Stereoselective Synthesis of the C9-C19 Fragment of Peloruside A

Article abstract of DOI:10.1021/acs.orglett.6b01428

A concise synthesis of the C9-C19 fragment of peloruside A that is both highly stereoselective and efficient is described. Achieving an overall yield of 23% over 14 steps, this synthesis not only is high yielding but also involves four chromatography step

Full text of DOI:10.1021/acs.orglett.6b01428

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of the C9−C19 Fragment of Peloruside A
Stuart C. D. Kennington, Juan M. Romo, Pedro Romea,* and Felix Urpí*
̀
Seccio
́ ̀ ̀ ̀
de Química Organica, Departament de Química Inorganica i Organica and Institut de Biomedicina de la Universitat de
Barcelona (IBUB), Universitat de Barcelona, Carrer Martí i Franques
́
1-11, 08028 Barcelona, Catalonia, Spain
S
* Supporting Information
ABSTRACT: A concise synthesis of the C9−C19 fragment of
peloruside A that is both highly stereoselective and efficient is
described. Achieving an overall yield of 23% over 14 steps, this
synthesis not only is high yielding but also involves four
chromatography steps. This approach is based on the addition of
metal enolates of chiral auxiliary scaffolds generated by either
catalytic or stoichiometric amounts of nickel(II) or titanium(IV)
Lewis acids.
(+)-Peloruside A is a polyketide macrolide that was first
isolated by Northcote and co-workers in 2000 from the marine
sponge Mycale found in Pelorus Sound, off the coast of New
Zealand.1 It displays potent antitumor activity against P388
murine leukemia cells with an IC50 value of 10 ng mL−1.2 In
addition, peloruside A shows powerful microtubule-stabilizing
activity similar to paclitaxel and is synergistic with it.3−6
Structurally, it consists of a 16-membered lactone with an
internal pyran ring and an unsaturated lateral chain, containing
a total of 10 stereocenters (Scheme 1). The macrolide itself has
a geminal dimethyl group and various hydroxyl and methoxy
groups, while the unsaturated lateral chain contains a Z-olefin
and a primary alcohol.
natural product.7 After this approach, other significant efforts
have been directed to the total synthesis of peloruside A8,9 or
certain fragments of it.10 More specifically, the synthesis of
fragments containing the lateral chain of the macrolide has been
a challenging goal due to the structural complexity.9−11
In this context and considering the need for alternative
routes toward such fragments, we envisaged a new and efficient
approach to the C9−C19 fragment of peloruside A (Scheme 1)
that could take advantage of several highly selective trans-
formations based on chiral N-acyl thiazolidinethione scaffolds,
developed in our group.12−14 As seen in Scheme 2, our
retrosynthetic analysis hinges on three asymmetric carbon−
carbon bond forming reactions, involving the use of metal
enolates of either the (R)- or (S)-enantiomer of N-acyl-4-
isopropyl-1,3-thiazolidinethiones, and also a substrate-con-
trolled Mukaiyama aldol reaction.15 The use of highly effective
chiral auxiliaries allows the control of reactional selectivity and
also minimizes the steps needed in the synthesis by
functionalization during removal of the auxiliary.16−18 Beyond
this we aimed to make the synthesis as concise and simple as
possible and minimize the amount of purification processes. By
doing this we would reduce both material used and time
needed to carry out the synthesis, which in turn would reduce
the cost and environmental impact of making the molecule.19
In short, the aim was to create a simple and more effective
synthesis of the C9−C19 fragment of peloruside A.
The first total synthesis of peloruside A was reported by De
Brabander in 2003, confirming the absolute configuration of the
Scheme 1. (+)-Peloruside A and C9−C19 Fragment
Our synthesis started with the first catalytic direct-type
reaction applied to a peloruside A synthesis. This reaction is
based on the catalytic addition of nickel(II) enolates to an
oxocarbenium ion generated in situ.14 The reaction was carried
out using (S)-N-butanoyl-4-isopropyl-1,3-thiazolidine-2-thione
(1)20 as the substrate, trimethyl orthoformate as the electro-
phile, and a simple, robust, and commercially available
(Me3P)2NiCl2 as the precatalyst (Scheme 3); the addition of
TESOTf was necessary to both activate the electrophile and
Received: May 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01428
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Organic Letters
Letter
Scheme 2. Retrosynthetic Analysis of the C9−C19 Fragment
to the pure α,β-unsaturated ester 6 in a yield of 80% over five
steps on a 10 mmol scale.
Scheme 3. Synthesis of the α,β-Unsaturated Ester 6 (C15−
C19 Fragment)
Continuing the synthesis, the reduction of α,β-unsaturated
ester 6 with DIBAL-H24 and the subsequent oxidation of the
resultant allylic alcohol 7 with MnO2 afforded the aldehyde 8
(Scheme 4), which served as the substrate for the next key aldol
Scheme 4. Synthesis of the Adduct 10 (C13−C19 Fragment)
create the truly active catalyst. Importantly, full conversion was
achieved with only 5 mol % of NiCl2(PMe3)2, which provided
the corresponding adduct 2 as a single diastereomer with an
82% yield at a multigram scale. Removal of the chiral auxiliary
with an excess of LiBH4 and treatment of the resulting alcohol
with TBDPSCl afforded the protected hydroxy acetal 3.
Furthermore, we were able to recover 90% of the auxiliary
from this process; simple extraction in the workup allows for
recycling and reuse of the chiral scaffold. Then, following a
procedure described by Denmark, this acetal was converted
into the aldehyde 4 using silica and oxalic acid in a simple and
effective reaction.21 Finally, the trisubstituted double bond was
selectively inserted with a Still−Gennari reaction22 using the
phosphonate 523 to obtain the α,β-unsaturated ester 6. Because
the aforementioned reactions proceeded efficiently and
impurities were negligible, we could conduct all five reactions
in sequence, with only one chromatographic purification
process conducted after the Still−Gennari coupling. This led
reaction with the titanium(IV) enolate of (R)-N-acetyl-4-
isopropyl-1,3-thiazolidine-2-thione (R-9).20 Despite the chal-
lenge of such an acetate aldol reaction,25 the application of the
experimental conditions previously developed in our group12
afforded the desired aldol adduct 10 with an excellent 85:15
diastereomeric ratio. Furthermore, we were able to carry out
this reaction in succession, purifying only after the aldol step to
achieve a 74% yield of pure single diastereomer 10 (C13−C19
fragment) over three steps at 8 mmol scale.
Treatment of 10 with TBSOTf afforded protected aldol 11,
which was reduced with DIBAL-H at −78 °C to give the
desired aldehyde 12 (Scheme 5). Remarkably, this process was
able to stop chemoselectively at the aldehyde stage, enabling
removal of the chiral auxiliary and adjustment of the oxidation
state in a single step. Also notable is our recovery of the chiral
B
DOI: 10.1021/acs.orglett.6b01428
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Scheme 5. Synthesis of the Adduct 14 (C11−C19 Fragment)
auxiliary in 85% purity from extraction. After various screening
tests, dimethyl acetal 13 was efficiently prepared by treatment
with MeOH, trimethyl orthoformate, and Amberlyst-15
without affecting the TBS protecting group. Differing from
most strategies based on the stereoselective installation of the
C13 hydroxyl group and subsequent methylation with energetic
agents, we explored an alternative route. Indeed, we established
that the Lewis acid-mediated addition of titanium enolates of
N-acyl thiazolidinethiones to dimethyl acetals afforded β-
methoxycarboxylic substructures stereoselectively in a single
step.13 As use of SnCl4 as Lewis acid led to partial removal of
the TBS protecting group, a comprehensive optimization was
carried out. This was a lengthy process, balancing the maximum
conversion against selectivity and the extent of deprotection of
the TBS group that was occurring. Eventually, minimizing the
equivalents of the enolate and the second Lewis acid, increasing
the reaction time, and keeping the temperature at −50 °C
afforded the desired adduct 14 (C11−C19 fragment) in a
highly efficient manner. Indeed, we found that the addition of a
slight excess of the titanium enolate from S-920 to 13 in the
presence of 1.05 equiv of SnCl4 (added as a 1 M solution in
CH2Cl2) at −50 °C gave a full conversion and a selectivity of
88:12 alongside a small amount of the TBS-deprotected adduct.
Again we were able to eliminate further purification processes
by performing the protection, the removal of the auxiliary, the
dimethyl acetal formation, and the addition in a continuous
sequence, using only a single chromatographic purification at
the end. This yielded 58% of a pure single diastereomer 14 over
four steps.
Scheme 6. Synthesis of the Ester 17 (C9−C19 Fragment)
Once again removal of the auxiliary with DIBAL-H gave the
aldehyde 15 with a 92% recovery of the auxiliary. The last step
involved a substrate-controlled Mukaiyama-aldol addition of
silyl ketene acetal 16 to 15 in the presence of BF3·OEt2
(Scheme 6). The stereochemical outcome of this reaction
relied heavily on the configuration of the chiral aldehyde 15.26
Particularly, comprehensive studies reported by Evans estab-
lished that the Mukaiyama aldol addition to β-alkoxy aldehydes
provides the corresponding anti aldol as the major diaster-
eomer.27 In accord with this model, the reaction of 15 and 16
produced a 88:12 mixture of diastereomers in a high yield. As in
former sequences, we were able to run directly a two-step
sequence after the removal of the chiral auxiliary to afford
enantiomerically pure ester 17 in 68% yield with a single SiO2
column purification. This final reaction concluded the synthesis
of the C9−C19 fragment of peloruside A, and, with a methyl
ester terminus, such an intermediate is suitably tailored for
continuation of the total synthesis.
In conclusion, we have developed a concise synthesis of the
C9−C19 fragment of peloruside A. The synthesis has been
achieved in a total yield of 23% over 14 steps. Remarkably, not
only have we achieved this very competitive yield compared to
other attempts, but we have also been able to perform a very
effective synthesis, by removing many of the purification steps,
running just four chromatographic purifications over all 14
steps. The main benefit of this is a dramatic reduction of the
time needed to execute the synthesis. It also permits work on a
C
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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.6b01428.
Complete experimental procedures; physical and spec-
troscopic data for new compounds (PDF)
(12) Gonzal
1996, 37, 8949−8952.
(13) (a) Cosp, A.; Romea, P.; Talavera, P.; Urpí, F.; Vilarrasa, J.;
Font-Bardia, M.; Solans, X. Org. Lett. 2001, 3, 615−617. (b) Cosp, A.;
Romea, P.; Urpí, F.; Vilarrasa, J. Tetrahedron Lett. 2001, 42, 4629−
́ ́
ez, A.; Aiguade, J.; Urpí, F.; Vilarrasa, J. Tetrahedron Lett.
Copies of 1H and 13C spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
4631. (c) Baiget, J.; Cosp, A.; Gal
Urpí, F. Tetrahedron 2008, 64, 5637−5644. (d) Checa, B.; Gal
Parello, R.; Sau, M.; Romea, P.; Urpí, F.; Font-Bardia, M.; Solans, X.
Org. Lett. 2009, 11, 2193−2196.
(14) Romo, J. M.; Galvez, E.; Nubiola, I.; Romea, P.; Urpí, F.;
dez-
́
vez, E.; Gom
́
ez-Pinal, L.; Romea, P.;
́
vez, E.;
́
*E-mail: pedro.romea@ub.edu.
*E-mail: felix.urpi@ub.edu.
Notes
́
Kindred, M. Adv. Synth. Catal. 2013, 355, 2781−2786. (b) Fernan
́
Valparís, J.; Romo, J. M.; Romea, P.; Urpí, F.; Kowlaski, H.; Font-
Bardia, M. Org. Lett. 2015, 17, 3540−3543.
The authors declare no competing financial interest.
(15) For an overview on the impact of the Mukaiyama aldol reaction
in the synthesis of natural products, see: Kan, S. B. J.; Ng, K. K.-H.;
Paterson, I. Angew. Chem., Int. Ed. 2013, 52, 9097−9108.
(16) The use of chiral 1,3-thiazolidne-2-thiones as chiral auxiliaries
was introduced by Nagao and Fujita; see: Nagao, Y.; Hagiwara, Y.;
Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org.
Chem. 1986, 51, 2391−2393.
ACKNOWLEDGMENTS
Financial support from the Spanish Ministerio de Economia y
Competitividad and Fondos Feder (Grant Nos. CTQ2012-
31034 and CTQ2015-65759) and the Generalitat de Catalunya
(2009 SGR825 and 2014SGR586), as well as a doctorate
■
́
studentship to J.M.R. (FPU, Ministerio de Educacion
acknowledged.
́
), are
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DOI: 10.1021/acs.orglett.6b01428
Org. Lett. XXXX, XXX, XXX−XXX