Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

Article abstract of DOI:10.3762/bjoc.15.53

The synthesis of the polyketide section present in the potently cytotoxic marine cyclodepsipeptide jasplakinolide and related natural products, geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl

Full text of DOI:10.3762/bjoc.15.53

Synthesis of the polyketide section of seragamide A and
related cyclodepsipeptides via Negishi cross coupling
Jan Hendrik Lang and Thomas Lindel*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 577–583.
TU Braunschweig, Institute of Organic Chemistry, Hagenring 30,
doi:10.3762/bjoc.15.53
38106 Braunschweig, Germany
Received: 01 November 2018
Accepted: 12 February 2019
Published: 28 February 2019
Email:
Thomas Lindel* - th.lindel@tu-bs.de
*
Corresponding author
Associate Editor: A. Kirschning
§
Fax: (+49) 531-391-7744, http://www.oc.tu-bs.de/lindel
©
2019 Lang and Lindel; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
jasplakinolide; marine natural products; Negishi coupling; polyketides;
stereoselective synthesis
Abstract
The synthesis of the polyketide section present in the potently cytotoxic marine cyclodepsipeptide jasplakinolide and related natural
products, geodiamolides and seragamides, is reported. The key step is a Negishi cross coupling of (R)-(3-methoxy-2-methyl-3-oxo-
propyl)zinc(II) bromide and an (E)-iodoalkene that was synthesized via an aluminium ester enolate attack at (R)-propylene oxide.
The overall synthesis comprises nine steps with an overall yield of 21%. It proved to be possible to liberate the free 8-hydroxy-
nonenoic acid and to couple it with a protected tripeptide composed of L-alanine, N,O-dimethyl-D-iodotyrosine, and TIPS-pro-
tected L-threonine, which occurs as partial structure of seragamide A. The tripeptide section of seragamide A was assembled by
solution-phase synthesis and an open-chain analogue of the natural product was obtained.
Introduction
Our program on the synthesis of biologically active natural the actin skeleton in vivo, resulting in pronounced cytotoxicity
products with peptide partial structures is driven by an interest [3]. A photoreactive derivative of the cytotoxic jasplakinolides,
in the chemistry of photoreactive amino acids and heterocycles geodiamolides [4,5], or seragamides (2–6, seragamides A–E)
that may find application in photoaffinity labelling. Knowing [6] could also enable the search for additional targets in the cell,
the binding of a natural product to a biological target at atomic including proteins involved in transport or even membrane
resolution, as it is the case for the cyclodepsipeptide jasplakino- components. For this purpose, the 2-bromoabrine unit of 1
lide A (1, Scheme 1) [1,2], is an ideal situation for the valida- could be replaced by phototryptophan [7], whereas photo
tion of the chemoselectivity and efficiency of photoaffinity β-phenylalanine [8] could replace the β-tyrosine moiety. For
labelling. Recently, it has been determined by cryo-electron photoaffinity labelling studies with seragamides and geodi-
microscopy how jasplakinolide A (1) binds to F-actin and alters amolides, D-photophenylalanine could be incorporated.
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Beilstein J. Org. Chem. 2019, 15, 577–583.
Scheme 1: Actin-binding cyclodepsipeptides, photo amino acids, retrosynthetic cuts of polyketide 7 leading to organozinc compound 8.
In this paper we describe, as the first step of such an endeavour, Results and Discussion
a new synthesis of the polyketide section present in seragamides In our approach the polyketide section (7, Scheme 1) of
and most of jasplakinolides and geodiamolides. We also include seragamide A (2) was to be assembled via construction of the
the synthesis of the protected tripeptide section of seragamide A C3–C4 bond by sp3–sp2 Negishi cross coupling. The required
(
2), even if the macrocycle still remains to be assembled. organozinc reagent 8 has been applied occasionally and is
Seragamide A (2) from the marine sponge Suberites japonicus accessible from the corresponding commercially available
Thiele) has been synthesized only once, with relay ring-closing chiral bromide [30-34]. The coupling partner would be an (E)-
(
metathesis being the key step [9]. Characteristically, iodoalkene that was to be constructed from enantiomerically
seragamides A–E exhibit a L-threonine unit at the C-terminus pure (R)-propylene oxide. The C4–C5 double bond would be
of the peptide moiety.
formed by Corey–Fuchs reaction. Reaction of the aluminium
enolate of tert-butyl propionate (9, Scheme 2) with (S)-propy-
There is a considerable body of work on the synthesis of the lene oxide had provided Taylor et al. with a mixture of dia-
C12 polyketide section. In most cases, the C2–C3 bond was stereomers of α-methylated γ-hydroxyester 11 favouring the
formed by Ireland-, Johnson-, or Eschenmoser–Claisen rear- (2S,4S)-syn over the (2R,4S)-anti isomer [35,36]. As the config-
rangement [10-17]. Alternatively, Evans methodology has been uration at C4 was expected to be invertible in a later step, we
used [18-20]. The central C4–C5 double bond has also been aimed for the (2R,4R) configuration by choosing (R)-propylene
constructed by Wittig reaction, cross metathesis, and ring- oxide as electrophile. We obtained an acceptable ratio of dia-
closing metathesis [9,21,22]. The C3–C4 bond has been assem- stereomers of 11 (84:16 in favour of (2R,4R), 62% combined)
bled by 1,2-cuprate rearrangement [23]. Iterative construction after having treated tert-butyl propionate (9) with LDA/Et2AlCl
of the polyketide from smaller building blocks has been (Scheme 2). Performing the reaction at −78 °C instead of
achieved by Matteson homologation [24], that was also applied −40 °C unexpectedly diminished the dr, which is in agreement
to the synthesis of the related polyketide section of lagunamide with results by Liu, Petersen and co-workers [37]. The analo-
A [25]. In addition, the shorter C11 polyketide section of the gous reaction of adamantyl ester 10 (obtained from adamantan-
closely related chondramides has been assembled in several 1-ol and propionyl chloride/pyridine, 85%) instead of 9 gave a
ways [26-29].
quantitative yield of the hydroxy ester 12, but a lower dr (4:1).
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Beilstein J. Org. Chem. 2019, 15, 577–583.
Scheme 2: Synthesis of γ-hydroxy esters 11 and 12, followed by Mitsunobu inversion.
For both cases, we inverted the carbinol centre by Mitsunobu DCM] in DCM) afforded a satisfying 75% yield of the pro-
reaction employing p-methoxyphenol. DEAD was used instead tected nonenoic acid 20 (Scheme 3). For the synthesis of
of DIAD because of facilitated purification. It was possible to organozinc homoenolate 8, the MnBr2/CuCl-catalyzed reaction
separate the diastereomers of product 13 by column chromatog- of diethylzinc with β-bromopropionic acid ester 19 in DMPU
raphy. The use of DMEAD (di-2-methoxyethyl azodicarbox- proved to be the best choice [42]. Racemization was avoided.
ylate) [38] was inferior (33%). The PMP protecting group was
envisioned to be stable during the following steps and to be The PMP protecting group was removed (CAN) affording
selectively cleavable with ceric ammonium nitrate (CAN).
methyl ester 7 (82%, Scheme 3). For comparison with literature
data we converted 7 to the free carboxylic acid carrying a TBS-
Reduction of tert-butyl ester 13a to the alcohol by portionwise protected hydroxy group at C8 by silylation with TBSOTf/2,6-
addition of DIBAL and careful temperature control (slow lutidine, followed by saponification with LiOH.
warm-up from −78 to −30 °C) afforded the alcohol without
α-epimerization, which was oxidized to aldehyde 15 (IBX, To investigate whether polyketide 7 could be coupled in an
Scheme 3). Adamantyl ester 14 resisted reduction under the unprotected form with the peptide fragment of seragamide A
same conditions and was abandoned.
(2), we synthesized the tripeptide section. The assembly of the
iodotyrosine moiety commenced with D-3-iodotyrosine that
Dibromoalkene 16 was accessed from aldehyde 15 under was obtained in 63% yield from D-tyrosine upon treatment with
Corey–Fuchs conditions and treated with n-hexane to separate iodine (1 equiv, added via syringe pump over 90 min to avoid
triphenylphosphane oxide. For the conversion of 16 to the diiodination) in aqueous ammonia [43] (Scheme 4). This setup
internal alkyne 17, the use of a large excess of freshly prepared also served to avoid the formation of excess amounts of the
LDA and iodomethane with a slow warm-up from −78 °C to rt explosive iodinating reagent NI3. On work-up, the pH had to be
[
39] proved to be superior to the more commonly employed adjusted to exactly 4.5 to destroy remaining NI3 and to precipi-
n-BuLi/MeI reagent combination that led to the formation of a tate the product. Other iodination conditions such as use of NaI/
series of side products. We also attempted a Bestmann–Ohira NaOCl [44,45] or I2/CAN [46] did not convince. Boc protec-
reaction with in situ formation of the diazo phosphonate [40] tion yielded N-Boc-D-3-iodotyrosine (21), which underwent
that gave a slightly inferior yield after methylation of the alkyne three-fold methylation to N-methyl-O-methyliodotyrosine
terminus. Hydrozirconation/iodination of alkyne 17 required methyl ester 22 (82% yield, er 4:1, CHIRALPAK® IA, hexane/
freshly prepared Schwartz reagent (3 equiv) and iodine iPrOH 9:1). Partial racemization of 21 could not be suppressed
(
3 equiv) to obtain yields of (E)-olefin 18 above 80% with since a slight excess of base was always necessary, whereas the
perfect stereo- and regioselectivity. For comparison, as part of a use of exactly stoichiometric amounts resulted in incomplete
study towards kendomycin, Arimoto and co-workers had N-methylation. Treating the Boc-protected methyl ester of
published a route to a 1:1 mixture of diastereomers of a TBS- iodotyrosine 21 with a larger excess of base and methyl iodide
protected analogue of building block 18 [41].
(10 equiv each) led to the formation of the α-quaternary amino
acid 23 (Scheme 4). An alternative route to the N-methylated
Negishi cross coupling of sp3 organozinc homoenolate 8 product via oxazolidinone 24 was hampered by low yield on
2.75 equiv) and iodoalkene 18 (10 mol % [Pd(dppf)Cl2 × reaction with paraformaldehyde [47,48]. Although subsequent
(
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Beilstein J. Org. Chem. 2019, 15, 577–583.
Scheme 3: Synthesis of the polyketide section 7.
Scheme 4: Access to methylated D-iodotyrosine derivatives 22, 23, and 25.
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Beilstein J. Org. Chem. 2019, 15, 577–583.
reduction of 24 with Et3SiH/TFA and reprotection of the free lower dr of about 7:3. The analogous product 30 carrying an
N-methyl amino acid with Boc2O proceeded smoothly and 8-OPMP group was obtained from PMP-protected polyketide
delivered iodotyrosine 25, the overall yield via 24 was not satis- 28.
fying.
The endgame of a total synthesis of seragamide A (2) will have
After Boc removal at 22, HATU/HOAt-mediated coupling with to address the macrocyclisation, desilylation of the threonine
Boc-protected L-alanine afforded dipeptide 26, which was moiety, and O-demethylation of the D-iodotyrosine unit of 31.
saponified and coupled with TIPS-protected threonine methyl In orienting reactions on small scale, desilylation of 31 (TBAF)
ester (obtained with TIPSCl/DBU/MeCN) to provide tripeptide was a spot-to-spot conversion. Saponification of both the sily-
2
7 (Scheme 5). Peptides 26 and 27 were obtained in nearly lated and desilylated methyl esters with LiOH was possible, as
quantitative yield, albeit as mixtures of inseparable diastereo- long as very mild acidic conditions were applied on work-up.
mers (4:1), as consequence of the optical impurity of 22. Only However, macrocyclisation of the TIPS-protected or the desily-
when following the coupling order shown in Scheme 5, high lated acid did not occur. Under Yamaguchi conditions, we ob-
yields could be obtained.
served complete decomposition in both cases. Shiina condi-
tions gave a complex product mixture, if the TIPS group was
The labile carboxylic acid 29 was formed by saponification of present, whereas the desilylated acid provided a product that
methyl ester 7 (LiOH, H2O/MeOH) and underwent BEP-medi- apparently had undergone dehydration, as judged by TLC–MS
ated coupling with tripeptide 27 (Scheme 5). Product 31 (60%) coupling. In course of their recent synthesis of plusbacin A3,
was obtained with a higher dr of 9:1 than tripeptide 27 (dr 4:1). Ichikawa et al. experienced similar difficulties when attempting
We have evidence that the major side product of 31 was a desi- esterification of a bulky β-OTIPS-substituted amino acid with a
lylated analogue, for which the 1H NMR spectrum indicated a secondary alcohol under a variety of conditions [49].
Scheme 5: Synthesis of the doubly protected open chain peptide-polyketide 31.
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7
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We developed a short synthesis of the polyketide building block
present in most of the jasplakinolides, geodiamolides, and
seragamides, potently cytotoxic peptide-polyketide cyclodep-
sipeptides stabilizing filamentous actin. The key step is a
Negishi cross coupling, and the carbon atoms stem from
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