have
established an effective approach utilizing Birch reduction, Pinnick
oxidation, Staudinger reaction, hydroboration, and reductive elim-
ination reactions, for the linear stereoselective synthesis of (À)-
tadanalactam (1), starting from the abundantly available aceto-
3b,4a-dihydroxy-2-piperidinone (3) and 5,6-dihydro-2(1H)-pyrid-
inone (4) isolated1 from Piper longum, showing a superior anti-HBV
activity in vitro, Piperlongumine (PL) alkaloid (5) with anti-cancer
activity, isolated2 from the various parts of long pepper, Piper lon-
gum L. also possesses 2-piperidone in its structure. (3S,4R)-3,4-
dihydroxy-1-(3-phenylpropanoyl)piperidin-2-one (6) isolated3
from Piper longum, demonstrated significant activity, with IC50 val-
ues of 1.80 and 0.21 mM against HBsAg (hepatitis B virus surface
antigen) and HBeAg (hepatitis B virus e antigen) correspondingly.
Kaousine (7) isolated4 from the aerial part of Piper capense L.f (Pip-
eraceae), shows lower antiplasmodial activity. Alkaloids, Piplarox-
ide (8), isolated5 from Piper tuberculatum, 3,4-epoxy-8,9-
dihydropiplartine (9) isolated6 from leaves and twigs of Piper ver-
rucosum, and 3,4-epoxy-5-pipermethystine (10) isolated7 from
roots of the kava shrub (Piper methysticum) are all substituted
piperidones.
nide-D-glucose.
As shown retrosynthetically (Scheme 1), synthesis of (À)-tadan-
alactam could be accomplished from 18, via Birch reduction, which
in turn could be prepared from 17 by reduction (Staudinger reac-
tion), followed by cyclization. Compound 17 is accessible from 15
via acetonide deprotection, oxidative cleavage, and Pinnick oxida-
tion followed by esterification. Hydroboration of 13 resulted in the
primary alcohol, which was then converted into azido compound
15, by tosylation, followed by nucleophilic substitution reaction.
Compound 13 could be achieved from 11 by O-benzylation, regio-
selective acetonide deprotection, oxidative cleavage, and finally
reduction.
(À)-Tadanalactam, (3
a,4a-epoxy-2-piperidone), an antifungal
agent, was first isolated from sponge Tedania ignis and its chemical
and biological characterization was carried out in 1994 by
Our synthesis (Scheme 2) started with acetonide-D-glucose (11),
⇑
Corresponding author. Tel.: +91 40 27191509; fax: +91 40 27193382.
which was converted to O-benzylated compound by a known pro-
tocol.12,13 Regioselective deprotection of the 5,6 acetonide group in
O-benzylated compound with 0.8% H2SO4 in MeOH for 5 h afforded
Tel.: +91 40 27191511; fax: +91 40 27193382.
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