Stereoselective synthesis of 5′-hydroxyzearalenone

Article abstract of DOI:10.1016/j.tetlet.2018.08.030

A first stereoselective total synthesis of 14-memebered β-resorcylic macrolactone 5′-hydroxyzearalenone (1) has been achieved. The key steps are Jocobsen hydrolytic kinetic resolution, Sharpless asymmetric dihydroxylation, Vilsmeier-Haack reaction, Mitsunobu esterification and ring-closing metathesis.

Full text of DOI:10.1016/j.tetlet.2018.08.030

Accepted Manuscript
Stereoselective synthesis of 5'-hydroxyzearalenone
Srilatha Avuluri, Sheshurao Bujaranipalli, Saibal Das, J.S. Yadav
PII:
S0040-4039(18)31019-0
https://doi.org/10.1016/j.tetlet.2018.08.030
TETL 50205
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 June 2018
13 August 2018
15 August 2018
Please cite this article as: Avuluri, S., Bujaranipalli, S., Das, S., Yadav, J.S., Stereoselective synthesis of 5'-
hydroxyzearalenone, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.08.030
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Graphical Abstract
Stereoselective synthesis of 5'-hydroxyzearalenone
Srilatha Avuluri, Sheshurao Bujaranipalli, Saibal Das*, J. S. Yadav*

2
Tetrahedron Letters
Stereoselective synthesis of 5'-hydroxyzearalenone
Srilatha Avuluri, Sheshurao Bujaranipalli, Saibal Das*, J. S. Yadav*
Natural Products Chemistry Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A first stereoselective total synthesis of 14-memebered β-resorcylic macrolactone 5'-
hydroxyzearalenone (1) has been achieved. The key steps are Jocobsen hydrolytic kinetic
resolution, Sharpless asymmetric dihydroxylation, Vilsmeier-Haack reaction, Mitsunobu
esterification and Ring-closing metathesis.
Available online
Keywords:
Macrolactone
.
Jacobsen hydrolytic kinetic resolution
Sharpless asymmetric dihydroxylation
Vilsmeier-Haack
Mitsunobu esterification
Ring Closing Metathesis.
dimethoxybenzoic acid 10 and alcohol 9 could be prepared from
aldehyde 11 and alkyne 12 which inturn prepared from 1,4-
butane diol 14 and racemic propylene oxide 13 respectively.
Introduction
Marine organisms are an important source of various bioactive
metabolites.1 Several seagrasses which are subset of marine
plants have produced many interesting bioactive compounds,2 In
2011, Vatcharin and coworkers isolated
a 14-membered
resorcylic acid lactone (RAL), 5'-hydroxyzearalenone (1) along
with other known RALs, zearalenone (2)3, 8'-hydroxyzearalenone
(3)4, 7'-dehydrozearalenone (4)5, β-zearalenol (5)6 and 5'-
hydroxyzearalenol (6)7 from ethyl acetate extract of the culture
medium of the fungus Fusarium sp. PSU-ES73, isolated from
T.hemprichii an endophytic fungi which inturn isolated from
seagrass. Their structures were determined by spectroscopic
methods. Owing to interesting biological profiles of these class of
compounds prompted us to synthesize 1. Although, various
zearalenones have been synthesized8 to the best of our knowledge
there are no synthetic reports on 5'-hydroxyzearalenone (1).
Herein, we report the first stereoselective total synthesis of 5'-
hydroxy zearalenone (1) by using Sharpless asymmetric
dihydroxylation, Jocobsen hydrolytic kinetic resolution,
Vilsmeier Haack reaction, Mitsunobu esterification and ring
closing metathesis as key steps.
Figure 1: Representative examples of β-resorcylic acid lactones.
Our starting point for alkyne 12 was synthesized from
commercially available racemic propylene oxide 13 (Scheme 2)
which was resolved by using (R,R)-salen-CoIIIOAc catalyst to
give (R)-propylene oxide 15.9 Regioselective opening of the
epoxide 15 was achieved with lithiated TMS acetylene in the
presence of BF3.OEt2 to provide homo propargyl alcohol 16 in
80% yield. Newly generated secondary alcohol in 16 was
protected as its PMB ether using PMBCl/DIPEA to furnish 17 in
82% yield.10 TMS functionality in 17 was then removed by
treatment with K2CO3 in MeOH to furnish the alkyne compound
12 in 86% yield.
Results and Discussion:
The retrosynthetic analysis of the target molecule 1 is depicted in
Scheme 1. Accordingly, 1 could be synthesized from compound
7 by using RCM protocol. Compound 7 was envisaged from
coupling of aromatic acid 8 and alcohol 9 through Mistunobu
esterification. Wherein, acid 8 could be obtained from 3,5-
*Corresponding author.E-mail: yadavpub@gmail.com;
jsyadav@indrashiluniversity.edu.in

treated with one-carbon ylide to furnish olefin 27 in 70% yield
over two steps. The PMB ether was deprotected with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to furnish
required secondary alcohol 9 in 81% yield.
Scheme 3: Reagents and conditions: (a) NaH, BnBr, THF, 0 °C-rt, 4
h, 86%; (b) (1) (COCl)2, DMSO, TEA, CH2Cl2, -78 °C; (2)
̶
Ph3P+CH3I , K tOBu, THF, 0 °C-rt, 2 h, 74% over two steps; (c) AD-
mix-β, MeSO2NH2, t-BuOH/H2O, 0 °C, 24 h, 84%; (d) TBSCl,
Imidazole, DCM, 0 oC to rt, 4 h, 85%; (e) MOMCl, DIPEA, DCM, 0
o
oC to rt 8 h, 96%; (f)TBAF, THF, 0 C to rt 3 h, 86%; (g) IBX,
DMSO/DCM, rt, 1 h.
Scheme 1: Retrosynthetic analysis of compound 1.
Scheme 2: Reagents and conditions: (a) (R,R)-salen-CoIIIOAc
o
catalyst, AcOH, Toluene, 0 C-rt, 24 h, 46%; (b) TMSacetylene, n-
BuLi, BF3.OEt2, THF, -78 oC, 3 h, 80%; (c) PMBCl, DIPEA, 150 oC,
4 h, 82%; (d) K2CO3, MeOH, rt, 5 h, 86%.
o
Scheme 4. Reagents and conditions: (a) n-BuLi, -78 C, 2 h, 79%
o
over two steps; (b) TBSCl, Imidazole, DCM, 0 C to rt, 12 h, 90%;
The synthesis of aldehyde 11 was started from commercially
available 1,4-butane diol 14 (Scheme 3). Accordingly, l,4 -butane
diol was selectively mono protected as its benzyl ether using
BnBr, NaH in THF to provide 18 in 80% yield. Alcohol present
in 18 was oxidized by using Swern oxidation condition {(COCl)2,
DMSO, TEA, CH2Cl2, -78 °C} to provide the corresponding
aldehyde which was added to a one-carbon ylide (prepared from
(c)Raney-Ni, H2, EtOH, 12 h, 92%; (d) (1) IBX, DMSO/ DCM, rt,
(2) Ph3P+CH3I , KtOBu, 0 °C-rt, 2 h, 70% over two steps; (e) DDQ,
̶
DCM:H2O(19:1), NaHCO3, rt, 1 h, 81%.
Having synthesized aliphatic fragment 9 then we turned our
attention to synthesize another coupling partner 8 which was
prepared from commercially available 3,5-dimethoxybenzoic
acid 10 (Scheme 5). Treatment of compound 10 with LAH in
THF provided the alcohol 28 in 92% yield. Oxidation of
compound 28 with PCC furnished corresponding aldehyde
followed by the addition to one carbon ylide to furnish the
compound 29 in 74% yield which was further treated with POCl3
to give corresponding aldehyde 30 in 82% yield. Oxidation of
compound 30 with Pinnick oxidation13 conditions to furnish the
required acid fragment 8 in 75% yield.
+
CH3PPh3 I-, KtOBu in THF) to afford olefin 19 in 74% yield
over two steps. Exposure of the compound 19 to Sharpless
asymmetric dihydroxylation conditions11 using AD-mix-β
produced the required diol 20 in 84% yield. The primary alcohol
was protected as its TBS ether by treatment with TBSCl and
imidazole to furnish 21 in 85% yield. Protection of the free
hydroxy group as its MOM ether was achieved by treating
compound 21 with Hunig’s base and MOMCl in CH2Cl2 to
furnish 22 in 96% yield. Deprotection of the TBS group in
compound 22 was achieved by using TBAF to furnish alcohol 23
in 86% yield which was oxidized with IBX to furnish
corresponding aldehyde 11.
With 11 in hand, we next focused our attention on the completion
of 9 via an alkynyl addition to the aldehyde moiety (Scheme 4).
Treatment of the compound 12 with n-BuLi provided the lithium
alkynyl nucleophile which smoothly underwent addition to the
aldehyde 11 to furnish the desired diastereomeric alcohol 24 in
79% yield12 (over two steps). The secondary alcohol present in 24
would be converted into keto functionality in the later stage of
the synthesis. Alcohol 24 was then protected as its TBS ether
using TBSCl/Imidazole to furnish the compound 25 in 90%
yield. One pot alkyne reduction as well as benzyl deprotection
was achieved by using Raney-Ni under hydrogen atmosphere to
provide compound 26 in 92% yield. The primary alcohol was
then oxidized to corresponding aldeyde with IBX which was then
o
Scheme 5: Reagents and conditions: (a) LAH, THF, 0 C - rt, 4 h,
92%; (b) (1) PCC, DCM, rt, 2 h, (2) Ph3P+CH3I , K OBu, 0 °C-rt, 2
h, 74% over two steps; (c) POCl3, dry DMF,0 oC to rt, 8 h, 82%; (d)
NaClO2, NaH2PO4, 2-methyl-2-butene, THF/t BuOH/H2O (3:3:1), rt,
4 h, 75%.
̶
t

4
2. Kontiza, I.; Stavri, M.; Zloh, M.; Vagias, C.; Gibbons, S.; Roussis,
V. Tetrahedron. 2008, 64, 1696-1702.
With both alcohols 8 and 9 in hand, we proceeded for the
construction of the macrocyclic framework (Scheme 6). The
esterification reaction between 8 and 9 was carried out under the
mistunobu reaction conditions14 to obtain the desired ester 7 in
84% yield. Then, ester 7 was treated with 10 mol% of the
Hoveyda–Grubbs second generation catalyst in degassed toluene
to provide the required lactone 31 in 76% yield and with
exclusive E-selectivity. Removal of the TBS group in 31 was
achieved by treatment with TBAF (1M in THF) to furnish the
hydroxy lactone 32 in 86% yield. Then, the hydroxy group in the
lactone was oxidised with Dess-Martin periodinate to give keto
lactone 33 in 84% yield, which was then treated with 4N HCl in
MeOH at room temperature to give compound 34 in 82% yield.
Finally the cleavage of the OMe groups on aromatic ring by
using AlI3 in dry bezene15 to furnish the target molecule 1 in 70%
yield. The spectral data (1H, 13C, MS and IR) of the synthesized
target compound were in good agreement with reported values of
the natural product.2
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Scheme 6: Reagents and conditions: (a) PPh3, DIAD, toluene, 0 °C-
rt, 90 min, 84%; (b) Hoveyda-Grubbs second generation catalyst (10
mol %), toluene, 80 °C, 6 h, 76%; (c) TBAF/THF (1M in THF), 16
o
h, rt, 86%.(d) DMP, NaHCO3, DCM, 0 C, 2 h, 84%, (e) 4N HCl,
MeOH, 36 h, 82%, (f) AlI3, TBAI, Benzene, 5 oC, 70%.
In conclusion, we have accomplished the first stereoselective
total synthesis of 5'-hydroxy Zearalenone (1) by employing the
Sharpless asymmetric dihydroxylation, Jacobsen hydrolytic
kinetic resolution, Vilsmeier-Haack reaction, Mitsunobu reaction
and RCM as the key reactions in 18 longest linear sequence with
an overall yield of 3.6% starting from compound 14.
Acknowledgments:
A.S.L and S.B thanks CSIR, New Delhi, India for fellowship.
Authors thank CSIR New Delhi for financial supports.
Supporting Information:
Supplementary data associated with this article can be found, in
the online version.
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Highlights:




First total synthesis of 14 membered 5'-
hydroxyzearalenone has been achieved.
Starting material used are easily available 1,4-
butane diol and propylene oxide.
Two chiral centers are created using well
established protocols (Sharpless, Jocobsen).
Synthesis was achieved in 18 longest linear
sequence with an overall yield of 3.6%.