The total synthesis of (S)-2,4-dihydroxy-1-butyl (4-hydroxyl) benzoate

Article abstract of DOI:10.1016/j.tetlet.2009.04.016

This study is the first synthesis of (S)-2,4-dihydroxy-1-butyl (4-hydroxy) benzoate, a newly discovered natural product with anti-tumor properties from the fungus, Penicillium auratiogriseum. The key steps are a 1,3 diol protection followed by the couplin

Full text of DOI:10.1016/j.tetlet.2009.04.016

Tetrahedron Letters 50 (2009) 3827–3828
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The total synthesis of (S)-2,4-dihydroxy-1-butyl (4-hydroxyl) benzoate
*
Joel Seagren, Atanas Radkov, Samuel David
Department of Chemistry, University of Wisconsin, Oshkosh, 800 Algoma Blvd., Oshkosh, WI 54901, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 February 2009
Revised 6 April 2009
Accepted 7 April 2009
Available online 11 April 2009
This study is the first synthesis of (S)-2,4-dihydroxy-1-butyl (4-hydroxy) benzoate, a newly discovered
natural product with anti-tumor properties from the fungus, Penicillium auratiogriseum. The key steps
are a 1,3 diol protection followed by the coupling of p-anisic acid to the protected alcohol and subsequent
de-protection steps.
Ó 2009 Elsevier Ltd. All rights reserved.
(S)-2,4-Dihydroxy-1-butyl (4-hydroxy) benzoate (1) was iso-
lated from the fungus, Penicillium auratiogriseum from the sponge,
Mycale plumose from Quingdao, China.1 The pure compound
showed cytotoxic inhibition against the mouse cdc2 mutant cell
Of note is a recent publication where serendipitous use was
made of both 1,2-and 1,3-protected 1,2,4-butanetriol to make iso-
prostanes, prostaglandin-like compounds that were recently dis-
covered in humans.10
line (tsFT210) in the micromolar range (8
l
g/mL or 35
lM). The
The first step in the synthesis of 1 was the 1,3 protection7 of
commercial (S)-(ꢀ) 1,2,4-butanetriol as an acetal (2, 90% yield).
For both 1,2 and 1,3 diol protections in butanetriol, it should be
noted that the diol protecting group tends to be unstable with in-
ter-conversion occurring between the five-membered ketal and
six-membered acetal rings, the products of which are not easy to
separate. Therefore all reactions subsequent to the diol protection
were carried out under nitrogen and aqueous work-up was either
avoided where possible or was carried out at 4 °C in the shortest
possible time.
first total synthesis of this molecule is presented here. This synthe-
sis would help in further evaluating the medicinal properties of the
compound and its analogs (Fig. 1).
The synthesis of 1 (Fig. 2) started with (S)-(ꢀ)-1,2,4-butanetriol.
1,2,4-butanetriol is a versatile synthetic building block used in a di-
verse array of synthetic targets. For example, the 1,2 protected diol
portion of 1,2,4-butanetriol was replaced by a highly activated
cyclopropane ring en route to substituted pyrrolidines which are
common in natural products.2 Lewis acid (BF3ꢁEt2O) catalyzed 1,2
protection of 1,2,4-butanetriol was used to form the oxepane core
of Zoapatanol,3 a diterpenoid exhibiting contragestational activity.
Commercial 1,2,4-butanetriol was used to make chiral derivatives
of glyceraldehyde, a C3 synthon that has widespread synthetic
use: a bi(dihydropyran) derivative6 was used for 1,2 diol protection
which proceeded as a dispiroketal, which is sterically hindered and
hence serves as a chiral auxiliary.
Most syntheses require either a 1,2 diol protection or a 1,3 diol
protection of 1,2,4-butanetriol. Exclusive 1,2 protection methods
generally use ketones or dimethyl acetals thereof2,3 with catalytic
amounts of organic acids2 or Lewis acids.3,4 Other reagents include
phenanthrenedione5 and the above-mentioned bi(dihydropyran)
derivative.6
The 1,3 diol protection step was followed by an attempt to couple
this protected alcohol with p-hydroxybenzoic acid using thionyl
chloride and excess triethylamine. The reaction proceeded with very
poor yield and hence was abandoned. Another attempt at coupling
was made with N,N0-dicyclohexylcarbodiimide (DCC). Despite an
earlier report of a similar reaction,11 attempts to directly couple p-
hydroxybenzoic acid with the protected alcohol 2 using DCC were
unsuccessful, presumably due to interference by the phenol.
Coupling was then tried after acetylating p-hydroxybenzoic acid
using acetic anhydride.12 Coupling the acetylated p-hydroxybenzo-
HO
H
For exclusive 1,3 diol protection, simple aldehydes or their cor-
responding acetals have been used. One such commonly seen
example is the exclusive protection of 1,3 diols in sugars bearing
multiple hydroxyl groups.7 Other examples involving chemistries
very different from the aldehyde-based reagents include a sili-
con-ester reagent8 and a Lewis acid-based route.9
O
O
OH
1
OH
* Corresponding author. Tel.: +1 920 424 1400; fax: +1 920 424 2042.
E-mail address: davids@uwosh.edu (S. David).
Figure 1. (S)-2,4-Dihydroxy-1-butyl (4-hydroxyl) benzoate.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.016

3828
J. Seagren et al. / Tetrahedron Letters 50 (2009) 3827–3828
MeO
OMe
O
O
p
-TsOH
HO
H
HO
O
CH2Cl2, 24 hrs, N2
+
OH
HO
O
H
2
O
O
O
O
O
t
-BuOK/DMF
O
H
p-Anisic Acid
H
Et2NCH2CH2SH.HCl
DCC,DMAP,CH3CN
3
4
OMe
OH
HO
H
TFA
O
O
s
OH
THF/H2O/ 4 °C
1
OH
(S)-2,4-dihydroxy-1-butyl (4-hydroxy) benzoate
Figure 2. Synthetic scheme.
ic acid to 2 proceeded smoothly enough, with about 60–70% yield
of the purified product. However, the subsequent phenolic de-pro-
tection with aniline or ammonium acetate13 was problematic. Be-
sides obtaining poor yields, neither reagent gave de-protected
products that could be reasonably purified.
An ether protecting group for the phenol was used next, simply
because p-anisic acid was cheaply available. The coupling of p-ani-
sic acid to 2 with DCC proceeded very smoothly and yields were
around 70% and very pure compound (3) was obtained.
What remained was the sequential de-protection of the phenol
and the diol in 3. An attempt to de-protect the acetal first using
camphorsulfonic acid failed.14 However, the next attempt with tri-
fluoroacetic acid (TFA) was successful.15 Next, the ether was de-
protected to the phenol by refluxing with 2-(diethylamino) etha-
nethiol.16 Unfortunately, the reaction conditions chosen did not
yield the product. The work-up was very acidic (pH 1) and under
these conditions the stability of the alcohol is suspect.
Therefore the de-protection sequenced was reversed and the
ether in 3 was de-protected first to phenol 4 using the ethanethiol
reagent (60% yield), followed by acetal de-protection with TFA to
yield the final product (1, 50% yield). Characterization data were
in complete agreement with the existing literature.1
Supplementary data
Supplementary data (experimental details for the synthesis and
the characterization data for intermediates are provided) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.04.016.
References and notes
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Acknowledgments
14. Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.; Schedel, H. J. Am. Chem.
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We would like to express our deepest gratitude to Brant Ked-
rowski (UW-Oshkosh) for helpful suggestions and thank UW-Osh-
kosh and the department of chemistry for financial support.
16. Magano, J.; Chen, M.; Clark, J.; Nussbaumer, T. J. Org. Chem. 2006, 71, 7103–7105.