A stereoselective approach for the total synthesis of (-)-tadanalactam from acetonide-d-glucose

Article abstract of DOI:10.1016/j.tetlet.2014.12.115

A stereoselective and realistic approach for the total synthesis of naturally occurring δ-lactam (-)-tadanalactam, has been accomplished from the commercially existing acetonide-d-glucose involving Birch reduction, Pinnick oxidation, Staudinger reaction,

Full text of DOI:10.1016/j.tetlet.2014.12.115

Tetrahedron Letters 56 (2015) 834–836
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Tetrahedron Letters
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A stereoselective approach for the total synthesis
of (À)-tadanalactam from acetonide-D-glucose
⇑
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.
E-mail addresses: lnagarapuiict@yahoo.com (L. Nagarapu), dattatray.akkewar@
gmail.com (A.M. Dattatray).
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.
http://dx.doi.org/10.1016/j.tetlet.2014.12.115
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

S. Konda et al. / Tetrahedron Letters 56 (2015) 834–836
835
OH
O
O
HO
O
O
OH
O
O
O
HO
O
b
O
a
N
H
O
N
H
O
N
H
N
H
2
O
O
O
HO
BnO
12
11
4
3
1
(synthetic molecule)
OH
O
O
O
OH
O
O
O
HO
c
d
N
O
N
O
O
BnO
OMe
OMe
O
N
BnO
O
O
13
14
O
OMe
5
7
6
O
O
OH
OH
N3
O
N3
e
f
O
O
O
AcO
O
BnO
BnO
16
15
N
O
N
O
N
O
OMe
OMe
OMe
OMe
O
O
O
OTs
O
OH
O
OBn
g
h
OMe
N3
O
N
O
N
H
O
H
OBn
8
9
10
1
17
18
Figure 1. Naturally and synthetically occurring 2-piperidones.
Scheme 2. Reagents and conditions: (a) (i) Ref. 12 (ii) 0.8% H2SO4, MeOH, rt, 8 h,
95%; (b) PPh3, imidazole, I2, toluene, reflux, 4 h, 86%; (c) (i) 9-BBN, THF, 0 °C, rt, 4 h.
(ii) 3 N NaOH, H2O2, rt, 3 h, 93% (for two steps); (d) (i) Ts-Cl, Et3N, DCM, 0 °C, rt, 2 h.
(ii) NaN3, DMF, 60 °C, 5 h, 87% (for two steps); (e) 4% H2SO4, THF, reflux, 6 h, 94%; (f)
(i) NaIO4, MeOH/H2O (2:1), rt, 0.5 h. (ii) NaClO2, NaH2PO4, H2O2, MeOH/H2O, 0 °C, rt,
4 h. (iii) SOCl2, MeOH, 0 °C, rt, 12 h (overall 3 steps), 76%; (g) (i) Ts-Cl, Py, DCM, 0 °C,
rt, 8 h, (ii) PPh3, THF:H2O (8:2), rt, 3 h, (overall 2 steps), 92%; (h) Li/liq. NH3, À78 °C,
10 min, 78%.
the dihydroxy compound 12 with 95% yield. Reductive elimina-
tion14 of 12 with iodine–PPh3–imidazole in toluene at reflux condi-
tions for 2 h gave olefin 9 in 86% yield. Compound 9 was subjected
to hydroboration15 using 9-BBN, which resulted in the addition of
borane, regioselectively at C-3 position in 4 h, which was immedi-
ately subjected to oxidation with H2O2 in the presence of 3 N NaOH
at rt to provide the primary alcohol 14 in 93% yield. The primary
alcohol was converted into the corresponding tosylate with p-tol-
uenesulfonyl chloride and catalytic amount of DMAP in pyridine/
CH2Cl2 to furnish O-tosylated compound, which was then treated
with sodium azide in DMF at 60 °C for 12 h to give 15 in 87% yield.
Deprotection of 1,2-acetonide in 15 with 4% H2SO4 in THF at reflux
temperature for 12 h afforded diol 16 in 94% yield. Oxidative cleav-
age of the diol 16, with NaIO4 in methanol/water furnished the
aldehyde, which was then subjected to oxidation (Pinnick oxida-
tion) using NaClO2 and H2O2 in methanol/water for 4 h in the pres-
ence of a basic buffer NaH2PO4 to afford the acid, which was then
(without further purification) taken up for selective methylation
(esterification) in the presence of SOCl2 in methanol for 12 h at
room temperature to furnish the ester 17. Reaction of 17 with p-
toluenesulfonyl chloride in pyridine and catalytic amount of DMAP
produced the tosylate, at this stage, reduction of azide using the
Staudinger conditions. That is, treatment with triphenylphosphine
in THF/H2O resulted in one-pot reductive lactonization, to give lac-
tam 18 in 76% yield. Compound 18 was subsequently subjected to
deprotection of the benzylether using Li/liq.NH3 in dry THF (Birch
reduction). The ammonia present in the reaction facilitated the
oxirane ring formation, thus forming the target molecule (À)-
tadanalactam in a single step with 78% yield. The spectroscopic
data16 were in agreement with the recently synthesized structure
of (À)-tadanalactam (1).10
OTs
O
In conclusion, a stereoselective synthesis of (À)-tadanalactam
OBn
O
Birch reduction
Staudinger reaction
has been achieved from the commercially available acetonide-D-
N
H
1
O
glucose via a high yielding route (34% overall yield) by using Birch
reduction, Pinnick oxidation, Staudinger reaction, hydroboration,
and reductive elimination reactions.
N
H
18
O
OH
O
O
N3
Pinnick oxidation
Acknowledgments
N3
OMe
O
BnO
O
OBn
15
The authors gratefully acknowledge DST-SERB/EMEQ-078/2013
for financial assist. S. Konda and B.K. thank CSIR – India for award
of research fellowship.
17
reductive
O
O
O
Hydroboration
elimination
O
O
Supplementary data
O
BnO
O
HO
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12.
115.
11
13
Scheme 1. Retrosynthetic analysis of (À)-tadanalactam.

836
S. Konda et al. / Tetrahedron Letters 56 (2015) 834–836
16. Spectral data for selected compounds:
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a
]
27 = À7.21 (c 0.162 MeOH) [lit.10
.
D
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[a
]
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1H), 3.36 (dd, J = 12.4, 4.4 Hz, 1H), 3.05 (ddd, J = 12.3, 6.1, 1.4 Hz, 1H), 2.38–
2.26 (m, 1H), 2.07 (dd, J = 12.3, 6.1, 1.4 Hz, 1H). 13C NMR (125 MHz, CDCl3): d
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