Tetrahedron Letters 51 (2010) 1367–1370

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Proline-like b-turn mimics accessed via Ugi reaction involving monoprotected hydrazines
Mikhail Krasavin a,b,*, Vladislav Parchinsky b, Alexei Shumsky b, Igor Konstantinov b, Anton Vantskul b
a b

Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University 150000, Russia Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg. 141400, Russia

a r t i c l e

i n f o

a b s t r a c t
A four-center, three-component Ugi-type reaction of a variety of keto acids, Boc- or Cbz-protected hydrazine, and isocyanides offers a simple and high yielding access to cyclic products containing an Naminolactam unit. The latter are shown to form consistently an intramolecular hydrogen bond leading to a b-turn-like secondary structure. The possibility of integrating such N-aminolactam units (without disruption of the folded structure) into pseudotripeptide fragments is demonstrated. Ó 2010 Elsevier Ltd. All rights reserved.

Article history: Received 15 November 2009 Revised 16 December 2009 Accepted 23 December 2009 Available online 7 January 2010 Keywords: Isocyanide-based multicomponent reactions Ugi reaction Bifunctional reagents Hydrazine b-Turn mimics Secondary structure by NMR Pseudopeptides

The successful use of keto (as well as aldehydo) carboxylic acids as bifunctional inputs for isocyanide-based multicomponent reactions (IMCR) was demonstrated by Harriman1 and Ugi.2 This fourcenter, three-component process was found to provide a simple and efficient (as well as atom-economical) entry into novel dipeptoid lactam structures. The strategy has been widely exploited to give rise to a large variety of novel small- and medium-size lactam-type heterocyclic scaffolds3 and validated, in general, the use of bifunctional reagents in IMCR as a source of significant product diversity.4 Replacement of the amine component in the Ugi reaction with various surrogates has had a number of successful outcomes, as documented in the literature. For example, the use of hydrazine (as N-acylhydrazine, N,N-dialkylhydrazine, or even a symmetrical hydrazone) in IMCR was described in the earlier work of Ugi5 and others.6 O-Protected and unprotected hydroxylamines7 were also found to be good partners for Ugi-type IMCR while N-benzylhydroxylamine additionally provided a reactive N-hydroxy group as the site for acyl migration.8 We recently developed a modified protocol to prepare a variety of hydrazinopeptide-like units via the Ugi reaction involving N-acyl- and alkoxyacyl-hydrazines.9 Besides their general appeal as hydrolytically more stable pseudopeptide ‘inserts’ for the development of new biologically ac* Corresponding author. Tel.: +7 495 995 4944; fax: +7 495 626 9780. E-mail address: myk@chemdiv.com (M. Krasavin). 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.12.141

tive peptidomimetics,10 short hydrazinopeptides are known to adopt a b-turn-like secondary structure known as a ‘hydrazino turn’ (due to an intramolecular bifurcated hydrogen bond involving the sp3-hybridized nitrogen atom of the hydrazine motif).11 In this work, we have investigated the possibility of a new IMCR design using various aliphatic keto carboxylic acids in combination with a Boc- or Cbz-protected hydrazine as a surrogate for the
2 1











R1 = t-Bu, Bn O N X H N 1 O R


O R1 O

2 R N


O R1 O


Scheme 1. A new IMCR design toward susbstituted N-aminolactams 1.

Using the optimized reaction protocol we prepared analogous N-aminolactams 1b–v using Boc. mass spectrometry. N-benzylhydroxylamine. but also in terms of its potential ability to mimic b-turns when introduced into a polypeptide chain—a secondary structure bias typically associated with proline in natural polypeptides. 2b. We have also demonstrated that the synthesized N-aminolactams could be elaborated into useful proline-like building blocks as well as incorporated into short peptide structures. which was expected to yield substituted Naminolactams 1 (Scheme 1).8 and (ii) a surprisingly efficient four-center. three-component reaction of substituted a-hydrazino acids with aldehydes and isocyanides reported to yield strained aza-b-lactams. Such a design was primarily inspired by: (i) a successful (but low-yielding) five-center.and Cbz-hydrazine. b-Turn-like hydrogen bonding pattern in 1a as evidenced by X-ray analysis. Bochydrazine. in principle. Krasavin et al. as illustrated by the conversion of 1g into the ‘BnNHGly-WPro-GlyBoc’ tripeptoid 4. the reaction outcome was more favorable in aqueous methanol when equimolar ammonium chloride was employed as a mildly acidic promoter. the N-Boc group was easily removed from the N-terminus of the N-aminolactam which was then acylated with Boc-protected glycine. Table 1 Optimization results for model compound 1a O OH O O O N H NH2 O N O NH OH O O N H N O O 1a H N O O + O N C Entry 1 2 3 4 5 Keto acid (equiv) 1 1 2 1 2 BocNHNH2 (equiv) 1 1 1 2 2 Isocyanide (equiv) 1 1 1 1 1 Solvent MeOH MeOH/H2O MeOH/H2O MeOH/H2O MeOH/H2O (3:1) (3:1) (3:1) (3:1) Acid catalyst — NH4Cl NH4Cl NH4Cl NH4Cl (1 equiv) (1 equiv) (1 equiv) (1 equiv) + Time (h) 72 72 36 36 24 Isolated yield (%) 18 34 71 54 84 . in our view. and 4-methoxybenzylisocyanide in methanol were stirred at room temperature. / Tetrahedron Letters 51 (2010) 1367–1370 amine component. in the more complex ‘tripeptide’ 4. and elemental analyses (see Supplementary data). but also revealed the presence of a pronounced hydrogen bond between the carbonyl oxygen atom of the Boc group and the exocyclic secondary amide side-chain (Fig.12 In a trial experiment. As is evident from the results presented in Table 1. makes 1a (as well as its subsequently prepared analogs) similar to proline.3c and the newly synthesized 2d (Scheme 2). without disruption of the lactam ring or the exocyclic amide bond. As shown in Scheme 3. provide an insight on how consistent is this H-bonding pattern for these compounds in the solid state. Fortunately.13 This feature. compounds 1e and 1f were hydrolyzed by aqueous KOH in methanol into the respective ‘glycine-WPro’ carboxylic acids 3a and 3b. The products 1 were isolated by column chromatography in good to excellent yields (Table 2) and their identity and purity was established by NMR spectroscopy. the expected product 1a was isolated by chromatography in low yield (<25%). Although the reaction was markedly slow and proceeded to only a limited conversion over 72 h at room temperature. and ethyl isocyanoacetate. we were curious to see if the intramolecular hydrogen bonding pattern (leading to a b-turn-like secondary structure) that we initially observed by X-ray analysis for 1a (vide supra) continued to persist in the newly synthesized compounds and. three-component (hence ring-forming) reaction of 4-acetylbutyric acid. 1). not only from the viewpoint of shape and chemical structure. equimolar amounts of levulinic acid. by recording 1H NMR spectra of Figure 1. likewise. Finally. While obtaining X-ray structures for the crystalline compounds 1 could. Prompted by this exciting finding we proceeded to optimize the reaction toward 1a. various isocyanides and the known or commercially available keto acids 2a.14 The reaction also required excess amounts of both the keto acid and the hydrazine in order to go to completion (with respect to isocyanide) for reasons that so far remain unclear. 2c. it would not determine if the same was true in solution. A single crystal of this compound was obtained and the X-ray crystallographic analysis not only confirmed the identity of this new type of N-aminolactam.15 2e. especially.1368 M.

a similar downfield shift was not observed for the amide proton proximal to the lactam ring. X = direct bond 2b. It was then partitioned between EtOAc (25 mL) and H2O (25 mL). DMSO-d6 as a solvent capable of hydrogen bonding with the solute. 4. CDI. 9H). rt 2) BocGly. 3H). b-turn-like conformation. X = CH2 2c. which also confirms its intramolecular H-bonded character (Table 3). In conclusion.37 (s.5 equiv) was added followed by water (2 mL). J = 8.21 (dd. 2H). CDCl3) d 8. 1s. which is consistent with the expected intramolecular hydrogen bonding. and the protected ‘tripeptide’ 4. py/CH 2Cl2. .4 Hz. 13C NMR (75 MHz. 1H). the same amide proton appears almost insensitive to the solvent change. 1H).48 (s. 2. X = S 2d. 4. These structures can be elaborated into ‘dipeptide’ acid building blocks and incorporated into a ‘tripeptide’ structure and thus holds potential as key elements for the design of mimetic analogs of bioactive peptides.93– 2. 72% O R O N HN O H N O 1g H N O O 1) HCl/dioxane (4 equiv. Likewise. 6.5 equiv) was added and the reaction mixture was stirred under an argon atmosphere at rt for 18–24 h. Once a clear solution had formed. and 1v. 7. 18-24 h X O N H N R O H N 1 X O 2a. 1b. 1. R = t-Bu H N O H N O O R aq. Preparation of N-aminolactams 1a–v.4 Hz. The combined organic extracts were dried over anhydrous MgSO4. Solid NH4Cl (0. KOH (1 equiv) MeOH. we have developed an efficient method to prepare a novel racemic proline-like N-aminolactams 1 which exist in a folded. rt 56% HN O H N O N H N O O 4 N H O O Scheme 3. 4. Efforts are currently underway in our laboratories to prepare non-racemic versions of these useful structural motifs. R 2 1a-v Table 2 N-Aminolactams 1a–v prepared in this work Product 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1n 1o 1p 1q 1r 1s 1t 1u 1v X Direct Direct Direct Direct Direct Direct Direct Direct bond bond bond bond bond bond bond bond R1 t-BuO t-BuO t-BuO BnO BnO t-BuO t-BuO t-BuO t-BuO R2 4-MeOC6H4CH2 4-FC6H4CH2 MeOCH2CH2CH2 4-FC6H4CH2 EtOOCCH2 EtOOCCH2 PhCH2NHCOCH2 t-Bu Isolated yield (%) 84 86 69 75 69 65 71 92 O Direct bond Direct bond CH2 CH2 CH2 CH2 S S S S O O MeSO2N MeSO2N * 77 67 91 O t-BuO t-BuO t-BuO Cycloheptyl 4-FC6H4CH2 O * 92 76 89 73 O t-BuO t-BuO t-BuO t-BuO Cycloheptyl t-Bu 4-FC6H4CH2 O * 79 67 94 84 68 72 78 O t-BuO t-BuO t-BuO t-BuO t-BuO t-BuO Cycloheptyl t-Bu 4-FC6H4CH2 Cycloheptyl Cycloheptyl 4-FC6H4CH2 the compounds in chloroform-d and in DMSO-d6 and observing the resulting changes in the chemical shift of the protons ‘suspected’ of participation in intramolecular hydrogen bonding versus those protons that do not. 1H). 1l. CDCl3) O N O O 1e. 1H NMR (300 MHz. J = 14. 1. Compound 1a: White solid. both in solid state and in solution. The N-aminolactams 1 were isolated by chromatography (SiO2) using EtOAc–hexane mixtures as eluents. aq. Typical procedure: Synthesis of N-aminolactams 1: The syntheses reported herein have been performed on 1–3 mmol scale. Preparation of the N-protected ‘dipeptides’ 3a.74 (br s. Equimolar amounts of keto acid 2 and monoprotected hydrazine were dissolved in MeOH (6 mL).04 (m. and concentrated in vacuo. 1H).14 (d.1 Hz.5 Hz. X = NSO2Me Scheme 2. 16 h HO O H N O N H N O O 3a. led to a downfield shift (compared to CDCl3) of both heteroatom-bound protons in model compound 5 where no intramolecular H-bond is possible. the isocyanide (0.73 (s. Krasavin et al.22–2.0. J = 8. 3. 1k.77 (d. 89% 3b. 3H).4.16 Indeed. The organic layer was separated and the aqueous layer was back-extracted with an equal volume of EtOAc. for selected N-aminolactams 1a. 6. R = Bn. The results of these studies will be reported in due course. / Tetrahedron Letters 51 (2010) 1367–1370 1369 OH O O R1NHNH2 R2NC NH4Cl.36 (dd. 1H). mp = 189–191 °C.b. as demonstrated by X-ray and 1H NMR analyses. X = O 2e.M. 1. R = Bn 1f. 3H). in the ‘tripeptide’ 4. R = t-Bu. MeOH rt.). J = 14. filtered. it was possible to ascertain the existence of intramolecular hydrogen bonds in solution. 2H). rt. 7.43 (m. However.07 (s.

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