An efficient chiral-pool synthesis of botryolide-E

Article abstract of DOI:10.1016/j.tetlet.2012.08.019

An efficient stereoselective total synthesis of botryolide-E by a chiral-pool approach is described. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.019

Tetrahedron Letters 53 (2012) 5539–5540
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Tetrahedron Letters
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An efficient chiral-pool synthesis of botryolide-E
⇑
Sridhar Madabhushi , Kondal Reddy Godala, China Ramanaiah Beeram, Narsaiah Chinthala
Fluoroorganics Division, 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:
An efficient stereoselective total synthesis of botryolide-E by a chiral-pool approach is described.
Received 13 June 2012
Revised 2 August 2012
Accepted 4 August 2012
Available online 10 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Chiral pool approach
Synthesis
Botryolide-E
Natural product
Chiral pool synthesis, which involves the application of readily
available enantiopure natural products such as monosaccharides
and amino acids as starting materials, has become an increasingly
important approach in recent years for the synthesis of complex
organic molecules,1 Recently, Gloer co-workers,2 isolated a metab-
olite botryolide-E from the cultures of the fungicolous Botryotri-
chum sp. (NRRL 38180) and it exhibits an anti-bacterial activity
against Bacillus subtilis (MTCC 441), Staphylococcus aureus (MTCC
96), and Escherichia coli (MTCC 443), and an antifungal activity
against Aspergillus niger (MTCC 1344) and Saccharomyces cerevisiae
(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl) methanol 5
in 82% yield.5 Oxidation of 5 with o-iodoxybenzoic acid (IBX)
and subsequent Wittig olefination of the resulting aldehyde with
ethylene triphenylphosphonium bromide furnished (4S,5S,Z)-4-
(benzyloxymethyl)-2,2-dimethyl-5-(prop-1-enyl)-1,3-dioxolane 6
in 90% yield. Here, the Z-configuration of the double bond was
confirmed from the homodecoupled 1H NMR spectrum of 6,
which shows the coupling constant (J) between two olefinic pro-
tons as 10.847 Hz.6 Next, 6 was subjected to Wacker oxidation7
using PdCl2 as the catalyst to obtain 1-((4S,5S)-5-(benzyloxym-
(MTCC 171). Botryolide-E is a
c
-butenolide derivative and it con-
ethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one
7
in 91%
tains three chiral carbon centers. In the literature only one report
exists on stereoselective total synthesis of botryolide-E and it
was reported by a non-chiral pool approach in 14-steps with 8%
overall yield, starting from racemic propylene oxide.3 Herein we
report the first chiral-pool approach to the total synthesis of bot-
ryolide-E in enantiopure form with 40% overall yield in 12-steps
yield, which upon stereoselective reduction8 with triethyl lithium
borohydride and K-SelectrideÒ was converted into (R)-1-((4S,5S)-
5-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-ol
8 in 90% yield. In the next step, the hydroxyl group present in 8
was protected as an acetyl ester9 with acetic anhydride and
pyridine to obtain (R)-1-((4S, 5S)-5-(benzyloxymethyl)-2,2-di-
starting from (+)-diethyl (
The sequence of reaction steps in stereoselective total synthe-
sis of botryolide-E starting from (+)-diethyl- -tartrate is shown in
Scheme 2. In the first step, (+)-diethyl- -tartrate 2 was reacted
with 2,2-dimethoxypropane using p-toluenesulfonic acid as the
catalyst to obtain (4R,5R)-diethyl-2,2-dimethyl-1, 3-dioxolane-
4,5-dicarboxylate 3 in 90% yield.4 Next, the acetonide 3 was re-
duced with lithium aluminum hydride to obtain ((4S, 5S)-2,2-di-
methyl-1,3-dioxolane-4,5-diyl)dimethanol 4 in 95% yield. In the
next step, compound 4 was converted into a mono O-benzyl ether
using sodium hydride and benzyl bromide to obtain ((4S, 5S)-5-
L
)-tartrate as shown in Scheme 1.
methyl-1,3-dioxolan-4-yl)propan-2-yl acetate 9 in 93% yield.
Reductive debenzylation10 of 9 with H2-Pd/C gave (R)-1-((4S,5S)-
5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-yl
acetate 10 in 97% yield. Oxidation of 10 with IBX and subsequent
modified Horner–Wadsworth–Emmons olefination using an
Ando’s phosphonate11 (ethyl (diphenyl-phosphono) acetate)
gave (Z)-ethyl-3-((4S,5S)-5-((R)-2-acetoxypropyl)-2,2-dimethyl-1,
3-dioxolan-4-yl)acrylate 11 in 90% yield. In the final step, 11
was treated with 50% aqueous trifluoroacetic acid12 at room tem-
perature to obtain botryolide-E 1 (½a2D5ꢀ = ꢁ37.737 (c 0.05, CHCl3);
Lit.2 (½a2D5ꢀ = ꢁ38.0 (c 0.05, CHCl3)) in 95% yield. We obtained sat-
isfactory spectral data (1H NMR, Mass, and 13C NMR) and optical
rotation value for botryolide-E 1, which were identical to the
reported data of the isolated botryolide-E.
L
L
⇑
Corresponding author. Tel.: +91 40 27191772; fax: +91 40 27160387.
E-mail address: smiict@gmail.com (S. Madabhushi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.019

5540
S. Madabhushi et al. / Tetrahedron Letters 53 (2012) 5539–5540
O
O
OH
HO OH
EtOOC COOEt
(+)-diethyl (L)-tartrate
O
O
O
O
O
OH
O
BnO
BnO
botryolide-E
Scheme 1. Retrosynthetic route to botryolide-E starting from (+)-diethyl-
L
-tartrate.
HO OH
EtOOC COOEt
O
O
O
O
O
O
a
b
c
EtOOC
COOEt
BnO
OH
HO
OH
2
5
3
4
d
O
O
O
O
O
O
O
O
O
O
g
BnO
f
e
O
OH
O
BnO
BnO
O
BnO
8
6
9
7
h
O
O
OH
O
O
O
O
O
j
O
i
O
O
O
O
HO
11
1
10
Scheme 2. Total synthesis of botryolide-E. Reagents and conditions: (a) 2,2-DMP, p-TsOH, dry benzene, 60 °C, 8 h, 90%; (b) LAH, THF, 70 °C, 4 h, 95%; (c) BnBr, NaH, THF, rt,
5 h, 82%; (d) (i) IBX, dry DMSO, DCM, 5 h; (ii) EtPh3P+.Brꢁ, n-BuLi, THF, ꢁ78 °C, 2 h, (90% for two steps); (e) PdCl2, CuCl, DMF/H2O (7:1), O2, 60 °C, 6 h, 91%; (f) (i). K-Selectride,
THF, ꢁ78 °C, 2 h; (ii) LiEt3BH, ꢁ78 °C, 1 h, 90%; (g) Ac2O, pyridine, 5 h, 0 °C to rt, 93%; (h) 5% Pd/C, H2, MeOH, 6 h, rt, 97%; (i) (i) IBX, dry DMSO, DCM, 5 h; (ii)
(PhO)2P(O)CH2COOEt, NaH, THF, ꢁ78–0 °C, 3 h, (90% for two steps); (j) 50% aq. CF3COOH, 0 °C to rt, 12 h, 95%.
2. Sy, A. A.; Swenson, D. C.; Gloer, J. B.; Wicklow, D. T. J. Nat. Prod. 2008, 71, 415–
419.
for an efficient and stereoselective total synthesis of botryolide-E
3. Kumar Reddy, D.; Shekhar, V.; Prabhakar, P.; Chanti Babu, D.; Ramesh, D.;
In conclusion, this work describes the first chiral pool approach
in 12-steps and 40% overall yield starting from (+)-diethyl-
L-
Siddhardha, B.; Murthy, U. S. N.; Venkateswarlu, Y. Bioorg. Med. Chem. Lett.
2011, 21, 997–1000.
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Acknowledgements
K.R.G., C.R.B. are thankful to CSIR, New Delhi and C.N. is thankful
to UGC, New Delhi for the financial support in the form of Senior
Research Fellowship.
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spectrum of 6.
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Supplementary data (experimental procedures, characteriza-
tion data, and 1H & 13C NMR spectra of the compounds) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.08.019.
References and notes
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A Practical Approach; Wiley-VCH:
Weinhem, 1994.