A catalytic approach to the MH-031 lactone: Application to the synthesis of geralcin analogs

Article abstract of DOI:10.1016/j.tetlet.2014.09.088

A concise, 5-step synthesis of the hepatoprotective lactone MH-031 was achieved. Our approach utilizes several catalytic processes, namely, a Rauhut-Currier reaction, a chemoselective Fisher esterification, and a ring closing metathesis. Further elaboration of this lactone yielded the hydrazide natural product geralcin A and dihydrogeralcin B, a saturated analog of geralcin B. Biological evaluation of the latter indicated that the presence of the enehydrazide moiety in geralcin B is critical for anticancer activity.

Full text of DOI:10.1016/j.tetlet.2014.09.088

Tetrahedron Letters 55 (2014) 6266–6268
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A catalytic approach to the MH-031 lactone: application to the
synthesis of geralcin analogs
a
b
Rodolfo Tello-Aburto a, , Alyssa N. Lucero , Snezna Rogelj
⇑
a Department of Chemistry, New Mexico Institute of Mining and Technology, 801 Leroy Place, Socorro, NM 87801, USA
b Department of Biology, New Mexico Institute of Mining and Technology, 801 Leroy Place, Socorro, NM 87801, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise, 5-step synthesis of the hepatoprotective lactone MH-031 was achieved. Our approach utilizes
several catalytic processes, namely, a Rauhut–Currier reaction, a chemoselective Fisher esterification, and
a ring closing metathesis. Further elaboration of this lactone yielded the hydrazide natural product ger-
alcin A and dihydrogeralcin B, a saturated analog of geralcin B. Biological evaluation of the latter indicated
that the presence of the enehydrazide moiety in geralcin B is critical for anticancer activity.
Published by Elsevier Ltd.
Received 19 August 2014
Revised 10 September 2014
Accepted 18 September 2014
Available online 28 September 2014
Keywords:
Natural products
Hydrazide
Geralcin
Anticancer
Analogs
Hydrazine derivatives have ubiquitous applications, varying
from polymers and dyestuff to pharmaceuticals.1 Valuable hydra-
zine therapeutics include antidepressants such as the MAO inhibi-
tors iproniazid and isocarboxazid, and the antituberculosis agent
isoniazid.2 In contrast, natural products containing a hydrazine-
derived motif are rarely found.3 Recently, the study of Streptomyces
sp. LMA-545 yielded the hydrazine derivatives geralcins A–E
(Fig. 1).4,5 Of these, geralcin B, containing an enehydrazide
motif, showed activity against MDA231 breast cancer cell line
LMA-545, the same culture producing the geralcins.4 For this rea-
son, lactone 1 has been proposed as the plausible biogenetic pre-
cursor of both geralcin A and B. Martin and co-workers8 prepared
the benzyl and methyl derivatives of 1, as an inseparable mixture
of endo and exo olefins, using an ethylene oxide epoxide opening
reaction. More recently, during the first total synthesis of geralcin
A, Ouazzani accomplished the synthesis of 1 in six steps and 33%
yield.6
We became interested in lactone MH-031 because of its poten-
tial use in the total syntheses of the geralcins, and aimed to
develop a different approach to 1, that would be practical and com-
pare favorably with the previous synthesis.
(IC50 = 5
moieties showed activity against KB and HCT116 cancer cell lines
(IC50 = 0.8 M).
lM) and geralcin C, containing both hydrazide and azoxy
l
The interesting biological properties along with the unusual
structural motifs make the geralcin family of natural products
attractive targets for total synthesis.
Catalytic methods are preferred over stoichiometric alternatives
because of the potential to reduce the amount of chemical waste
and increase step, atom, and redox economies. Herein, we wish
Using a bio-inspired approach, Ouazzani reported the first total
synthesis of geralcin A, featuring the coupling of lactone MH-031
(1) with a protected hydrazine derivative.6 Herein, we wish to
report our work on a new synthesis of MH-031, the plausible bioge-
netic precursor of the geralcins, using catalytic transformations,
and its use in the total synthesis of geralcin A and dihydrogeralcin B.
Lactone MH-031 (1) was first isolated from a strain of Strepto-
myces rishiriensis by Itoh et al.,7 and was shown to possess hepato-
protective activity. MH-031 was also isolated from Streptomyces
⇑
Corresponding author. Tel.: +1 575 835 5168; fax: +1 575 835 6453.
E-mail address: rtello_a@nmt.edu (R. Tello-Aburto).
Figure 1. MH-031 and the geralcin natural products.
http://dx.doi.org/10.1016/j.tetlet.2014.09.088
0040-4039/Published by Elsevier Ltd.

R. Tello-Aburto et al. / Tetrahedron Letters 55 (2014) 6266–6268
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to report a synthetic approach to MH-031 (1) relying on a catalytic
Rauhut–Currier reaction, a chemoselective Fisher esterification,
and a ring closing metathesis reaction.
Initial attempts using 5–10 mol % of the 2nd generation Grubbs
precatalyst in dichloromethane at 0.01 M substrate concentration
met limited success, affording the desired lactone 6 in 40–50%
yield, along with variable amounts of recovered starting material.
Increasing the reaction temperature by changing the solvent to
dichloroethane slightly increased the chemical yield to 55%.
Increasing the temperature by performing the reaction in refluxing
toluene did not provide any improvement in the isolated yield. For
the experiments conducted in dichloroethane, unreacted starting
material was accompanied by homodimerization at the allyl olefin
as the major side-product. Both recovered starting material and
homodimer could be re-subjected to the reaction conditions,
slightly increasing conversion to about 60% after one cycle. Fortu-
nately, the formation of the dimer byproduct was completely
eliminated by decreasing the substrate concentration to 0.005 M
and using 10 mol % of the Grubbs 2nd generation precatalyst,
affording lactone 6 in an excellent 97% isolated yield.
Our synthetic approach commenced with a Rauhut–Currier
reaction9 of methyl acrylate to give diester 3 (Scheme 1). This
nucleophile-catalyzed transformation has been reported in the lit-
erature for the synthesis of polymer products and building blocks.
Of note, Verkade has reported yields of 85% for this reaction, using
a proazaphosphatrane as catalyst,10 and Yi has achieved yields of
91% using a ruthenium complex.11 We chose to use the conditions
reported by Coward using n-Bu3P as catalyst12 because of its
commercial availability and the practical experimental setup and
purification. Using 10 mol % of tributyl phosphine as the nucleo-
philic catalyst, we routinely obtain compound 3 in 65% yield in
gram scale after distillation.
Hydrolysis of diester 3 under standard conditions afforded the
corresponding diacid,12 which was then subjected to a chemose-
lective Fisher esterification using p-TsOH as catalyst to produce
mono-ester 4 in 89% yield. The basis for the observed selectivity
might involve mesomeric resonance contribution in the case of
the conjugated carboxylic acid.13 The structure of mono-ester 4
was tentatively assigned by spectroscopic methods, and later con-
firmed by conversion to MH-031 as described below. Allylation of 4
under standard conditions gave diene 5 in 89% yield.
Comparison of the spectroscopic data for 6 with literature val-
ues6,8 showed an excellent match, confirming the anticipated che-
moselectivity of our Fisher esterification. Hydrolysis was carried
out as described by Ouazzani6 to afford MH-031 (1) in good yield.
Our approach to lactone 1 proceeds in five steps and 47% overall
yield.
Following Ouazzani’s work,6 treatment of 1 with oxalyl chloride
led to the formation of the corresponding acid chloride (Scheme 2),
which was then reacted with hexyl carbazate 7 to give hydrazide 8.
Cleavage of the Boc protecting group and acylation with glycolic
acid afforded geralcin A as described previously.6 Coupling of the
acid chloride derived from 1 with acyl hydrazine derivative 915
was also carried out to give dihydrogeralcin B (10), an analog of
geralcin B containing a saturated side chain.
With diene 5 in hand, the formation of the required butenolide
moiety by ring closing metathesis was examined. Although many
examples of the use of olefin metathesis for the construction of
butenolides are known, substrates bearing a 1,1-disusbstituted
olefin conjugated to a carbonyl are less common.14 Based on a
survey of the literature, we chose to work with the Grubbs 2nd
generation precatalyst.
Scheme 1. Synthesis of MH-031.
Scheme 2. Synthesis of geralcin A and dihydrogeralcin B.

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R. Tello-Aburto et al. / Tetrahedron Letters 55 (2014) 6266–6268
Ouazzani has previously shown that geralcin A is inactive against
HCT116, MCF7, HT29 and MDA231 cancer cell lines, whereas geral-
cin B shows inhibition of MDA231 breast cancer (IC50 = 5 M) and
acknowledged with thanks. S.R. acknowledges the support by the
National Institute of General Medical Sciences – United States
P20GM103451) via NM INBRE. The Mass Spectrometry Facility at
University of New Mexico is acknowledged for HRMS analyses.
l
promoted 42% growth inhibition on MCF7 cells at 10À5 M concen-
tration (no IC50 was reported for this cell line).4 For this reason, we
focused on the biological evaluation of dihydrogeralcin B (10), in
order to gain insight into the role of the unsaturation on the side
chain. Cytotoxicity assays were performed using a standard tetrazo-
lium dye-based colorimetric test (MTT, details are provided in Sup-
porting information). Dihydrogeralcin B (10) was tested against
HeLa, U87 and MCF7 cell lines as models for cervical, brain, and
Supplementary data
Supplementary data (experimental details, characterization
data and copies of 1H and 13C NMR spectra for new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.09.088.
breast cancer, respectively, resulting in no significant activity (IC50
-
P 100 M) in all three cell lines tested. As the only structural differ-
l
References and notes
ence between geralcin B and analog 10 is the absence of the alkene
on the side chain, this result indicates that the enehydrazide moiety
present in geralcin B is likely essential for anticancer activity.
In summary, we have presented here a catalytic approach for
the synthesis of the lactone MH-031 (1) using a Rauhut–Currier
reaction, a chemoselective Fisher esterification and ring closing
metathesis as key steps. The synthesis of 1 proceeds in five steps
and 47% overall yield, which compares favorably with previous
syntheses. Lactone 1 was further elaborated to geralcin A and dihy-
drogeralcin B (10). Biological studies on 10 suggest that the ene-
hydrazide moiety present in geralcin B is likely critical for activity.
Our synthetic approach should prove applicable to the synthesis of
other hydrazides containing the MH-031 fragment. These investi-
gations are currently underway in our laboratory, and the results
will be reported in due course.
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Acknowledgments
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Financial support for this project in the form of a startup pack-
age from New Mexico Institute of Mining and Technology is