Enantioselective construction of 6-substituted-α,β-unsaturated- δ-lactone: Total synthesis of anti-bacterial agent (-)-cleistenolide

Article abstract of DOI:10.1016/j.tetlet.2013.07.164

An efficient and straightforward stereoselective synthesis of α,β-unsaturated lactone (1) cleistenolide is described. The synthesis was started from commercially available d-tartaric acid and completed within 13 steps with an overall yield of 7.92%. The cis-olefin was generated from Still-Gennari protocol and one of the hydroxyl groups was from dihydroxylation methodology. All the reactions were very clean and the products were obtained in very good yields.

Full text of DOI:10.1016/j.tetlet.2013.07.164

Tetrahedron Letters 54 (2013) 5674–5676
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective construction of 6-substituted-
a,b-unsaturated-d-
lactone: total synthesis of anti-bacterial agent (ꢀ)-cleistenolide
⇑
Ramesh S. Ghogare, Sachin B. Wadavrao, A. Venkat Narsaiah
Organic and Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and straightforward stereoselective synthesis of
described. The synthesis was started from commercially available
13 steps with an overall yield of 7.92%. The cis-olefin was generated from Still–Gennari protocol and
one of the hydroxyl groups was from dihydroxylation methodology. All the reactions were very clean
and the products were obtained in very good yields.
a
,b-unsaturated lactone (1) cleistenolide is
-tartaric acid and completed within
Received 8 June 2013
Revised 26 July 2013
Accepted 31 July 2013
Available online 11 August 2013
D
Ó 2013 Published by Elsevier Ltd.
Keywords:
Protection
Reduction
Dihydroxylation
cis-Olefination
Cyclization
Natural products possessing pyrone moieties exhibit a variety
of pharmacological properties, which include antifungal, antitu-
mor, antibacterial, and antigrowth effects. The broad range of bio-
logical activities reported for this class of compounds has been
ascribed to their inherent tendency to act as good Michael accep-
tors. In accordance with its biological importance, the syntheses
of the naturally occurring pyrone structural moieties have been
the subject of intense research.1
The compound (R)-2-acetoxy-2-[(2S,3R)-3-acetoxy-6-oxo-3,6-
dihydro-2H-pyran-2-yl]ethylbenzoate (1) called cleistenolide is a
natural product isolated by the Nkunya group from a traditionally
used medicinal plant Cleistochlamys kirkii Oliver belonging to the
family of Annonaceae occurring in Tanzania and Mozambique.2
Cleistenolide reportedly exhibits in vitro anti-bacterial activity
against Staphylococcus aureus and Bacillus anthracis and anti-fungal
activity against Candida albicans.3 The fascinating structural
features and potential biological activity of cleistenolide attracted
many synthetic chemists and led to its synthesis in various routes
(Fig. 1).
The earlier reports for the synthesis of cleistenolide were based
on ring closing metathesis,4 Wittig olefination, selective acetal for-
mation followed by Yamaguchi esterfication,5 and Barbier allyla-
tion, Still–Gennari olefination6 methodologies.
As part of our regular research program for the synthesis of bio-
logically active molecules,7 herein we report the enantioselective
synthesis of cleistenolide, based on mixed hydride reduction of
benzylideneacetal, cis-olefination using Still–Gennari reagent and
Birch reduction followed by cyclization. As shown in Scheme 1,
O
O
O
O
OMe
O
OBz
OBz
OAc OAc
O
OBn
1
13
O
O
O
OAc OAc
OH
HO
O
O
Figure 1.
O
OH
O
OH
OBn
6
2
⇑
Corresponding author. Tel.: +91 40 2691 1608; fax: +91 40 27160387.
E-mail address: vnakkirala2001@yahoo.com (A.V. Narsaiah).
Scheme 1. Retrosynthesis.
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.07.164

R. S. Ghogare et al. / Tetrahedron Letters 54 (2013) 5674–5676
5675
Ph
OH
O
O
O
O
O
OH
O
HO
HO
a
b
d
c
MeO
OMe
OH
OH
OH
OH
OBn
O
O
OH
OBn
O
3
4
5
2
O
OH
OH
O
O
OH
f
e
O
O
O
O
OBz
OBz
+
OBn
8a
OBn
OBn
OBn
8b
7
6
Scheme 2. Reagents and conditions: (a) (i) SOCl2, MeOH, rt, 12 h, (ii) benzaldehyde dimethyl acetal, p-TsOH, cyclohexane, reflux, 6 h; (b) LAH, AlCl3, THF, ꢀ30 °C-reflux, 3 h;
(c) 3-pentanone, CSA, THF, reflux, 4 h; (d) (i) Swern oxidation, ꢀ78 °C, 2 h, (ii) Ph3P+CH3Brꢀ, tBuOK, THF, 0 °C, 1.5 h; (e) OsO4, NMO, tBuOH:H2O, rt, 6 h; (f) Bz-Cl, pyridine,
DMAP, DCM, 0 °C, 30 min.
our synthetic strategy started from commercially available
taric acid (2) (Scheme 2).
D
-tar-
to afford the acetonide deprotected compound, (2R,3S,4R)-3-(ben-
zyloxy)-2,4,5-trihydroxy pentyl benzoate (9) in 90% yield and the
D-Tartaric acid was treated with thionyl chloride (SOCl2) in
optical rotation of 9, ½a D25
ꢁ
+24.4 (c 0.3, CHCl3). The trihydroxy com-
pound upon silylation using TBDPS-chloride, imidazole, and DMAP
at low temperature gave the primary hydroxyl protected silyl
methanol (MeOH) to obtain ester, which was reacted with benzal-
dehyde dimethyl acetal, para-toluene sulfonic acid (p-TSA) in
cyclohexane at reflux to obtain, (4S,5S)-dimethyl-2-phenyl-1,3-
dioxolane-4,5-dicarboxylate (3) in 67% yield; optical rotation of
ether,
(2R,3R,4R)-3-(benzyloxy)-5-(tert-butyl-diphenylsilyloxy)-
2,4-di hydroxylpentylbenzoate (10) in 92% yield with optical rota-
3, ½a 2D5
ꢁ
ꢀ45.1 (c 1, MeOH). Hydrogenolysis of compound 3 with
tion of 10, ½a 2D5
ꢁ
+17.3 (c 1, CHCl3) (Scheme 3).
mixed hydride of aluminum trichloride (AlCl3) and lithium alumi-
Thus obtained compound 10 was again subjected for hydroxyl
protections with 2,2-dimethoxy propane (DMP), p-TSA in acetone
to afford, {(4R,5R,6R)-5-(benzyloxy)-6-[(tert-butyldiphenylsilyl-
oxy)methyl]-2,2-dimethyl-1,3-dioxan-4-yl} methyl benzoate (11)
num hydride (LAH)8 yielded (2R,3R)-3-(benzyloxy) butane-1,2,4-
triol (4) in 70% yield and optical rotation of 4, ½a D25
ꢀ14.5 (c 1,
ꢁ
MeOH). Selective protection of 1,2-diol was carried out using
3-pentanone, camphor sulfonic acid (CSA) in tetrahydrofuran
(THF) at reflux conditions to yield 80% of (R)-2-(benzyloxy)-2-
[(R)-2,2-diethyl-1,3-dioxolan-4-yl] ethanol (5), and the optical
in 86% yield and the optical rotation of 11 is ½a D25
ꢁ
+42.4 (c 0.4,
CHCl3). Compound, [(4R,5S,6R)-5-(benzyloxy)-6-(hydroxylmeth-
yl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl benzoate (12) was
obtained in 90% yield by deprotection of silyl ether with tetrabutyl-
rotation is ½a 2D5
ꢁ
+15.2 (c 3.75, CHCl3). The resulted aldehyde by oxi-
dation under Swern conditions,9 was treated for one carbon Wittig
with methyl triphenyl phosphonium bromide in the presence of
potassium tert-butoxide (tBuOK) at 0 °C to afford, (R)-4-[(R)-1-
(benzyloxy)allyl]-2,2-diethyl-1,3-dioxolane (6) in 57% yield over
ammonium fluoride (TBAF) and optical rotation of 12 is ½a D25
ꢁ
+61.1
(c 0.3, CHCl3). Oxidation of 12 with Swern condition gives aldehyde
followed by Still–Gennari olefination11 to get stereoselective prod-
uct,
{(4R,5S,6R)-5-(benzyloxy)-6-[(Z)-3-methoxy-3-oxoprop-1-
two steps and the optical rotation of 6 is ½a D25
ꢁ
+20.8 (c 0.9, CHCl3).
enyl]-2,2-dimethyl-1,3-dioxan-4-yl}methylbenzoate (13) in 90%
Dihydroxylation of olefin 6 using OsO4-NMO in tert-BuOH:
water (1:1) mixture10 gives diastereomeric mixture of (3R)-3-(ben-
zyloxy)-3-[(R)-2,2-diethyl-1,3-dioxolan-4-yl] propane-1,2-diol (7)
in 96% yield. This mixture was reacted with benzoyl chloride, pyr-
idine and a catalytic amount of 4-dimethylamino pyridine (DMAP)
in CH2Cl2 at low temperature to afford pure diastereomeric iso-
mers 8a and 8b with 8:1 ratio, which was easily separated by col-
umn chromatography. Compound 8a was obtained as major
product in 90% yield, thus separated diastereomeric pure isomer
of (2R,3R)-3-(benzyloxy)-3-[(R)-2,2-diethyl-1,3-dioxolan-4-yl]-2-
hydroxy propyl benzoate (8a) was reacted with p-TSA in methanol
yield, optical rotation of this compound is ½a D25
ꢀ33.3 (c 0.3, CHCl3).
ꢁ
Cis-olefin compound was treated for Birch conditions12 [sodium
metal (Na) and liq. NH3 in dry THF at ꢀ30 °C] to afford the cyclized
product, [(4R,4aS,8aR)-2,2-dimethyl-6-oxo-4,4a,6,8a-tetrahydro-
pyron (3,2d) (1,3) dioxin-4-yl] methyl benzoate (14) in 85% yield,
optical rotation of 14 is ½a D25
ꢀ14.5 (c 0.7, CHCl3). Acetonide depro-
ꢁ
tection was done by using 50% aq trifluoroacetic acid (TFA) in DCM
at 0 °C. Finally, 14 was reacted with acetic anhydride (Ac2O), pyri-
dine, and a catalytic amount of DMAP in CH2Cl2 at 0 °C to afford the
target product, (R)-2-acetoxy-2-[(2S,3R)-3-acetoxy-6-oxo-3,6-
dihydro-2H-pyran-2-yl]-ethyl benzoate (1) in 70% yield over two
O
O
OH
OH
OH OH
O
OH
TBDPSO
TBDPSO
OBz
HO
OBz
g
O
OBz
i
OBz
h
OBn
OBn
OBn
OBn
11
10
9
8a
OMe
O
O
O
OAc OAc
O
O
O
O
OBz
OBz
HO
l
k
j
OBz
OBz
m
O
O
OBn
12
OBn
O
O
13
14
1
Scheme 3. Reagents and conditions: (g) p-TSA, MeOH, rt, 30 min; (h) TBDPS-Cl, imidazole, DMAP, DCM, 0 °C, 1 h, (i) 2,2-DMP, acetone, p-TSA, rt, 1 h; (j) TBAF, THF, 0 °C, rt, 3 h;
(k) (i) Swern oxidation, ꢀ78 °C, 2 h, (ii) (F3CCH2O)2P(O)CH2CO2Me, NaH, THF, ꢀ78 °C, 1 h; (l) Na, NH3, THF, ꢀ30 °C, 30 min; (m) (i) 50% aq TFA, DCM, 0 °C, 30 min, (ii) Ac2O,
pyridine, DMAP, DCM, 0 °C, 30 min.

5676
R. S. Ghogare et al. / Tetrahedron Letters 54 (2013) 5674–5676
steps and the optical rotation of 1, ½a D25
ꢁ
ꢀ140 (c 0.4, CHCl3), lit.5
3. Samwel, S.; Mdachi, S. J. M.; Nkunya, M. H. H.; Irungu, B. N.; Moshi, M. J.;
½
a 2D5
ꢁ
ꢀ147 (c 0.4, CHCl3). All the products were characterized by
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the data were compared with literature reports.
In conclusion, the stereoselective synthesis of cleistenolide (1)
has been carried out successfully, starting from a commercially
available D-tartaric acid with an overall yield of 7.92%. In this syn-
thetic strategy, all the reactions were very clean and the products
were obtained in very good yields.
Acknowledgment
R.S.G. and S.B.W. are thankful to CSIR-New Delhi for providing
fellowship.
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