A model study toward the concise synthesis of bromotyrosine-derived spiroisoxazoline natural products and analogous core structures

Article abstract of DOI:10.1002/ejoc.201400009

A model study of the first nonaromatic ring based approach toward α-hydroxyspiroisoxazolines resembling the bromotyrosine-derived natural product and analogous spiroisoxazoline core structures was implemented. The desired molecular architecture was achieved through the multifunctionalization of a key 1,3-diketo spiroisoxazoline. Our strategy could serve as an efficient alternative to previously developed approaches that involve aromatic ring oxidation as the essential step to synthesize this class of natural products. The efficient syntheses of functionalized spiroisoxazolines that closely resemble bromotyrosine-derived spiroisoxazoline natural product core structures are described. This described strategy could serve as an efficient alternative to previously developed approaches that involve aromatic ring oxidation as the essential step to synthesize this class of natural products. Copyright

Full text of DOI:10.1002/ejoc.201400009

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201400009
A Model Study toward the Concise Synthesis of Bromotyrosine-Derived
Spiroisoxazoline Natural Products and Analogous Core Structures
Prasanta Das,[a] Edward J. Valente,[b] and Ashton T. Hamme II*[a]
Keywords: Natural products / Heterocycles / Spiro compounds / Synthetic methods / Multifunctionalization / Cyclization
A model study of the first nonaromatic ring based approach
toward α-hydroxyspiroisoxazolines resembling the bromo-
tyrosine-derived natural product and analogous spiro-
isoxazoline core structures was implemented. The desired
molecular architecture was achieved through the multifunc-
tionalization of a key 1,3-diketo spiroisoxazoline. Our strat-
egy could serve as an efficient alternative to previously de-
veloped approaches that involve aromatic ring oxidation as
the essential step to synthesize this class of natural products.
Introduction
natural products can easily be distinguished by three major
Over the past 50 years, marine sponges of the order structure categories in which the brominated spiroisoxaz-
Verongida have been distinguished as affluent sources of α- oline core contains a cyclohexadiene, a bromo epoxy
oximinotyrosine-derived marine natural products (Fig- ketone, or a bromohydrin moiety (Figure 1). The structural
ure 1).[1] Most recently, the Red Sea sponge Suberea mollis diversity arising from the unique spiro linkage between a
was also found to be a source of two new bromotyrosine- brominated cyclohexadiene, an ioxazoline, and a wide range
derived natural products, subereamollines A and B, as sec- of amine and diamine linkages brings about a broad spec-
ondary metabolites containing the spirocyclohexadienyl trum of pharmacological activities including antiviral,[3]
isoxazoline moiety.[2] These widespread spiroisoxazoline antimicrobial,[4] anti-HIV,[5] antifungal,[6] antifouling,[7]
Figure 1. Spiroisoxazoline natural products.
Na+/K+ ATPase inhibition,[8] histone deacetylase (HDAC)
inhibition,[9] histamine H3 antagonism,[10] mycothiol S-con-
[a] Department of Chemistry & Biochemistry, Jackson State
University
jugate amidase inhibition,[11] isoprenylcysteine carboxy
1400 J. R. Lynch St, P. O. Box 17910, Jackson, MS 39217, USA
methyltransferase (Icmt) inhibition,[12] and antineoplastic
E-mail: ashton.t.hamme@jsums.edu
properties.[13]
http://www.jsums.edu/chemistry/ashton-t-hamme-ii/
[b] Department of Chemistry, University of Portland,
Therefore, constructing the unique and synthetically
challenging spiro skeleton has been of great interest to
5000 N Willamette Blvd., Portland, OR 97203, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400009.
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Das, E. J. Valente, A. T. Hamme II
SHORT COMMUNICATION
many chemists.[14,15] However, continuing efforts have re-
sulted in only a few synthetic strategies for the syntheses of
functionalized carbocyclic spiroisoxazolines.[15] Although
significant progress in the oxidation of an aromatic ring
with thallium(III) trifluoroacetate,[15a,15b] electroorganic
oxidation,[15c,15d] and N-bromosuccinimide (NBS)[15f] fol-
lowed by the intramolecular cyclization of a pendant oxime
has been achieved in past decades, oxidative methods for
spiroisoxazoline synthesis remain restricted to aromatic sys-
tems in which the desired products are sometimes isolated
in moderate yields and often require the use of toxic oxi-
dants.[15a–15d] However, the oxidative cyclization of oxime
esters by using diacetoxyiodobenzene was proven to be the
most suitable reagent to date.[15e,15g–15i]
Scheme 2. Retrosynthetic analysis.
hexane-1,3-dione and its analogues as suitable starting ma-
In this context, our continuing efforts and success in de- terials for a number of natural product syntheses.[18] How-
veloping new methodology[16] enabled us to generate a ever, for our synthetic strategy we needed to convert the
novel synthetic strategy toward the bromotyrosine class of diketone into a conjugated diene system for additional
natural products (Scheme 1). Herein, we report the multi- functionalization.
functionalization of a 1,3-cyclohexanedione to furnish the
desired spiroisoxazoline as a model study for the core struc-
ture of bromotyrosine-derived spiroisoxazoline natural
products and their analogues (Scheme 1). Furthermore, this
methodology could potentially serve as an alternative syn-
Scheme 3. Synthesis of the spirovinylogous acid of 3.
thetic strategy toward the targeted natural products and
closely related spiroisoxazolines as novel analogues of bio-
logical interest.
We subjected 3 to a variety of reported reaction condi-
tions[19] to determine the best reagent that would afford spi-
roisoxazoline regioisomers 4 and 5 in the highest yields
(Table 1). On the basis of the data shown in Table 1, entry 4,
which features TiCl4 (5 mol-%) in methanol[19d] with trieth-
ylamine, both spiroisoxazolines 5 and 4 were isolated in
97% yield in a 1:2.5 ratio in favor of spiroisoxazoline 4 after
15 min (Table 1). Owing to the fact that both regioisomers
were isolated, divergent synthetic pathways were explored
in which spiroisoxazoline 4 was utilized as a precursor for
the natural product core structure (analogous to 11-deoxy-
fistularin-3), whereas spiroisoxazoline 5 was developed into
a spiroisoxazoline that was more comparable to the agelorin
natural products in which the carbonyl and isoxazoline
moieties have a 1,4-relationship.[21]
Scheme 1. Our synthetic strategy.
Results and Discussion
Our synthesis basically relied on two approaches, a non-
aromatic approach towards the spirodiketone and a multi-
functionalization approach to furnish the desired molecular
architecture resembling the bromotyrosine-derived natural
product core. Retrosynthetic analysis of the aforementioned
natural product core model study showed that most syn-
thetically interesting core spiroisoxazolines 1 and 2 could
be obtained from corresponding spiromethoxyenone deriv-
atives 4 and 5, which in turn could be achieved from the
same spiro-1,3-diketone moiety 3. Spirodiketone 3 could be
easily prepared from base-mediated intramolecular conden-
sation of corresponding keto ester 6 (Scheme 2).
Table 1. Synthesis of methoxyenone.
Entry Procedure
5:4
Yield
[%]
1
2
3
4
5
6
7
10% HCl/MeOH
1:2
1:2
1:1.5
1:2.5
1:2
1:2
1:2.5
50
70
60
97
40
82
80
concd. H2SO4/MeOH, reflux, 12 h
2.5 mol-% pTSA[a]/MeOH, reflux, 6 h
5 mol-% TiCl4/MeOH/Et3N, reflux, 6 h
CeCl3·7H2O/MeOH, 6 min
NaH/THF, reflux 2 h, then Me2SO4
tBuOK/THF, 10 min, then Me2SO4
In our synthesis, acyclic isoxazole derivative 6[16b,17] was
used as a key precursor for this model study. After treating
6 with sodium hydride, diketone spiroisoxazoline 3 was iso-
1
lated in 80% yield (Scheme 3). Analysis of 3 by H NMR
spectroscopy showed that it existed as an enol, which results
in the fast exchange of one of the protons between the two
carbonyl groups. Notably, the ready availability of cyclohex-
[a] pTSA = p-toluenesulfonic acid.
With the anticipation of furnishing a conjugated double
ane-1,3-dione and its diverse reactivity often render cyclo- bond, we treated predominant isomer 4 with lithium hexa-
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Synthesis of Bromotyrosine-Derived Spiroisoxazolines
methyldisilazane (LHMDS) and PhSeCl followed by (Scheme 5). However, our target was to synthesize 1,3-di-
H2O2.[20,22] As a result, deprotonation of the allylic proton bromo derivative 2.
of 4 and subsequent formation and elimination of the sele-
After this setback, we then decided to switch the electro-
noxide afforded 8 in 75% yield (Scheme 4). To accomplish phile used in the synthesis of 1 from phenylselenium chlor-
the core structure, the spirodiene was then exposed to a ide to phenylselenium bromine. We anticipated that after
number of reaction conditions to bring about dibromin- treating 4 with an excess amount (2.5 equiv.) of LHMDS,
ation and concomitant dehydrohalogenation. Unfortu- treatment with an excess amount of bromine would provide
nately, after a number of attempts to introduce bromine to allylic geminal dibromo compound 12 through monobrom-
8 through a variety of bromine sources [pyridinium tri- ination. Therefore, we followed this reaction pathway, and,
bromide (PTB)/K2CO3, Br2/CCl4, NBS/CCl4], none of de- without further purification, crude allylic geminal dibromo
sired product 1 was isolated; instead, decomposition of the compound 12 was treated with 1,4-diazabicyclo[2.2.2]-
starting material was realized (Scheme 4).
octane (DABCO) in situ to afford 13 in 76% yield over two
steps in one reaction vessel (Scheme 6). Bromination of 13
adjacent to the carbonyl was achieved in 76% yield with
NBS in the dark. Diastereoselective reduction of 1 with
[24]
Zn(BH4)2
afforded desired spiroisoxazoline core struc-
tures (Ϯ)-14 and (Ϯ)-15 in a 4:1 diastereomeric ratio
(Scheme 6).
Scheme 4. First-generation synthesis of spirodiene.
Isomer 5 was also treated under a comparable reaction
series, as shown in Scheme 4, to introduce the other double
bond to furnish the natural product derivative as a model
study for the synthesis of the spiroisoxazoline analogue
(Scheme 5). Although isomer 5 was treated with LHMDS
and PhSeCl followed by H2O2, we isolated spiro derivative
9 in 71% yield (Scheme 5). Bromination of 9 with bromine
in the absence of light afforded vicinal dibromo derivative
10[23] in 90% yield, as result of over bromination followed
by dehydrohalogenation. We did not realize any dibromin-
ation of the α-carbon with respect to the ketone to afford
expected product 2. The feasibility of introducing the third
bromine at the α position of 10 was further attempted under Scheme 6. Second-generation synthesis of the bromospiroisoxaz-
oline core.
PTB/K2CO3 conditions, which afforded 11 in 82% yield
Purification of the crude mixture gave (Ϯ)-14 and (Ϯ)-
15 in 64 and 16% yield, respectively. The diastereomeric
ratio favoring desired trans isomer 14 over undesired cis iso-
mer 15 was rationalized by intramolecular hydride delivery
through a five-membered zinc chelate that avoids the steric
demands of the isoxazoline methylene group, and this re-
sults in the delivery of the hydride from the alpha face of
the ketone.[25] Though we synthesized racemic 14 and 15,
the rigid scaffold of the spiroisoxazolines showed signs of
distinct NOE interactions between the diagnostic protons
that enabled us to establish the relative stereochemical as-
signment of the hydroxy group on the basis of the NOESY
spectrum (Scheme 6). The distinct NOE interactions indi-
cated strong cross-peaks between H5 and H7 for 14, whereas
in the case of 15, strong cross-peaks were observed between
H5 and H7 and also between H1 and H8, which suggested
the formation of trans-14 and cis-15, as a result of dia-
stereoselective reduction (Scheme 6).
Having succeeded in constructing desired spiroisoxazol-
Scheme 5. First-generation synthesis of bromospiroisoxazoline.
ine 1 through our model studies, we then focused on trans-
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P. Das, E. J. Valente, A. T. Hamme II
SHORT COMMUNICATION
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Conclusions
In conclusion, we successfully accomplished the synthesis
of a core skeleton that is very similar to naturally available
spiroisoxazolines, such as 11-deoxyfistularin-3; we also syn-
thesized an isomeric spiroisoxazoline core in which the isox-
azoline moiety and the carbonyl group are positioned in a
fashion similar to that found in agelorin A and B. The di-
verse reactivity of the key 1,3-diketospiroisoxazoline pre-
cursor enabled us to quickly furnish the desired molecular
structures in good to very good yields. Owing to the success
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the reported synthetic methodology from this model system
toward the syntheses of spiroisoxazoline-containing natural
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Supporting Information (see footnote on the first page of this arti-
cle): Characterization data (1H NMR and 13C NMR spectra) for
all new compounds, 2D NMR (NOESY and HMBC) spectra for
14 and 15, and X-ray crystal structure of 10.
Acknowledgments
The project described was supported by the National Institutes of
Health/National Institute of General Medical Sciences (award
number SC3GM094081-04), and the Analytical and NMR CORE
Facilities were supported by National Institutes of Health/National
Center for Research Resources (award number G12RR013459),
and National Institutes of Health/National Institute on Minority
Health and Health Disparities (award number G12MD007581).
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Received: January 2, 2014
Published Online: March 13, 2014
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