Synthetic Studies toward the C14-C29 Fragment of Mirabalin

Article abstract of DOI:10.1021/acs.orglett.6b02162

A convergent synthesis of one isomer of the C14-C29 fragment of mirabalin is disclosed. The key steps include a Marshall allenylation, a Mukaiyama aldol reaction and a Crimmins aldolization, which allow the control of 10 out of 25 stereogenic centers pres

Full text of DOI:10.1021/acs.orglett.6b02162

Letter
pubs.acs.org/OrgLett
Synthetic Studies toward the C14−C29 Fragment of Mirabalin
Johan Cornil,† Pierre-Georges Echeverria,‡ Sebastien Reymond,† Phannarath Phansavath,*,‡
́
Virginie Ratovelomanana-Vidal,*,‡ Amandine Guerinot,*,† and Janine Cossy*,†
́
†Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI)-UMR 8231, ESPCI Paris/CNRS/PSL
Research University, 10 rue Vauquelin 75231 Cedex 05 Paris, France
‡PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 75005 Paris, France
S
* Supporting Information
ABSTRACT: A convergent synthesis of one isomer of the C14−C29
fragment of mirabalin is disclosed. The key steps include a Marshall
allenylation, a Mukaiyama aldol reaction and a Crimmins aldolization,
which allow the control of 10 out of 25 stereogenic centers present in the
molecule.
arine sponges belonging to the Theonellidae family are an
Mimportant source of macrolides exhibiting remarkable
biological activities.1 Among them, the macrocyclic mirabalin has
been extracted from Siliquariaspongia mirabilis, a lithistid
demosponge collected from the archipelago of Chuuk, Micro-
nesia.2 Mirabalin was found to inhibit the cell proliferation in the
tumor cell line HCT-116 (human colon carcinoma) with an IC50
of 270 nM ( 90 nM). In contrast, the growth of monkey kidney
carcinoma or human cervical carcinoma was not affected by
mirabalin even at a concentration as high as 70 μM. In addition,
the presence of the macrocycle appeared crucial to the biological
Figure 1. Structure of mirabalin, isomer 1.
activity as no inhibition of the proliferation of HCT-116 was
observed when treated with the pendant polyketide side chain.
The structure of mirabalin was partially elucidated using 2D
NMR experiments, ESIMS, and tandem MS techniques. From all
these data, mirabalin was identified as a 35-membered lactam
ring embedding a tetrasubstituted tetrahydropyran as well as a
fully conjugated pentaene moiety. A linear polyketide side chain
is connected to the macrocycle ring via an amide bond. However,
due to the scarce natural availability of mirabalin and the
structural complexity of the molecule, the absolute configuration
of 12 out of the 25 stereocenters could not be assigned. In
contrast, the geometry of the double bonds was established
unambiguously.
In the course of our ongoing studies toward the synthesis of
antiproliferative agents,3 we embarked on the synthesis of
mirabalin. These synthetic studies could help in establishing the
precise structure of mirabalin and allow the access to isomers
and/or analogues, which might eventually be shown to be more
bioactive and selective than the natural product itself. To begin,
the unknown stereocenters were arbitrarily assigned, and
compound 1 was targeted (Figure 1). Some efforts were made
to design a modular route that could open the way to the
synthesis of a library of isomers. Recently, we reported a
convergent and versatile synthetic strategy toward the C44−C65
polyketide side chain of mirabalin.4 Herein, we disclose the
synthesis of the C14−C29 fragment of mirabalin including the
tetrasubstituted tetrahydropyran and a (E)-trisubstituted double
bond. It is worth noting that the absolute configuration of nine of
the ten stereogenic centers present in this fragment has been
established previously.
Initially, a convergent synthesis of the C14−C29 fragment A
was envisioned from the stereoselective addition of a vinyl metal
prepared from the corresponding iodide C onto the Weinreb
amide B. The preparation of the vinyl iodide C would rely on a
stereoselective Marshall allenylation to control the C27 and C28
stereocenters and the stereocenters at C22−C23 in Weinreb
amide B would be introduced by a Crimmins aldolization
(Scheme 1).
Received: July 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02162
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Letter
followed by lactonization. The precursor of compound G would
be ester H in which the configuration of the stereogenic centers
at C16 and C17 would be controlled by a stereoselective
Mukaiyama aldol reaction applied to the (R)-α-methoxy
aldehyde I (Scheme 4).
Scheme 1. Retrosynthetic Approach toward A
Scheme 4. Retrosynthesis of Fragment B
The synthesis of the C25−C29 fragment started with the
monoprotection of ethylene glycol and a subsequent Swern
oxidation of the primary alcohol to give aldehyde 4. The latter
was subjected to a Marshall allenylation in the presence of the
optically active mesylate 2.5 Using an excess of indium iodide and
a catalytic amount of Pd(dppf)Cl2, the homopropargylic alcohols
were obtained in good yield (88%) with a diastereomeric ratio of
90:10 in favor of the anti-diastereomer. Pleasingly, the two
diastereomers were separable by purification on silica gel, and the
desired anti-5 secondary alcohol was isolated with an overall yield
of 77% from 3. After protection of the latter as a tert-
butyldimethylsilyl (TBS) ether, the terminal alkyne was
methylated (LiHMDS, 0 °C to rt followed by addition of MeI)
to afford the internal alkyne 7 (Scheme 2).
The synthesis of Weinreb amide B started from the
commercially available methyl isopropylidene-L-glycerate,
which was converted into ester 10 in three steps. An acidic
treatment (PTSA·H2O, MeOH/H2O) allowing the cleavage of
the acetal followed by a subsequent monoprotection of the
resulting diol and an etherification of the secondary alcohol
(Ag2O, MeI) afforded ester 10 with a global yield of 72%. To
permit the Mukaiyama aldol condensation, 10 was treated with
DIBAL-H, and the resulting aldehyde was directly treated with
the silyl enol ether 11 in the presence of a catalytic amount of
Eu(fod)3.7 The resulting alcohol was produced with a good yield
of 69% (two steps) and an excellent diastereocontrol (dr
>95:5).8 This high diastereoselectivity could be explained by a
tridentate coordination of the Lewis acid, which takes place in the
transition state TS 1. The ester was then reduced to the primary
alcohol 13 using LiBH4 (Scheme 5).
Scheme 2. Synthesis of Alkyne 7
Scheme 5. Synthesis of Diol 13
A range of conditions for the metalation/iododemetalation
sequence was then examined to access the vinyl iodide 8 from the
internal alkyne 7 (see the Supporting Information for details).
Finally, when a catalytic system composed of Pd(OAc)2 and
PCy3 was employed in the presence of Bu3SnH, an excellent yield
of 77% was obtained in favor of the vinylstannane, which was
then converted into the corresponding iodide 8 upon treatment
with iodine (Scheme 3).6
Scheme 3. Stannylation/Iododestannylation Process
To access the ester 17, the primary alcohol present in 13 had to
be oxidized to an aldehyde, which would be then engaged in a
Wittig reaction. However, due to difficulties encountered in
selectively oxidizing the primary alcohol, diol 13 was fully
protected using an excess of TBSOTf (2,6-lutidine, −78 °C to rt,
CH2Cl2) and then selectively deprotected with PPTS (rt,
EtOH). An oxidation of the resulting primary alcohol
(TEMPO, BAIB) was achieved, and the resulting aldehyde was
treated in the same pot with the ylide Ph3PCHCO2Me 15 to
provide the unsaturated ester 16 with an excellent (E)/(Z) ratio
superior to 95:5.9 When Me2CuLi was added to the unsaturated
We next turned our attention to the preparation of fragment B
containing the tetrasubstituted tetrahydropyran that could be
synthesized from tetrahydropyran (THP) D resulting from the
addition of an allylsilane on lactone F. The latter would be
formed from the unsaturated ester G after a stereocontrolled 1,4-
addition of a methyl cuprate to introduce the stereocenter at C18
B
DOI: 10.1021/acs.orglett.6b02162
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Letter
ester 16 in the presence of TMSCl, compound 17 featuring four
contiguous stereogenic centers was isolated in 92% yield as a
single diastereomer (Scheme 6).10−12
Scheme 8. Crimmins Aldolization
Scheme 6. Access to Ester 17
Upon treatment with CSA, ester 17 was transformed into
lactone 18 in 89% yield. To control the stereocenter at C20, we
planned to perform a diastereoselective allylation of the lactol
derived from lactone 18 that should deliver the trans-
tetrahydropyran as the major product.13 Thus, lactone 18 was
reduced by DIBAL-H and the obtained lactol was treated with
allyltrimethylsilane in the presence of BF3·OEt2. Under these
conditions, an efficient allylation of the lactol was obtained, albeit
with concomitant deprotection of the primary alcohol. In
addition, no diastereoselectivity was observed as cis- and trans-
THP were formed in a 55:45 ratio through a nucleophilic
addition on the oxocarbenium ions 18′ and 18″.14,15 Fortunately,
after reprotection of the primary alcohol using tert-butyldiphe-
nylsilyl chloride (TBDPSCl), the two diastereomers trans-19 and
cis-19 could be separated by flash chromatography on silica gel
allowing the isolation of the desired tetrahydropyran trans-19.16
An oxidative cleavage of the double bond then afforded aldehyde
20 (Scheme 7).
corresponding vinyllithium reagent (t-BuLi, Et2O, −78 °C), the
latter was condensed on the Weinreb amide 24 to produce the
expected ketone 25 as well as ketone 26 in which the TMS ether
was cleaved. Treatment of 25 with Amberlyst 15 afforded the
secondary alcohol 26 in 68% yield (Scheme 9).
Scheme 9. Synthesis of Ketone 26
The stereocenter at C24 was then introduced using a Prasad
reduction (Et2BOMe, NaBH4),18 and the resulting 1,3-diol was
transformed to the cyclic silyl ether 27. The relative stereo-
chemistry of the hydroxyl groups at C22 and C24 was confirmed
by nOe experiments (Scheme 10).
Scheme 7. Synthesis of Aldehyde 20
Scheme 10. Access to Fragment C14−C29 of Mirabalin (1)
To control the stereocenters at C22 and C23, a Crimmins
aldolization of aldehyde 20 was envisioned.17 Thus, an aldol
reaction involving the chiral thiooxazolidinone 21 and aldehyde
20 was performed in the presence of TiCl4, (−)-sparteine, and N-
methylpyrrolidinone (NMP). Gratifyingly, the reaction afforded
the expected aldol product as a single diastereomer with an
excellent yield (92%). The chiral auxiliary was cleaved by a
transamination with the Weinreb amide, and the secondary
alcohol was protected as a trimethylsilyl ether (Scheme 8).
Having fragments 8 and 24 in hand, the coupling reaction was
realized. After transformation of the vinyl iodide 8 to the
In summary, a synthesis of the C14−C29 fragment of
mirabalin was developed to allow the control of 10 stereocenters.
The strategy involved a Marshall allenylation, a Mukaiyama aldol
reaction, and a Crimmins aldolization as the key steps. This work
is the first synthetic approach of this mirabalin fragment and
C
DOI: 10.1021/acs.orglett.6b02162
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02162.
■
Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2011, 353, 3213.
(n) Perez, M.; Ratovelomanana-Vidal, V.; Ayad, T.; Fahy, J.; Maillos,
P. EP14306944, 2014; WO 2016/087596A1, 2016. (o) Perez, M.; Ayad,
T.; Maillos, P.; Poughon, V.; Fahy, J.; Ratovelomanana-Vidal, V. Eur. J.
Med. Chem. 2016, 109, 287. (p) Perez, M.; Ayad, T.; Maillos, P.;
Poughon, V.; Fahy, J.; Ratovelomanana-Vidal, V. ACS Med. Chem. Lett.
2016, 7, 403.
S
Experimental procedures and full spectroscopic data for all
new compounds (PDF)
(4) Echeverria, P.-G.; Prev
Guerinot, A.; Cossy, J.; Ratovelomanana-Vidal, V.; Phansavath, P. Org.
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(8) The configuration of the stereocenters was confirmed later using an
X-ray analysis of compound cis-19′, vide infra; see ref 16.
(9) (a) Lee, E. Y.; Kim, Y.; Lee, J. S.; Park, J. Eur. J. Org. Chem. 2009,
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́ ́
ost, S.; Cornil, J.; Ferard, C.; Reymond, S.;
X-ray data for compound cis-19′ (CIF)
́
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: phannarath.phansavath@chimie-paristech.fr.
*E-mail: virginie.vidal@chimie-paristech.fr.
*E-mail: amandine.guerinot@espci.fr.
*E-mail: janine.cossy@espci.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Agence Nationale de la Recherche for financial
support (ANR STIMAS, 2011-2014, J.C. and P.-G.E.).
■
(11) Kireev, A. S.; Manpadi, M.; Kornienko, A. J. Org. Chem. 2006, 71,
2630.
(12) At this stage, the absolute configuration of stereocenter C18 could
not be undoubtedly assigned using 1H NMR spectroscopy. It was
confirmed by X-ray analysis of cis-19′, vide infra; see ref 16.
(13) (a) Takemura, T.; Nishii, Y.; Takahashi, S.; Kobayashi, J.; Nakata,
T. Tetrahedron 2002, 58, 6359. (b) Bielitza, M.; Pietruszka, J. Chem. -
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(14) For some studies concerning the stereochemistry of nucleophilic
additions on oxocarbenium ions, see: (a) Ayala, L.; Lucero, C. G.;
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(15) Similar results were obtained with the acetate derived from the
lactol.
(16) Interestingly, the alcohol cis-19′ obtained after treatment of cis-19
with TBAF was crystalline, and an X-ray diffraction analysis confirmed
the relative stereochemistry of all the stereogenic centers (see the
Supporting Information for details).
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