Synthesis of the ABH rings of ecteinascidin 597 using a connective Pummerer-type cyclisation

Article abstract of DOI:10.1039/c1cc13992d

A connective Pummerer-type cyclisation involving a cysteine derivative and an N-benzyl glyoxamide 3 has been applied in an asymmetric synthesis of the protected ABH rings 2 of the antitumour and antimicrobial natural product ecteinascidin 597.

Full text of DOI:10.1039/c1cc13992d

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COMMUNICATION
Synthesis of the ABH rings of ecteinascidin 597 using a connective
Pummerer-type cyclisationw
Laura H. S. Smith,a Trung Thanh Nguyen,a Helen F. Sneddonb and David J. Procter*a
Received 4th July 2011, Accepted 9th August 2011
DOI: 10.1039/c1cc13992d
A connective Pummerer-type cyclisation involving a cysteine
derivative and an N-benzyl glyoxamide 3 has been applied in an
asymmetric synthesis of the protected ABH rings 2 of the
antitumour and antimicrobial natural product ecteinascidin 597.
Members of the family display a wide range of antitumour and
antimicrobial activities. For example, ecteinascidin 743 is
licensed as Yondeliss/trabectidin for the treatment of
advanced soft tissue sarcoma and is undergoing further clinical
trials for the treatment of breast, prostate, and paediatric
sarcomas. The limited availability of the ecteinascidins from
natural sources and their intriguing properties have prompted
studies that have culminated in a number of elegant syntheses
and synthetic approaches to members of the family.7 We have
Thionium ions are important electrophiles in organic
chemistry.1 These intermediates are most often encountered
in the Pummerer reaction of sulfoxides,2 a process that is now
firmly established as an important tool for organic synthesis.
We have recently exploited a convergent approach to thionium
ions from aldehyde and thiol starting materials that proceeds
via hemithioacetal intermediates (Scheme 1).3 The connective
Pummerer-type reaction has a number of attractive features: it
uses readily available starting materials, does not require the
synthesis of sulfides and sulfoxides and is useful for convergent
synthesis, as the structural features of the aldehyde, thiol and
nucleophile are incorporated into the product. We have
exploited the connective Pummerer reaction in a fluorous
synthesis of N-heterocycles, in which the introduction of the
focused our synthetic studies on ecteinascidin 597
1
(Scheme 2), a family member that was recently synthesised
for the first time by Zhu.8 We proposed that a connective
Pummerer-type cyclisation involving glyoxamide
3 and
cysteine derivative 4 could be used to assemble the ABH rings
of 1 (and of analogues) (Scheme 2). Our convergent approach
would negate the need to form sulfides and sulfoxides as
precursors to the requisite thionium ions for Pummerer
cyclisation.9
tag through the addition of
a fluorous thiol triggers
N-heterocycle formation,4 and in a dearomatising route to
azaspirocycles.5
Scheme 1 A convergent route to thionium ions.
Here we describe the application of the connective Pummerer
process to the construction of the ABH rings of the
biologically-active natural product ecteinascidin 597 1. The
ecteinascidins are a family of tetrahydroisoquinoline alkaloids
isolated from the Caribbean tunicate Ecteinascidia turbinata.6
a School of Chemistry, University of Manchester, Oxford Road,
Manchester, M13 9PL, UK.
E-mail: david.j.procter@manchester.ac.uk
Scheme 2 Retrosynthetic analysis of the ABH rings of Et 597 (P =
protecting group).
b Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road,
Stevenage, Herts, SG1 2NY, UK
As our previous studies had shown that tetrahydroisoqui-
nolinone formation using the connective Pummerer cyclisation
could be problematic,4,5 conditions for the efficient cyclisation
of the electron-rich benzyl amine systems present in the
ecteinascidins were developed. The use of ZnCl2 or Sc(OTf)3,
without addition of an electrophile to activate the
w Electronic supplementary information (ESI) available: Additional
experiments, details of substrate synthesis, full experimental details,
characterisation data and 1H and 13C NMR spectra for all new
compounds, chiral HPLC analyses and the X-ray crystal structure of
11. CCDC 808088. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc13992d
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Scheme 4 Asymmetric synthesis of hydroxyamide 8.
Scheme 3 Cyclisations of electron-rich N-benzyl glyoxamides.
hemithioacetal intermediate, gave the desired tetrahydroiso-
quinolinones in acceptable overall yield (Scheme 3).10 The
competency of hemithioacetals as intermediates in the cyclisation
was confirmed by in situ trapping of a glyoxamide from a
Swern oxidation with thiol to give the corresponding hemi-
thioacetal prior to the addition of ZnCl2 and cyclisation (75%
yield of 5). Trifluoroacetylation of the same hemithioacetal
prior to the addition of ZnCl2 and cyclisation gave similar
yields of 5.11 The cyclisations of substrates bearing amino
groups were more efficient when warmed to 60 1C in the
presence of stoichiometric ZnCl2.12
Scheme 5 Asymmetric synthesis of model ABH ring systems.
simple trimethoxy A-ring derivative at this stage although a
derivative with the necessary orthogonal protection is also
accessible using our approach. Substituted styrene 17 was
prepared in seven steps from 15 via the corresponding benzal-
dehyde.18 Sharpless asymmetric dihydroxylation13 followed by
a Mitsunobu sequence gave 18 (95% ee by HPLC).15 Reduc-
tive amination, coupling with acetoxy acetyl chloride, in situ
acetate hydrolysis and oxidation then gave glyoxamide 3
(Scheme 6).
We next prepared enantiomerically pure hydroxyamide 8, a
model compound for our approach to the ABH rings of
ecteinascidin 597, from styrene 6 using Sharpless asymmetric
dihydroxylation13 followed by a Mitsunobu sequence14 to give
7 (484% ee by HPLC)15 (Scheme 4). Reductive amination
and coupling with acetoxy acetyl chloride and in situ removal
of the acetate protecting group gave 8 in 85% overall yield.
Pleasingly, oxidation of 8, in situ trapping of the glyoxamide
with methyl 3-mercaptopropanoate or N-Troc cysteine t-butyl
ester and treatment with ZnCl2 gave 9 and 10 respectively in
good overall yield as inconsequential mixtures of diastereo-
isomers. Epimerisation occurred during silyl ether deprotec-
tion and ester hydrolysis to give cis diastereoisomers 11 and
12. The stereochemistry of 11 was confirmed by X-ray crystal-
lographic analysis.16 Treatment of 11 and 12 with the Shiina
reagent (MNBA, 2-methyl-6-nitrobenzoic anhydride)17 gave
ABH ring analogues 13 and 14 in moderate yield (Scheme 5).
We next prepared glyoxamide 3 (P = Me) possessing the
substituted A-ring of ecteinascidin 597. We chose to prepare a
Treatment of glyoxamide 3 with methyl 3-mercaptopro-
panoate or N-Troc cysteine methyl ester formed the corres-
1
ponding hemithioacetals (observed by H NMR) and subse-
quent exposure to Sc(OTf)3 gave 19 and 20 respectively in
good overall yield and as inconsequential mixtures of
diastereoisomers (Scheme 7). As seen previously, epimerisation
occurred during silyl ether deprotection and ester hydrolysis to
give cis hydroxyacids 21 and 22. Finally, macrolactonisation
using Shiina’s reagent17 gave the protected ABH ring system
of ecteinascidin 597 2 (P=Me) and additional analogue 23 in
good yield (Scheme 7).
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10822 Chem. Commun., 2011, 47, 10821–10823
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Scheme 6 Asymmetric synthesis of the protected ABH ring system.
In summary, a connective Pummerer-type cyclisation of
thiols and N-benzyl glyoxamides has been studied and applied
in an asymmetric approach to the protected ABH ring system
of the antitumour and antimicrobial natural product ecteinascidin
597. Studies aimed at completing the synthesis of the natural
product and its analogues are underway.
Scheme 7 Completing the asymmetric synthesis of the ABH ring
We thank the EPSRC and GSK (Industrial CASE award to
L. H. S. S.), University of Medicine and Pharmacy, Ho Chi
Minh City (Scholarship to T. T. N.), and the EPSRC and the
University of Manchester for additional funding.
system.
6 K. Suwanborirux, K. Charupant, S. Amnuoypol, S. Pummangura,
A. Kubo and N. Saito, J. Nat. Prod., 2002, 65, 935 and references therein.
7 For reviews of synthetic approaches to the ecteinascidins, see:
(a) C. Avendano and E. de la Cuesta, Chem.–Eur. J., 2010,
16, 9722; (b) C. Cuevas and A. Francesch, Nat. Prod. Rep., 2009,
26, 322.
Notes and references
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8 J. Chen, X. Chen, M. Willot and J. Zhu, Angew. Chem., Int. Ed.,
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9 Cysteine S-oxides can be prone to elimination: M. C. Aversa,
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10 Conditions using Lewis acids and hemithioacetals, with no electro-
philic activator of the hemithioacetals, were ineffective for the
cyclisation of N-benzyl glyoxamides lacking electron-releasing
groups on the benzene rings.
11 See the ESIw for partial characterisation of the hemithioacetal and
trifluoroacetylated hemithioacetal intermediates.
12 It appears likely that more Lewis acid and more forcing conditions
were required for the cyclisation of these substrates as they contain
alternative sites on the aromatic ring for Lewis acid coordination
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16 See the ESIw for X-ray structure and CCDC number.
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This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10821–10823 10823