Concise and protecting group-free synthesis of botryolide-E

Article abstract of DOI:10.1016/j.tetlet.2012.11.061

A simple highly concise protective group-free synthesis of botryolide-E from (R)-propylene oxide was developed using Hoveyda Grubbs cross metathesis, Still's modified Horner-Wadsworth-Emmons reaction, and Sharpless asymmetric dihydroxylation, as key steps.

Full text of DOI:10.1016/j.tetlet.2012.11.061

Tetrahedron Letters 54 (2013) 828–829
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Concise and protecting group-free synthesis of botryolide-E
⇑
D. Chandra Rao, D. Kumar Reddy, V. Shekhar, Y. Venkateswarlu
Natural Products Chemistry Division, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple highly concise protective group-free synthesis of botryolide-E from (R)-propylene oxide was
developed using Hoveyda Grubbs cross metathesis, Still’s modified Horner–Wadsworth–Emmons reac-
tion, and Sharpless asymmetric dihydroxylation, as key steps.
Received 13 September 2012
Revised 15 November 2012
Accepted 18 November 2012
Available online 29 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Botryolide-E
Botryotrichum sp. (NRRL 38180) protection
free
Hoveyda Grubbs metathesis
Ring-closing
Still’s modified Horner–Wadsworth–
Emmons reaction Sharpless asymmetric
dihydroxylation
Protecting groups are essential in the synthesis of natural prod-
ucts.1 The fact is that skeleton-building reactions in organic syn-
thesis evolved to use mainly strongly basic reagents such as
enolates, Grignard reagents, or organolithium compounds made
it almost compulsory to protect hydroxyl and amino groups or car-
bonyl functions that were not targeted to react. Natural product
synthesis with readily available substances and without using pro-
tecting groups is challenging. The protecting group introduction
and removal lead to loss of material, as quantitative recovery is
not possible no matter how efficient the process may be.2 Hence,
at this stage of the methodological development, protecting-
group-free synthesis was essentially a fantasy.2 The natural prod-
against Staphylococcus epidermidis (MTCC 437) (50 lg/ml), Pseudo-
monas aeruginosa (MTCC 741) (50
lg/ml), and Klebsiella pneumonia
(MTCC 39) (50 g/ml).
l
O
O
O
HO
O
1
ucts containing
c-lactone motif are known to show a variety of
activities such as cytotoxic, antitumor,5 cyclo-oxygenase, or
3
4
6
phospholipase A2 inhibition. Botryolide-E (1) is a
c-lactone natu-
ral product isolated from cultures of the fungicolous Botryotrichum
sp. (NRRL 38180) by Gloer and co-workers, in 2008.7 We elabo-
rated its biological properties and absolute configuration by first
time synthesis of this molecule starting from (R)-propylene oxide
During the course of our program aimed at the synthesis of bioac-
tive molecules, the interesting biological activity and structure of
natural product botryolide-E (1), prompted us to establish a protec-
tion group-free synthesis of botryolide-E (1) from (R)-propylene
oxide 2 using Hoveyda Grubbs cross metathesis, Still’s modified
Horner–Wadsworth–Emmons reaction, and Sharpless asymmetric
dihydroxylation in a strategy devoid of standard protection/depro-
tection protocols. We achieved the synthesis of botryolide (1) in five
linear steps in 46% overall yield. The retro synthetic approach for
botryolide-E (1) is shown in Scheme 1.
(
2) using 13 steps with a yield of 20.24%.8
9
Recently, many groups have synthesized this molecule. Natural
product botryolide-E (1) exhibited a significant potent activity
against Staphylococcus aureus (MTCC 96) (6.25
ity against Escherichia coli (MTCC 443) (12.5
l
g/ml), good activ-
lg/ml) and Bacillus
subtilis (MTCC 441) (25 lg/ml), and exhibits moderate activity
⇑
Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.061

D. Chandra Rao et al. / Tetrahedron Letters 54 (2013) 828–829
829
O
O
OAc
O
O
HO
O
OMe
O
2
6
1
Scheme 1. Retro synthetic analysis of botryolide-E (1).
O
a
OH
OAc
b
c
2
3
4
OAc
OAc
d
OMe
CHO
O
6
5
O
N
N
O
OAc OH
O
e
HO
O
Cl
OMe
Ru
O
Cl
OH
O
7
1
Hoveyda Grubbs catalyst
Scheme 2. Reagents and conditions: (a) vinylmegnesium bromide, CuI, THF, ꢀ20 °C, 12h, 85%, (b) (Ac)
2
O, 0 °C to rt, 3 h, 90%, (c) CH
O (1:1), 0 °C, 24 h, 86%.
2
@CHCHO, dry DCM, Hoveyda Grubbs
catalyst, 3 h, rt, 92%, (d) MeO CH P(O)(OCH CF ,t-BuOH:H
2
2
2
3 2
)
, NaH, Dry THF ꢀ78 °C, 2 h, 76%, (e) AD Mix-
a
2
The synthesis of botryolide-E (1) is based on a sequence of reac-
tions starting from (R)-propylene oxide 2, which on vinylation was
converted to homoallylic alcohol 3. The secondary hydroxyl group
in compound 3 was reacted with acetic anhydride and pyridine to
afford compound 4. A mixture of compound 4 and acroline in 1:3
ratio was subjected to cross metathesis using second generation
Hoveyda Grubbs catalyst (5 mol %)10 in DCM under reflux condi-
tions to yield aldehyde 5 which was used for further reaction with-
out further purification (Scheme 2).
Supplementary data
Supplementary data (experimental procedure and analytical
data for all the compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.11.061.
References and notes
1.
Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994.
Then aldehyde 5 was subjected to Still’s modified Horner–
Wadsworth–Emmons reaction11 using NaH and bis(2,2,2-trifluoro
2.
Young, Ian S.; Baran, Phil S, Nat. Chem. 2009, 1, 193.
3
.
Fridkin, S. K.; Edwards, J. R.; Courval, J. M.; Hill, H.; Tenover, F. C.; Lawton, R.;
Gaynes, R. P.; McGowan, J. E., Jr Ann. Intern. Med. 2001, 135, 175.
Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94.
Li, D. H.; Zhu, T. J.; Liu, H. B.; Fang, C. Y.; Gu, Q. Q.; Zhu, W. M. Arch. Pharm. Res.
ethyl) (methoxy carbonyl methyl) phosphonate in dry THF at
4
5
.
.
ꢀ
78 °C to afford (E,Z)-ester 6 exclusively in 88% yield with the
traces of (E,E)-ester, that was separated by normal silica gel column
chromatography. Compound 6 was subjected to diastereo and
enantioselective Sharpless asymmetric dihydroxylation1 to afford
the final desired compound botryolide-E (1) instead of dihydroxy
ester 7. The dihydroxy compound (7) in situ was converted into fi-
nal botryolide-E (1). This indicates that lactonization has taken
2006, 29, 624.
6. Cateni, F.; Zilic, J.; Zacchigna, M.; Bonivento, P.; Frausin, F.; Scarcia, V. Eur. J.
Med. Chem. 2006, 41, 192.
2
7
8
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Sy, A. A.; Swenson, D. C.; Gloer, J. B.; Wicklow, D. T. J. Nat. Prod. 2008, 71, 415.
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9.
(a) Sridhar, M.; Kondal Reddy, G.; China Ramanaiah, B.; Narsaiah, C. Tetrahedron
Lett. 2012, 53, 5539; (b) Veeranjaneyulu, B.; Srilatha, M.; Chinna Reddy, G.; Das,
B. Helv. Chim. Acta 2012, 95, 1152.
place with a formation of the more stable
c
-lactone botryolide-E
2
5
7
25
D
(
1). The physical {½
a
ꢁ
ꢀ35.1 (c 0.1, CHCl
3
). Lit
½
aꢁ
ꢀ38 (c 0.05,
D
8
1
25
D
1
CHCl
3
), lit
½
a
ꢁ
ꢀ36.7 (c 0.05, CHCl
3
)}, and spectral data ( H
10. (a) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 11360; (b) Bouz Bouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6,
3
NMR and C NMR) of synthetically prepared compound 1 were
3
465.
1. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
12. Kolb, H. C.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
7
,8
found to be in good agreement with the natural product.
1
A concise total synthesis of botryolide-E (1) has been achieved
in five linear steps from (R)-propylene oxide 2 in 46% overall yield,
in a strategy devoid of standard protection/deprotection protocols.
Acknowledgement
The authors D.C.R., D.K.R. and V.S. are thankful to CSIR, New
Delhi, for the financial support.