Letter Cite This: Org. Lett. 2018, 20, 2707−2710
pubs.acs.org/OrgLett
Total Synthesis of L‑156,373 and an oxoPiz Analogue via a Submonomer Approach Yassin M. Elbatrawi,† Chang Won Kang,† and Juan R. Del Valle* Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States S Supporting Information *
ABSTRACT: The first chemical synthesis of L-156,373 (1), a potent oxytocin receptor antagonist isolated from Streptomyces silvensis, is reported. Assembly of the unusual D-Piz-L-Piz dipeptide subunit was achieved through a sequential electrophilic amination−acylation−deprotection strategy followed by late-stage Piz ring formation. Synthesis and incorporation of a novel N-hydroxyL-isoleucine building block is also described. This submonomer approach was further applied to the expedient synthesis of a di-δoxopiperazic acid analogue of 1 starting from Fmoc-Glu(tBu)-OH building blocks.
he piperazic acid (Piz) residue and its derivatives are components in over 75 nonribosomal peptides isolated primarily from Streptomyces bacteria.1 Piz natural products have garnered considerable interest from the synthetic chemistry community owing to their important and diverse biological activities. Synthetic access to the Piz family of cyclic αhydrazino acids has also enabled initial studies of their impact on peptide conformation.2 The unusual propensity for Nαacylated derivatives of Piz and dehydropiperazic acid (Δ-Piz) to exclusively adopt a trans amide conformation contrasts with those of proline and pipecolic acid, which both exhibit significant cis amide rotamer populations.3 Despite its occurrence in nature and unique structural properties, Piz is not commonly employed in residue scanning applications. This is mainly due to the fact that suitably protected Piz building blocks require multiple steps to prepare in enantiopure form and often suffer from moderate coupling yields during peptide elongation.1a,b,2c Methods to more efficiently incorporate Piz into host structures may prompt its wider use in peptidomimetic drug design. In the 1980s, Merck, Sharp, and Dohme Research Laboratories initiated a medicinal chemistry campaign around the Piz-containing natural product L-156,373 (1, Figure 1),
T
isolated from the fermentation broth of Strepomyces silvensis.4 Compound 1 features an unusual D-Piz-L-Piz dipeptide subunit embedded within a hexapeptide macrocycle. Radioligand binding assays showed that 1 possesses a 150 nM binding affinity (Ki) for the oxytocin receptor (OTR) and approximately 20-fold selectivity over the related arginine vasopressin receptors AVPR-V1 and AVPR-V2. Semisynthetic modifications of 1 led to a small set of analogues with enhanced biological activity.4b,5 For example, treatment of a des-hydroxy derivative of 1 with alkaline hydrogen peroxide led to 2, which exhibits a Ki of 9.6 nM against OTR and over 160-fold selectivity over AVPR subtypes. Compound 2 features both Δ-Piz and an unprecedented δ-oxopiperazic acid (oxoPiz) residue. Although these macrocycles proved to be useful leads for drug development, optimization efforts initially relied on obtaining small quantities of 1 through fermentation. To date, the chemical synthesis of 1 has not been described. Strategies for the synthesis of enantiopure Piz monomers1a,b,2c typically rely on α-hydrazination of oxazolidinones6 or aldehydes7 (C−Nα bond formation), chiral auxiliarybased azo-Diels−Alder cycloaddition8 (C−N and C−C bond formations), or electrophilic amination of amino acid derivatives9 (N−N bond formation). A recent multicomponent reaction approach to Piz-containing dipeptides has also been described.10 To facilitate access to peptides featuring Piz and its congeners, we sought to employ a sequential electrophilic amination−acylation−deprotection strategy, followed by latestage Piz ring formation, as depicted in Figure 2. The efficiency of this route relies on oxaziridine-mediated amination of primary amines, a process often complicated by undesired diamination or poor conversion when the nucleophile is not employed in excess.9c,11 We were particularly interested in
Figure 1. L-156,373 (1) and a semisynthetic analogue (2).
Received: March 21, 2018 Published: April 18, 2018
© 2018 American Chemical Society
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DOI: 10.1021/acs.orglett.8b00912 Org. Lett. 2018, 20, 2707−2710
Letter
Organic Letters
Scheme 2. Synthesis of N-Hydroxyisoleucine Derivative 11
Figure 2. Submonomer approach to di-Piz and di-oxoPiz.
targeting structures such as 1, which contain Piz-Piz dipeptide subunits that can be difficult to prepare using preformed building blocks due to steric and stereoelectronic factors.12 Here, we report the total synthesis of 1 and an unnatural dioxoPiz analogue via this submonomer approach. The precursors to the L- and D-Piz residues in 1 were envisioned to be protected δ-hydroxynorvaline derivatives that would eventually undergo SN2 ring closure. The required orthogonally protected building blocks were synthesized as shown in Scheme 1. Glutamic acid benzyl esters (L and D) were
OH gave 10 in 62% yield. A Mitsunobu reaction with N,O-diAlloc-hydroxylamine was then followed by ester cleavage with dilute TFA/DCM to afford 11 as a single isomer. With the requisite building blocks in hand, we carried out the synthesis of 1, as depicted in Scheme 3. Tripeptide 12 was obtained in 71% yield over three steps via HATU-mediated coupling reactions. Deprotection of the Fmoc group was then followed by N-amination using oxaziridine 1911a,b to provide 13. The poor nucleophilicity of the α nitrogen in N′-carbamate protected hydrazino esters/amides is well documented and typically requires the use of acid chlorides for successful coupling. Incorporation of (R)-4 was thus achieved through preactivation using the Ghosez’s reagent and treatment with a mixture of 13 and NaHCO3 in DCM. Tetrapeptide 14 was then aminated in the same manner as 12 to afford 15 in 84% yield. The (N-OH)-Ile building block 11 was similarly converted to the acid chloride and reacted with 15 to provide the intermediate pentapeptide. Removal of both Alloc groups was followed by chemoselective N-acylation with the preformed acid chloride of Cbz-Phe-OH to give 16 in 47% yield over three steps. Pd/C-mediated hydrogenolysis of the terminal protecting groups in 16 proceeded without appreciable N−O bond cleavage. The crude zwitterion then underwent rapid macrocyclization in the presence of HATU/DIEA to provide 17 in 82% yield over two steps. Silyl ether cleavage of 17 and conversion to the dimesylate was followed immediately by K2CO3-promoted cyclization to form both Piz rings. Slow elimination of water at the sensitive (N-OH)-Ile residue led to some erosion of product yield, but was largely avoided through careful reaction monitoring. Acidolysis of the Boc groups finally afforded 1 in 41% over three steps. Synthetic 1 exhibits a well-resolved 1H NMR spectrum devoid of any conformational isomers, despite the presence of five tertiary amide bonds. The 1H NMR spectrum of 1 taken in C6D6 was identical to that previously disclosed for the natural product,4a thus confirming the structure of L156,373. Inspired by the reported semisynthesis of 2, we sought to apply our submonomer approach to an expedient synthesis of peptides featuring oxoPiz residues. Thus, we selected an oxidized variant of 2 as a synthetic target. As shown in Scheme 4, both L and D Fmoc-Glu(tBu)-OH were employed as oxoPiz precursors. Macrocycle 20 was synthesized using a route analogous to that described for the assembly of 17. Treatment
Scheme 1. Synthesis of δ-Hydroxynorvaline Building Blocks
subjected to Fmoc-protection followed by reduction of their mixed anhydride derivatives to give 3. Silyl protection and hydrogenolysis then afforded orthogonally protected monomers 4. In addition to the Piz residues, 1 harbors the unusual nonproteinogenic amino acid N-hydroxy-L-isoleucine (N−OHIle). N-Hydroxy amino acids are components of various nonribosomal peptides, often appearing alongside Piz and its oxidized derivatives. β-Branched variants are found in only a small subset of natural products, including the pargamicins,13 polyoxypeptins,14 pulcherrimin,15 and callyspongidipeptide A.16 The presence of N-OH-Ile in 1 results in five contiguous tertiary amide linkages, three of which are N-heteroatom substituted. Scheme 2 depicts our efforts toward a suitably protected NOH-Ile building block for incorporation into 1. The additional steric demand of β-branching became evident in our failed attempts to prepare 6 via the triflate derived from α-hydroxy ester 5. In contrast, the same SN2 reaction with O-benzylhydroxylamine proceeded readily with triflates derived from both leucine and phenylalanine methyl esters.17 Although a Mitsunobu reaction between 5 and (N-Alloc)-O-benzylhydroxylamine was unsuccessful, O-Boc-N-Alloc-hydroxylamine was sufficiently nucleophilic to provide 8 as a single isomer in moderate yield.18 However, alkaline hydrolysis or Lewis acid mediated methyl ester rupture led to rapid elimination of tertbutyl carbonic acid (across the C−N bond) or Boc deprotection, respectively. The propensity for elimination under mildly basic conditions was circumvented through the use of a PMB ester in conjunction with N,O-di-Alloc protection. Thus, diazotization and alkylation of H-D-allo-Ile2708
DOI: 10.1021/acs.orglett.8b00912 Org. Lett. 2018, 20, 2707−2710
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accomplished via N-amination and acid-promoted cyclization of glutamic acid-γ-tert-butyl ester subunits. The submonomer approach described herein represents a convenient method to access an array of Piz-containing peptides and natural products, including those harboring consecutive Piz residues. We anticipate that these results will facilitate the use of Piz and oxoPiz in peptide scanning applications and prompt further studies on their utility as potential proline surrogates.
Scheme 3. Synthesis of L-156,373 (1)
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00912. Experimental procedures, characterization data, copies of 1 H and 13C NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Juan R. Del Valle: 0000-0002-7964-8402 Author Contributions †
Y.M.E. and C.W.K. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (CHE1709927). We thank the USF Interdisciplinary NMR Facility and USF Mass Spectrometry Facility for assistance.
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REFERENCES
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Scheme 4. Synthesis of Di-oxoPiz Analogue 21.
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