PTSA-catalyzed tandem cyclization protocol for the stereoselective total synthesis of obolactone

Article abstract of DOI:10.1016/j.tetlet.2010.02.133

Stereoselective total synthesis of obolactone by the Br?nsted acid (PTSA) mediated tandem cyclization of the appropriately substituted diketone in one-pot in a highly selective and efficient manner is reported.

Full text of DOI:10.1016/j.tetlet.2010.02.133

Tetrahedron Letters 51 (2010) 2295–2296
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
PTSA-catalyzed tandem cyclization protocol for the stereoselective total
synthesis of obolactone
*
Palakodety Radha Krishna , Palabindela Srinivas
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective total synthesis of obolactone by the Brønsted acid (PTSA) mediated tandem cyclization of
the appropriately substituted diketone in one-pot in a highly selective and efficient manner is reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 December 2009
Revised 15 February 2010
Accepted 20 February 2010
Available online 24 February 2010
Keywords:
Dihydropyrones
Methylene bridge
(Z)-Wittig olefination reaction
PTSA
Tandem cyclization
Recently, pyrone containing natural product, obolactone 1 was
isolated by Guéritte and co-workers from Cryptocarya obovata.1
Obolactone 1 is unique in the sense that two dihydropyrones,
{(R,R)-BINOL/Ti(OiPr)4/allyltributyltin/CH2Cl2/À78 °C to À20 °C) to
afford homoallyl alcohol 5 in good yield (75%, over two steps)
and diastereoselectivity (dr 9:1). The absolute stereochemistry of
the newly created stereogenic center was assigned based on Rych-
novsky’s analogy of the corresponding acetonide 5a.7 For instance,
the 13C NMR of 5a revealed the carbon atoms due to the acetonide
methyls at d 19.8 and at d 30.1 ppm characteristic of the acetonide
of a syn-1,3-diol moiety. Thus the relative stereochemistry of the
newly created stereogenic center was unequivocally assigned as
syn to the existing one and its absolute stereochemistry as ‘R’.
Having obtained the 1,3-diol 5 that is differently functionalized
at both the ends, the free hydroxyl group was protected as its silyl
ether under the conventional reaction conditions to afford 6 (90%).
Since the terminal olefin present in 6 was conceived as the masked
carbonyl group, its dihydroxylation (OsO4/NMO/acetone/H2O) and
oxidative cleavage (NaIO4/satd NaHCO3/CH2Cl2/rt) gave the
corresponding aldehyde which on a Wittig olefination reaction8
{(CF3CH2O)2POCH2COOCH3/KHMDS/18-Crown-6/THF/À78 °C to rt/
namely a
bridge thus presenting a rare structural motif. We are interested
in the total synthesis of -pyrone containing natural products
c-pyrone and a-pyrone are linked through a methylene
a
due to their structural diversity, substitution pattern on the side-
chain, their ubiquitous presence coupled with varied biological
activity2 and reported the synthesis of some 6-alkyl
a-pyrone con-
taining natural products earlier.3 Recently Pan and co-workers re-
ported the first asymmetric total synthesis of 1 via RCM protocol.4
Attracted by its structural elegance and complexity, we explored
alternative strategies that allow far simpler and efficient access
to such skeleton containing natural products. Herein we report
the stereoselective total synthesis of 1 by the Brønsted acid-medi-
ated tandem cyclization of the diketone 2 in one-pot.
The synthetic strategy envisaged (Scheme 1) stems from a sim-
ple logic that a Brønsted acid (PTSA)-mediated tandem cyclization
of the appropriately substituted diketone 2 maybe invoked to
result in the target 1. Diketone 2 in turn could be accessed from
3 through oxidation and 3 could be realized from the known alco-
hol 4 through a series of reactions as enumerated in Scheme 1.
Accordingly, the synthesis (Scheme 1) begins from the commer-
cially available homopropargyl alcohol and its transformation into
a known alcohol 4.5 Later, 4 was oxidized to aldehyde under Swern
conditions and immediately subjected to Keck allylation6 reaction
12 h} furnished the a,b-unsaturated ester 7 (70%, over three steps)
predominantly as the (Z)-isomer, as characterized by 1H and 13C
NMR spectroscopy. The coupling constant (J = 11.7 Hz) and the
chemical shift values (d 6.35–6.26 ppm as a multiplet and at d
5.80 ppm as a doublet) confirmed the (Z)-geometry of the olefin.
Later the PMB group was deblocked (DDQ/CH2Cl2/H2O/rt/30 min)
to afford compound 8 (90%).
The alcohol 8 was oxidized to aldehyde under Swern reaction
conditions which on crucial aldol reaction with the in situ gener-
ated anion of benzylideneacetone (LHMDS/THF/À78 °C) furnished
compound 3 (65%) as a 1:1 diastereomeric mixture. The diastereo-
* Corresponding author. Tel.: +91 40 27160123; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.133

2296
P. Radha Krishna, P. Srinivas / Tetrahedron Letters 51 (2010) 2295–2296
TBSO
OH
OTBS
Ref. 5
a
b
HO
PMBO
PMBO
PMBO
OH
5
Homopropargyl
alcohol
4
c
O
O
5a
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
d
e
PMBO
PMBO
HO
O
O
8
7
O
6
O
OTBS
OTBS
O
O
O
OH OTBS OTBS
f
g
Ph
Ph
O
O
2
3
O
O
O
O
O
O
h
Ph
H
1
Scheme 1. Reagents and conditions: (a) (i) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C, 1 h, 90%, (ii) (R,R)-BINOL, 4 Å MS, Ti(OiPr)4, allyltributyltin, CH2Cl2, À78 to À20 °C, 12 h, 75%;
(b) TBSCl, imidazole, DMAP, CH2Cl2, 3 h, 90%; (c) (i) HFÁPy, THF, 0 °C to rt, 12 h, (ii) 2,2-DMP, PPTS, CH2Cl2, rt, 2 h, (85% over two steps); (d) (i) OsO4, NMO, acetone/water (4:1),
(ii) NaIO4, satd NaHCO3, CH2Cl2, 0 °C to rt, 12 h, (iii) (CF3CH2O)2POCH2COOCH3, KHMDS, 18-Crown-6, dry THF, À78 °C to rt, 12 h, 70%, (70% over three steps); (e) DDQ, CH2Cl2/
H2O (19:1), 0 °C to rt, 30 min, 90%; (f) (i) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C, 1 h, 90%, (ii) benzylideneacetone, LHMDS, dry THF, À78 °C, 2 h, 65%; (g) Dess–Martin
periodinane, NaHCO3, CH2Cl2, 0 °C to rt, 1 h, 80%; (h) PTSA, benzene, rt, 4 h, 75%.
meric mixture was taken up for the next reaction without any puri-
fication since the alcohol transforms into ketone functionality in
the next step. Accordingly, the alcohol was oxidized (DMP/NaH-
CO3/CH2Cl2/0 °C to rt/1 h) to afford the diketone 2 (80%) which
was earlier identified as the crucial intermediate. The diketone 2
was characterized by its spectral data. For instance, 1H NMR spec-
trum revealed the protons due to characteristic methylene flanked
by two ketone groups at d 3.10–2.90 ppm as a multiplet integrating
for one proton while the other proton showed at d 2.78–2.67 ppm
as a multiplet. The same protons were present at d 2.89–2.64 as a
multiplet in compound 3. Later the tandem PTSA-catalyzed cycli-
zation of 2 to result in 1 was effected by the literature inspired re-
Acknowledgment
One of the authors (P.S.) thanks CSIR, New Delhi, for financial
support in the form a fellowship.
Supplementary data
Supplementary data (general procedures and spectral data of
the compounds) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2010.02.133.
References and notes
port for the
c
-pyrone ring construction.9 Thus, 2 on exposure to
PTSA in benzene at room temperature for 4 h afforded the target
natural product 1 (75%) through a multiple reaction set; namely
silyl deprotection-tandem ring-closing reactions in an unprece-
dented single step. The physical and spectroscopic data of syn-
thetic 1 are consistent with the reported values.10,1,4 The HRMS
spectrum displayed the [M+Na]+ 333.1109, calculated 333.1102
for the molecular formula C19H18O4Na.
In conclusion, herein we have described the total synthesis of 1
through a Brønsted acid-mediated tandem cyclization as the key
reaction to realize a methylene bridged bis-dihydropyrone ring
skeleton in one-pot in a highly efficient manner. This strategy
maybe adopted for the synthesis of similar ring-containing natural
products.
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Krishna, P.; Srinivas, R. Tetrahedron Lett. 2007, 48, 2013; (d) Radha Krishna, P.;
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4. Zhang, J.; Li, Y.; Wang, W.; She, X.; Pan, X. J. Org. Chem. 2006, 71, 2918.
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10. Please see Supplementary data for the experimental procedures and spectral
data.