A convergent synthesis of the fully elaborated macrocyclic core of TMC-95A

Article abstract of DOI:10.1021/ol403675c

A concise and straightforward synthesis of the fully elaborated macrocyclic core of TMC-95A is reported. A highly efficient organocatalyzed aldolization between isatin and dihydroxyacetone derivatives and formation of the biaryl subunit with concomitant macrocyclization are the characteristic features of this synthesis.

Full text of DOI:10.1021/ol403675c

Letter
pubs.acs.org/OrgLett
A Convergent Synthesis of the Fully Elaborated Macrocyclic Core of
TMC-95A
Alexis Coste,† Alexandre Bayle,† Jerome Marrot,† and Gwilherm Evano*,‡
́
†Institut Lavoisier de Versailles, UMR CNRS 8180, Universite
78035 Versailles Cedex, France
́
de Versailles Saint-Quentin-en-Yvelines, 45, avenue des Etats-Unis,
‡Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite
Roosevelt 50, CP160/06, 1050 Brussels, Belgium
́
Libre de Bruxelles, Avenue F. D.
S
* Supporting Information
ABSTRACT: A concise and straightforward synthesis of the fully
elaborated macrocyclic core of TMC-95A is reported. A highly efficient
organocatalyzed aldolization between isatin and dihydroxyacetone
derivatives and formation of the biaryl subunit with concomitant
macrocyclization are the characteristic features of this synthesis.
MC-95A (1a) and its diastereoisomers TMC-95B−D
(1b−d, Figure 1) were isolated in 2000 as fermentation
dense network of hydrogen bonds in addition to perfectly
fitting the active site of the latter.5 This unique binding mode
combined with their challenging structures have made them
especially attractive targets for synthesis. Indeed, in addition to
the development of simplified analogues of the TMC-95s6 and
to various synthetic studies,7 three total syntheses have been
reported since 2001 by the Danishefsky,8 Hirama,9 and
Williams10 groups. In all these syntheses, the macrocyclic
core was formed by standard macrolactamization techniques
and the biaryl subunit was installed in the middle stages of the
syntheses by an intermolecular Suzuki−Miyaura cross-coupling.
The Z-enamide side chain was introduced by a thermal
rearrangement from an α-silylallyl amide in Danishefsky’s
synthesis while the strategy implemented in the Hirama’s and
Williams’ syntheses relied on a decarboxylative elimination
from an allo-threonine intermediate. Finally, a direct acylation
with 3-methyl-2-oxopentanoic acid provided an epimeric
mixture of TMC-95A and B in the Danishefsky and Williams
approaches, a problem that was solved in Hirama’s synthesis by
using an α-hydroxy acid instead of the readily epimerizable α-
oxo-derivative, which allowed for a selective preparation of
TMC-95A. Examination of the number of steps involved in
these syntheses (between 18 and 35) and overall yields
(between 0.1 and 4%) revealed that the preparation of the
oxidized tryptophan fragment was the most problematic part of
all approaches, a problem that was partially addressed in
Pearson’s synthetic studies.7f Described herein is our approach
to the fully elaborated macrocyclic core of TMC-95A, featuring
an intramolecular Suzuki−Miyaura reaction for the key
T
Figure 1. Structure of the TMC-95A−D.
products of Apoispora montagnei Sacc. TC 1093, a strain
obtained from a soil sample from a bamboo forest in Kanagawa
(Japan).1,2 Common structural features of the TMC-95A−D
include (i) a cyclic polypeptide containing a L-tyrosine, a L-
asparagine, and a highly oxidized L-tryptophan bearing three
contiguous stereocenters; (ii) a biaryl linkage between the
tyrosine and tryptophan moieties; (iii) an appending Z-
enamide; and (iv) a 3-methyl-2-oxopentanamide side chain.
Besides their complex and most interesting structure,
biological evaluation of these macrocyclic peptides showed
that TMC-95A inhibited the chymotrypsin-like, trypsin-like,
and postglutamyl peptide hydrolytic activities of the protea-
some with IC50 values of 5.4, 200, and 60 nM, respectively.3
TMC-95B inhibited these activities to the same extent as TMC-
95A, while TMC-95C and D were shown to be weaker
inhibitors. TMC-95A also showed cytotoxic activities against
human cancer HCT-116 and HL-60 cell lines and was shown to
induce neurite outgrowth in PC12 cells.4
Unlike other synthetic or natural proteasome inhibitors, the
binding mode of TMC-95A−D to the proteasome involves a
Received: December 19, 2013
Published: February 21, 2014
© 2014 American Chemical Society
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macrocyclization step and an enantioselective, organocatalyzed
aldolization for the preparation of the oxidized tryptophan core.
From a retrosynthetic perspective, we envisioned installation
of the enamide and oxopentanamide side chains using strategies
developed in Hirama’s synthesis from advanced and fully
elaborated precursor 2 as depicted in Scheme 1. To install the
Table 1. Optimization of the Organocatalyzed Aldolization
Scheme 1. Retrosynthetic Analysis of TMC-95A
a
b
c
Yields of pure, isolated products. Reaction time: 1 week. Reaction
time: 2 days.
biaryl and simultaneously effect macrocyclization, we decided
to employ an intramolecular Suzuki−Miyaura reaction from
acyclic precursor 3. Further analysis of 3 suggested that it could
be disconnected at amide bonds to give simple amino acid
precursors and the oxidized tryptophan fragment 4. The amino
acid moiety in 4 could finally be installed from the
corresponding hydroxymethylketone in 5, which could in
turn be readily obtained in an enantioenriched form using an
enantioselective organocatalyzed aldolization between isatin
and dihydroxyacetone derivatives 6 and 7.
To determine the feasibility of our approach, we started by
examining the organocatalyzed aldolization between readily
available 7-iodo-isatin 6 and TES-protected dihydroxyacetone
7. While isatin and dihydroxyacetone derivatives had been
extensively used in various organocatalytic processes, there was
no report of a cross-aldolization between these carbonyl
derivatives when we started this project, although an efficient
organocatalyzed aldol reaction between isatins and acetal-
protected dihydroxyacetone using a complex tetrazolyl-pseudo-
peptide organocatalyst prepared in 9 steps from N-Boc-valine
(with the ee in the 75−90% range and dr from 4:1 to 24:1) was
reported by the Pearson group during the preparation of this
manuscript.7f We initiated our studies by examining a set of
standard organocatalysts for the aldolization between 6 and 7
(Table 1). While amino acids, diamines, and tetrazoles gave no
conversion, aminoalcohols were found to be better promoters
for this reaction since most of them gave good enantiomeric
and diastereoisomeric ratios for the formation of 5.11 The
conversion was however disappointingly low in all trials
(maximum 19% with 20 mol % of catalyst after one week) as
shown with selected results collected in Table 1 (entries 1−5).
The origin of the low conversion and slow kinetics of the
reaction could be rationalized by performing a stoichiometric
reaction in which D-leucinol was used in slight excess (Table 1,
entry 6). A full conversion could be obtained under these
conditions, and to our surprise, oxazolidine 8, resulting from
the condensation of the aminoalcohol to the aldolization
product, was isolated in 36% yield, along with the aldol product
5 (51%). Capitalizing on this result, we hypothesized that it
might be possible to avoid the formation of this oxazolidine
byproduct, which results in the trapping of the catalyst, by
slightly modifying the nature of the organocatalyst. Indeed, by
using a cyclic trans-1,2-aminoalcohol, the resulting oxazolidine
would be embedded in the 5,5 bicyclic core with a trans ring
junction, which should be disfavored. Based on this hypothesis,
we therefore evaluated the efficiency of trans-1-amino-2-indanol
as the catalyst. To our delight, the reaction was greatly
accelerated, oxazolidine could not be detected in the crude
reaction mixture anymore, and the desired aldol product 5
could be obtained in 73% yield with good enantio- and
diastereoselectivities (Table 1, entry 7).
With these results in hand, we next briefly evaluated the
scope of the aldolization starting from 7-halo-isatins, protected
or not, that could potentially be used for the preparation of the
tryptophan fragment of TMC-95A. As shown by results
collected in Scheme 2, the use of trans-1-amino-2-indanol was
quite efficient and resulted in the formation of aldol products 5,
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the presence of diphenylphosphoryl azide. To our surprise, an
unexpected participation of the neighboring oxindole as an
internal nucleophile occurred once the alcohol was activated,
yielding, after addition of the azide to the intermediate iminium
ion, the formation of tetrahydrofuroindole 15.
Scheme 2. trans-1-Amino-2-indanol Catalyzed Aldolization
between Isatin and Dihydroxyacetone Derivatives
To avoid this participation of the oxindole, we slightly
modified our strategy by transforming the protected primary
alcohol in 14 to an ester prior to the nucleophilic substitution,
in hopes that the greater reactivity of the activated alcohol
would favor the intermolecular nucleophilic substitution. While
this strategy bore some risk and even seemed counterintuitive,
it turned out to be quite successful since the activation of the
hydroxyl group in hydroxyesters 17a,b, which were readily
obtained by classical transformations from 16, as a triflate
followed by a displacement with sodium azide indeed provided
the desired α-azido-esters 18a,b, therefore completing the
synthesis of the tryptophan fragment of TMC-95A in 9 steps
(12−35% overall yield).
With these two differentially protected advanced intermedi-
ates 18a,b in hand, we next proceeded to the final steps of the
synthesis and to the key macrocyclization. The elaboration of
the acyclic precursors and the end-game strategy are shown in
Scheme 4.
9−12 in good yields, with total diastereocontrol, and with
synthetically useful levels of enantioselectivity.
The azide in 18a,b was therefore reduced by a Staudinger
reaction, and the resulting unstable amine, which is in
equilibrium with the 4-(o-aminophenyl)pyroglutamate form
resulting from opening of the oxindole by the amine, could be
selectively acylated with Fmoc-protected asparagine, yielding
dipeptides 19a,b. Further deprotection of the Fmoc group
followed by coupling with boronate 20 finally gave the acyclic
precursors 3a,b. This set the stage for the final macrocyclization
step, which turned out to be quite challenging. After screening
various palladium-based systems such as PdCl2(S-Phos)2,
Pd2dba3/PtBu3, or Pd2dba3/S-Phos for the intramolecular
Suzuki−Miyaura reaction enabling the formation of both the
macrocycle and the biaryl subunit, we eventually evaluated the
efficiency of a combination of PdCl2(dppf) and potassium
carbonate in aqueous DME, conditions reported by the Zhu
group in various total syntheses.13 Gratifyingly, 3a,b could be
smoothly transformed to the corresponding macrocycles 2a,b,
in which the fully elaborated macrocyclic core of TMC-95A is
installed.14
The optimization of the organocatalyzed aldol reaction set
the stage for the completion of the synthesis of the tryptophan
fragment of TMC-95A (Scheme 3). Gratefully, the aldolization
could be conveniently performed on a multigram scale which
allowed for an easy synthesis of 5 which was then protected as a
TES ether to avoid problems associated with retro-aldolization.
Further treatment with sodium borohydride in methanol at 0
°C allowed for a clean and diastereoselective reduction of the
ketone in 13. The configuration of the resulting alcohol in 14,
which is in agreement with results reported by the Overman
group who rationalized the reduction of related β-keto-
oxindoles by chelation between the carbonyl groups of the
ketone and distal oxindole,12 could be established by X-ray
diffraction analysis of 16 obtained after selective deprotection
of the primary alcohol with PPTS in a mixture of methanol and
dichloromethane.
We next envisioned introducing the amino group required
for the assembly of the tryptophan fragment at this stage of the
synthesis by reacting alcohol 14 under Mitsunobu conditions in
In conclusion, a concise and straightforward (14 steps)
synthesis of the fully elaborated macrocyclic core of TMC-95A
Scheme 3. Synthesis of the Tryptophan Fragment of TMC-95A
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(11) Diastereoisomeric and enantiomeric ratios were determined by
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is reported. A highly efficient organocatalyzed aldolization
between isatin and dihydroxyacetone derivatives and the
formation of the biaryl subunit with concomitant macro-
cyclization are the characteristic features of this synthesis.
Further studies on TMC-95A−D and analogues will be
reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Experimental procedures, characterization, copies of H and
13C NMR spectra for all new compounds, and relevant HPLC
traces and cif files. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) It was previously shown that the macrocyclization would only
provide the desired atropoisomer which follows the stereochemistry of
the tertiary alcohol. See refs 1 and 8a, b.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gevano@ulb.ac.be.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Universite
■
́
Libre de Bruxelles, the
CNRS, and the ANR (project ANR-07-JCJC-0025-01) for
support. A.C. acknowledges the National Cancer Institute for a
graduate fellowship.
REFERENCES
■
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