Total synthesis of geralcin A, a representative of a new family of hydrazine-containing natural products

Article abstract of DOI:10.1016/j.tetlet.2013.07.087

The first total synthesis of geralcin A (2), a naturally occurring α,β-unsaturated γ-lactonohydrazide produced by Streptomyces sp. LMA-545, was achieved according to the hypothetical biosynthesis we have previously published. MH-031 (1), the plausible nat

Full text of DOI:10.1016/j.tetlet.2013.07.087

Tetrahedron Letters 54 (2013) 5299–5301
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of geralcin A, a representative of a new family of
hydrazine-containing natural products
Géraldine Le Goff a, Emmanuel Roulland b, Jamal Ouazzani a,
⇑
a Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, C.N.R.S., Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
b CNRS UMR 8638, Faculté de Pharmacie, Université Paris Descartes, 4 Avenue de l’Observatoire, 75270 Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of geralcin A (2), a naturally occurring a,b-unsaturated c-lactonohydrazide pro-
Received 16 June 2013
Revised 9 July 2013
Accepted 12 July 2013
Available online 24 July 2013
duced by Streptomyces sp. LMA-545, was achieved according to the hypothetical biosynthesis we have
previously published. MH-031 (1), the plausible natural precursor isolated together with geralcin A,
was synthesized in 6 steps and in a 25% overall yield. Condensation of glycolic acid with key intermediate
Boc-hexylhydrazine afforded the desired geralcin A in 46% overall yield. Spectroscopic data of the syn-
thetic compound were identical to those recorded for the natural one.
Keywords:
Geralcins
Ó 2013 Elsevier Ltd. All rights reserved.
N–N containing natural compounds
Hydrazide
MH-031
Biomimetic synthesis
N–N bond containing natural products are scarce and have been
isolated from plants, marine organisms, and microorganisms. In
2013, an updated inventory claimed that only 200 representatives
had been reported to date.1 Although rare, these compounds fea-
ture a remarkable structural diversity and are endowed with bio-
logical activities of interest.
The compounds of the geralcin family have been recently
isolated from Streptomyces sp. LMA-545, and the five described
relatives were named from A to E (Fig. 1).2,3 Geralcins A, B,
In our first report on geralcins,2 we postulated a probable bio-
synthetic pathway consisting in condensation of an alkyl
,b-unsaturated -lactone
a
hydrazine or hydrazide moiety with the
a
c
named MH-031 (Fig. 2).2,5
According to this hypothesis, we reported in this Letter the first
bio-inspired total synthesis of geralcin A, including the synthesis of
the MH-031 precursor and its condensation with the hydrazine
moiety.
Our retrosynthetic design is presented in Figure 3. Disconnection
and D appeared to be novel
a,b-unsaturated
c-lactono-hydra-
of the amide bonds revealed three key fragments; the
a,b-unsatu-
zides. It is noteworthy that the architecture of the seven-mem-
bered ring of geralcin D had never been found before and that
geralcin C is the only natural product bearing two N–N contain-
rated -lactone 3-(5-oxo-2H-furan-4-yl)-propanoic acid (1) (MH-
c
031), the Boc-hexylhydrazine (9), and the commercially available
glycolic acid. These three fragments could be assembled through
selective C–N bond formations using various coupling methods.
Our aim was to design a convergent synthesis starting from
MH-031 (1) allowing to access congeners of geralcins through
subsequent condensations of carboxylic acid moieties with the
N-substituted alkylhydrazine.
ing groups (hydrazide and azoxy) imbedded in
scaffold.
a unique
Geralcin B was found to be cytotoxic against MDA231 breast
cancer cells with an IC50 of 5 M and geralcin C exhibited an
IC50 of 0.8 M against KB and HCT116 cancer cell lines. Further-
l
l
more, geralcin C moderately inhibited the Escherichia coli DnaG
primase, a Gram-negative antimicrobial target, with an IC50 of
0.7 mM.
One of the main challenges was the synthesis of a highly func-
tionalized hydrazine derivative, with the correct N–N bond substit-
uents. Although the scaffold of geralcin A appeared to be quite
simple, there is no general strategy described for the synthesis of
trisubstituted hydrazides.6,7 The required reactions needed to be
selective to avoid undesired multiple N-alkylations and N-acyla-
tions. Our strategy was based on the selective reactivity of the
hydrazide group that should allow distinguishing between the
two N-atoms. The chemical properties of hydrazides can be
compared to those of amides. Thus, in hydrazides as in amides,
the lone pair of the nitrogen bonded to a carbonyl group is
The structural elucidation within this family of compounds re-
vealed to be particularly challenging. So much that ACD/Labs struc-
tural platform reports4 qualified the geralcin
A structural
assignment as ‘The elucidation of the month’ even if this com-
pound is not the most complex of the geralcin family.
⇑
Corresponding author. Tel.: +33 1 69 82 30 01; fax: +33 1 69 07 72 47.
E-mail address: Jamal.ouazzani@cnrs.fr (J. Ouazzani).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.087

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G. Le Goff et al. / Tetrahedron Letters 54 (2013) 5299–5301
Figure 1. Compounds isolated from Streptomyces sp. LMA-545.
Figure 2. The hypothetic biosynthetic pathway of geralcins A and B.
Figure 3. Retrosynthetic analyses of geralcin A and MH-031.
delocalized which leads to a decrease of its nucleophilicity. Accord-
ingly, the second nitrogen atom is not distracted by the carbonyl
group and its nucleophilicity remains intact. Therefore, the nucle-
ophilicity differentiation acting in conjunction with steric hin-
drance, the N-alkylation, and N-acylation are very selective.
We choose tert-butyl carbazate as the starting material to bring
a pre-existing hydrazide function as well as a hindered substituent
allowing the differentiation of the hydrazine nitrogens (Scheme 1).
MH-031 (1) synthesis started with the addition of thiophenol to
methyl acrylate in water, to furnish the corresponding b-phen-
ylsulfanyl ester (3) in a high yield.8 Reduction of (3) by LiAlH4 gave
(phenylthio)propan-1-ol (4) that was subsequently protected as a
methyl carbonate. Then the phenylsulfide function was oxidized
into phenylsulfoxide (5) in a good yield.9,10 Sulfoxide (5) was
chael addition of
quent sulfoxide elimination afforded the required
-lactone 3-(5-oxo-2H-furan-4-yl)-propanoic acid methyl ester (7).
c
-butyrolactone (6) to methyl acrylate and subse-
a,b-unsaturated
c
The desired carboxylic acid MH-031 (1)wasobtainedafter saponifica-
tion using LiOH. A similar strategy has been employed to furnish ben-
zyl and methyl ester derivatives of MH-031.12 Authors obtained an
inseparable mixture of the desired compounds together with its
exo-isomers. The first steps of our synthesis were quite safe and gave
higher yields, avoiding the use of ethylene oxide to generate the sulf-
oxide compound starting from thiophenylacetic acid. Moreover, no
isomers of the desired MH-031 were observed (Scheme 1).
Boc-hydrazone of hexanal (8) was synthesized in excellent yield
by coupling hexanal and tert-butyl carbazate through a dehydra-
tion reaction. Boc-hexylhydrazine (9) was then obtained by
reduction of the corresponding hydrazone (8) using BH3 in tetrahy-
drofuran.13 In our hands, this reduction procedure provided (9) in a
deprotonated with LDA in THF which led to
c-butyrolactone (6) by
intramolecular acylation of sulfinyl carbanion.11 Base-induced Mi-

G. Le Goff et al. / Tetrahedron Letters 54 (2013) 5299–5301
5301
Scheme 1. Synthesis of MH-031 (1).
Scheme 2. Synthesis of Boc-hexylhydrazine (9).
Scheme 3. Synthesis of geralcin A (2) from MH-031 (1).
relatively poor yield of 45%, but one can notice that some other
groups have reported similar difficulties with this method. Yields
using BH3 in THF did not exceed 40% (Scheme 2).14
function. This strategy is valuable to access highly substituted
hydrazine derivatives and further studies in this field will lead us
to report in due course the total syntheses of other members of
the geralcin family.
In principle, hydrazide intermediate (10) can be prepared by
forming a peptide type bond between the previously synthesized
MH-031 (1) and the protected hexylhydrazine (9).15 However,
our first attempts employing classical coupling reagents (DCC,
CMC, and CDI) afforded low yields of (10) (31–58%) after long reac-
tion times (>24 h). Undoubtedly, steric hindrance of the carboxyl
activating group and the Boc substituents are responsible for the
observed low reactivity. Hence, we turned our attention to a more
reactive unhindered carboxyl activating group and the acid chlo-
ride of (1) seemed to fulfill these requirements.16 This was indeed
the case and the crude acid chloride of MH-031 (1) (prepared with
oxalyl chloride and a drop of DMF) reacted smoothly with (9) (THF,
pyridine, 5 h, rt) to give the desired compound (10) in 72% yield
(Scheme 3). The selectivity was high as no product resulting from
any acylation at the N-Boc position was observed. The Boc protec-
tive group of intermediate 10 was removed under acidic conditions
to afford hydrazide derivative 11. This operation inverted the sense
of N–N function reactivity allowing then the selective introduction
of the desired glycolic acid substituent on the terminal nitrogen.
Activation of the carboxylic acid group of the latter was success-
fully achieved employing the DCC/HOAt peptide coupling system
that offered mild reaction condition for the final step. The first total
synthesis of geralcin A (2) was thus completed with an overall
yield of 46%, the spectroscopic data of the synthetic compound
(HRESIMS, 1H and 13C NMR) being identical to those recorded for
the natural one that was isolated and characterized by Le Goff
et al. in 20122 (Scheme 3).
Acknowledgment
The authors are thankful to Dr. Kevin Cariou (CNRS-ICSN) for
helpful discussions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.087.
References and notes
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2311.
In conclusion, we have achieved the first total synthesis of the
naturally occurring
a,b-unsaturated c-lactono-hydrazide geralcin
A. We developed an efficient and innovative strategy based on
concomitant electronic and steric effects to allow a full reactivity
differentiation between the two N-atoms of the hydrazide