From Stereodefined Cyclobutenes to Dienes: Total Syntheses of Ieodomycin D and the Southern Fragment of Macrolactin A

Article abstract of DOI:10.1021/acs.orglett.5b02149

A copper-promoted flexible synthesis of cyclobutenes carrying simple alkyl chains, enabling even the most hindered nucleophiles to be employed, has been developed. The versatility of this approach was exemplified by a short total synthesis of ieodomycin D and a straightforward preparation of the southeastern fragment of macrolactin A. The latter features a late-stage, double cyclobutene electrocyclic ring opening that directly delivers a bis-diene of defined geometry.

Full text of DOI:10.1021/acs.orglett.5b02149

Letter
pubs.acs.org/OrgLett
From Stereodefined Cyclobutenes to Dienes: Total Syntheses of
Ieodomycin D and the Southern Fragment of Macrolactin A
Caroline Souris, Antonio Misale,† Yong Chen,† Marco Luparia,‡ and Nuno Maulide*
University of Vienna, Faculty of Chemistry, Institute of Organic Chemistry, Wahringer Straße 38, 1090 Vienna, Austria
̈
S
* Supporting Information
ABSTRACT: A copper-promoted flexible synthesis of cyclo-
butenes carrying simple alkyl chains, enabling even the most
hindered nucleophiles to be employed, has been developed.
The versatility of this approach was exemplified by a short total
synthesis of ieodomycin D and a straightforward preparation of
the southeastern fragment of macrolactin A. The latter features
a late-stage, double cyclobutene electrocyclic ring opening that
directly delivers a bis-diene of defined geometry.
olyene motifs are widely represented in the skeleton of
biologically active compounds such as the eicosanoids,1 the
steps.6 We were drawn toward this natural product following
our initial studies on the stereoselective synthesis of dienes by
4π-electrocyclic ring opening of preformed cyclobutenes of
defined stereochemistry7 and, thus, proposed that trans-
cyclobutene 2 might be the direct precursor of 1. In the
retrosynthetic sense, we further speculated that a nucleophilic
ring opening of the bicyclolactone 3 with a properly
functionalized (and enantiopure) nucleophile might directly
afford the requisite trans-substituted cyclobutene 2 (Scheme 1).
P
retinoids,2 and the macrolides,3 a large group comprising over
200 members. To date, despite significant efforts from the
synthetic community in the area of diene synthesis, the
stereoselective preparation of substituted 1,3-butadienes
remains a challenge.4 Nature decorates these polyenes in a
variety of fascinating patterns, among which 1,3-butadienoic
carboxylates and diene carbinol fragments represent an
important subset of structural units. The latter find
representation in natural products of varying size and molecular
weight (Figure 1). In particular, the ieodomycins are extracted
Scheme 1. Retrosynthetic Analysis of Ieodomycin D
Featuring a 4π-Electrocyclic Ring-Opening Event
Our group has previously explored catalytic nucleophilic ring
opening of 3 employing allylic alkylation reactions with
stabilized nucleophiles,8 allylborane derivatives,9a and dialkyl
zinc reagents.9b However, none of those methods is suitable for
the direct introduction of a long alkyl chain such as the one
required for expeditious conversion of 3 into 2. We thus turned
our attention to the potential use of organocopper reagents.10
Although the considerable reactivity of both such reagents and
the highly strained lactone 3 could conceivably lead to an
unselective reaction, our preliminary experiments met with
encouraging results.
Figure 1. Diene containing natural products.
from marine bacteria of the Bacillus species,5 ubiquitous and
abundant microorganisms in the marine ecosystem. They were
isolated in 2011 by the group of Shin, who additionally
determined their absolute configuration and identified their
biological targets.5 One total synthesis of this natural product
has been reported, delivering ieodomycin D 1 in five linear
As shown in Scheme 2, simple exposure of lactone 3 to the
combined action of EtMgBr, CuCN, and LiCl smoothly
delivered the ethyl-substituted product 4. Importantly, 4 was
Received: July 25, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02149
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Letter
2g/h); the successful use of t-BuMgCl in a nucleophilic C−C
bond forming event is especially noteworthy.11 Furthermore,
this process is compatible with functionalized heteroatom
substituents based on oxygen or nitrogen (cf. 2i−k), delivering
functionalities ripe for further synthetic elaboration. The
exclusive formation of the trans-disubstituted cyclobutene
products can be assumed to result from a nucleophilic attack
on lactone 3 from the face opposite to the carboxylate leaving
group.12
Scheme 2. Preliminary Result for the Alkylation of Lactone 3
with an Organocopper Reagent
With this methodology in hand, we validated our original
blueprint for the synthesis of ieodomycin D, 1. As shown in
Scheme 3, alkylation of lactone 3 with the organometallic
formed as a single, trans-configured diastereoisomer (as
ascertained by crude H NMR analysis) in high yield.
1
Spurred by this initial success, we proceeded to examine the
scope of the transformation. As shown in Table 1, organo-
copper reagents appear to constitute very valuable tools to
achieve the straightforward appendage of varied alkyl and
cycloalkyl functionalities to the cyclobutene ring. Remarkably,
very congested tertiary alkyl groups could be introduced (cf.
Scheme 3. Asymmetric Synthesis of (−)-Ieodomycin D, 1
Table 1. Substrate Scope of the Diastereoselective Cuprate
a
Alkylations
reagent obtained by successive zincation and copper trans-
metalation of (+)-6 delivered 2k in 98% yield. Further removal
of the TIPS protecting group under mild acidic conditions in
methanol eventually led to concomitant esterification of the
carboxylic acid moiety. (−)-Ieodomycin D was finally obtained
after hydrolysis of the methyl ester and thermolysis of the
cyclobutene moiety. This expeditious route delivered (−)-1 in
only five steps from readily available alcohol (+)-513 and 43%
overall yield.
An interesting observation is that ieodomycin D bears an
alkyl chain identical to the one encompassed in the southern
fragment of the macrolactins.14 Aware of this, we hypothesized
that a strategy related to that depicted in Scheme 3 might be
employed for the preparation of the southeastern fragment of
macrolactin A. This led us to the generic plan outlined in
Scheme 4.
Scheme 4. Approach to Macrolactin A (southeastern
fragment highlighted)
Our approach relies on the recognition of two differently
configured diene moieties, which accordingly require different
strategies for their synthesis. The (E,E)-diene carbinol fragment
would arise through electrocyclic ring opening of a trans-
substituted cyclobutene (derived from lactone 3). For the
challenging (Z,E)-dienoic portion we anticipated the use of cis-
chlorocarboxylic acid 8.7
a
All products were isolated and characterized as the corresponding
1
benzylamides. dr >95:5 for 2a−2j as determined by crude H NMR
analysis. 2b was isolated as an inseparable 3:1 mixture with the
corresponding diene. For detailed reaction conditions, see the
Supporting Information. RMgCl. RMgBr. RZnBr. RZnI. 1:1
b
c
d
e
f
mixture of diastereomers.
B
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The synthesis, depicted in Scheme 5, begins with the
alkylation product 2k. As before, unravelling of the TIPS
competent nucleophiles, as exemplified by the successful
application of tBuMgCl in that role. The versatility of this
approach was then exemplified by two synthesis case studies. In
the first, ieodomycin D was prepared in a short sequence
involving the use of a functionalized, optically pure organo-
copper reagent. That route could be further capitalized for the
straightforward preparation of the southeastern fragment of
macrolactin A, featuring a late-stage, double cyclobutene
electrocyclic ring opening that directly delivers a bis-diene of
defined geometry.
Scheme 5. Synthesis of the Southeastern Fragment of
Macrolactin A
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02149.
General procedures; NMR spectra and GC/HPLC traces
(PDF)
AUTHOR INFORMATION
Corresponding Author
protecting group in acidic methanol simultaneously achieves
esterification of the carboxylic acid moiety, leading to 9 in 73%
yield. Taking advantage of the free alcohol, coupling with the
aforementioned cis-chlorocyclobutene 8 could now be
attempted. In the event, the use of common activating reagents
for ester formation, such as EDCI (HOBt, DMAP),14 proved to
be inefficient in this reaction and only starting material was
recovered. On the other hand, N,N′-dicyclohexylcarbodiimide
(DCC) together with 10 mol % of 4-dimethylaminopyridine
(DMAP)15 allowed the formation of the desired product,
although in less than 10% yield. We next turned our attention
to the use of Yamaguchi’s reagent for coupling.16 Nevertheless,
while delivering the desired ester in moderate to good yields,
these reaction conditions led to extensive epimerization of the
α-center, generating a mixture of cis-cyclobutene 10 and its
thermodynamically more stable trans-isomer (not shown). It
should be emphasized that the cis-configuration that is encoded
in 8 is a crucial prerequisite for being able to access a (Z,E)-
dienyl carboxylate by thermal, conrotatory electrocyclic ring
opening.
Realizing that protocols relying on acid activation were
inevitably prone to some degree of deleterious epimerization,
we considered the use of an esterification procedure where the
alcohol moiety undergoes activation. We thus turned our
attention to the use of a Mitsunobu-type esterification17 and, to
our delight, observed that the desired isomer 10 was exclusively
produced under these reaction conditions when benzene was
used as solvent.18
■
*E-mail: nuno.maulide@univie.ac.at.
Present Address
‡Aptuit Srl, via A. Fleming 4, 37135 Verona, Italy.
Author Contributions
†A.M. and Y.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the ERC (StG 278872, FLATOUT),
the Deutsche Forschungsgemeinschaft (Grant MA 4861/3-1),
and the Alexander van Humboldt Foundation (Postdoctoral
Fellowship to M.L.). We are also grateful for support by the
University of Vienna and the Max-Planck-Institut fur
Kohlenforschung, where parts of this research were carried out.
̈
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D
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