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Cite this: Org. Biomol. Chem., 2012, 10, 9085

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Preparation of enantioenriched iodinated pyrrolinones by iodocyclization ofα-amino-ynones†

Rosella Spina,a,b Evelina Colacino,a Bartolo Gabriele,b Giuseppe Salerno,c Jean Martineza andFrédéric Lamaty*a

Received 20th July 2012, Accepted 1st October 2012DOI: 10.1039/c2ob26427g

The unprecedented electrophilic iodo-mediated cyclization of α-amino-ynones afforded enantiomericallyenriched β-iodopyrrolin-4-ones in excellent yields under mild conditions. The starting substitutedα-amino-ynones were obtained from the chiral pool by selective mono-addition of an organolithium tooptically pure N-protected carboxyanhydrides of amino acids (UNCAs).

UNCAs (urethane N-protected carboxyanhydrides of aminoacid) 1 represent a unique class of stable, isolable and preacti-vated amino acid derivatives. UNCAs, crystalline solid, are veryreactive and they are important synthetic intermediates for thepreparation of various amino acid derivatives such as pepti-des,1a–c α-aminoaldehydes,1d statine analogues,1e,f pyrrolidi-nes,1g in kinetic resolution,1h,i and for the derivatization ofDL-amino acids.1j Due to our interest in using the chiral pool tohave access to heterocyclic compounds, we considered thatα-amino-ynones 2, which could be accessed by addition of orga-nometallic reagents on UNCAs 1, as presented in the first part ofour report, would be valuable synthons for further transform-ations such as cyclizations. In the second part of our investi-gation, the synthesis of β-iodopyrrolin-4-ones 3 is describedusing α-amino-ynones 2 as useful starting materials in an unpre-cedented electrophilic iodo-mediated cyclization.

The only reported example for the synthesis of α-amino-ynone derivatives 2 is a two-step procedure consisting in the acti-vation of amino acid derivatives as Weinreb amide, followed bythe addition of various lithium acetylides2 or Grignard reagents.3

Moreover, only two isolated examples are reported for theaddition of Grignard reagents to commercially availableUNCAs.1e,4 However, the monoaddition product was obtainedalways in low yields (11–29%), hampered by the formation ofmany by-products including the one issued from a non-

controlled double addition. We are presenting herein an all-in-one method in which UNCAs were effectively reacted in thepresence of a suitable alkynyl lithium reagent, leading to thedirect access to α-amino-ynones 2. Starting from the reportedprocedure1e in which Grignard reagents were added at 0 °C tothe UNCAs (inverse addition), we extended the method toalkynyl Grignard reagents, envisaging that the careful control oftemperature could avoid the possible double addition of theorganometallic reagent on the carbonyl group providing only theexpected product 2 (Table 1). The first explorative experimentwas carried out using equimolar amounts of commercially

Table 1 Addition of alkynyl organometallics to UNCAs

Entry R1 R2

T(°C)

Yielda

(%)e.e.b

(%)

1 1a CH2Ph Ph −60 2a 11c —d

2 1a −78 2a 60 103 1b Me Ph −60 2b 7c —d

4 1b Ph −50 2b 35 655 1c n-Bu −78 2c 95 946 1d c-Pr −78 2d 80 907 1e i-Pr Ph −50 2e 71 818 1e −60 2e 62 979 1f n-Bu −78 2f 81 9610 1g c-Pr −60 2g 94 10011 1h CH2Ph c-Pr −78 2h 64 1812 1i p-NMe2C6H4 −78 2i 46 95

a Isolated yields. b e.e. determined by chiral HPLC analyses (see ESI†).cReaction performed using a Grignard reagent (M = MgBr). dNotdetermined.

†Electronic supplementary information (ESI) available: Experimentalprocedures for the synthesis of α-amino-ynones 2, β-iodopyrrolin-4-ones3 and crossing coupling reactions leading to 4e and 5e; 1H and13C spectra and chiral HPLC data for each compound. See DOI:10.1039/c2ob26427g

aInstitut des Biomolécules Max Mousseron (IBMM) UMR 5247 CNRS –UM I-UM II Université de Montpellier II, Place E. Bataillon, 34095Montpellier Cedex 5, France. E-mail: frederic.lamaty@univ-montp2.fr;Fax: +33 (0)4 67 14 48 66; Tel: +33 (0)4 67 14 38 77bDipartimento di Scienze Farmaceutiche, Università della Calabria,87036 Arcavacata di Rende (CS), ItalycDipartimento di Chimica, Università della Calabria, 87036 Arcavacatadi Rende (CS), Italy

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available phenylethynylmagnesium bromide and Boc-Phe-NCAat −60 °C (Table 1, entry 1). The presence of the desired product2a was detected by HPLC after 4 h along with some by-pro-ducts. Even though the yield of 2a was very low (Table 1, entry1) after purification by column chromatography, this preliminaryexperiment confirmed that α-amino-ynone derivatives could beobtained using this method. In a second attempt a slight excess(1.1 equiv.) of the Boc-Ala-NCA was added to the Grignardreagent (direct addition) at −60 °C confirming the complete con-version of the starting material after 4 h, but the yield remainedpoor (Table 1, entry 3). To increase the yield and selectivity, thenature of the organometallic compound was changed to a morereactive organolithium derivative and two comparative experi-ments were carried out, involving Boc-Phe-NCA and Boc-Ala-NCA (Table 1, entries 2 and 4 respectively). The direct additionof Boc-Ala-NCA to 1.5 equiv. of phenylethynyl lithium at−50 °C was undertaken. In this case the α-amino-ynone 2b wasobtained with good purity albeit in low yield (35%, Table 1,entry 4). Boc-Phe-NCA displayed better reactivity at lower temp-erature, and the yield of 2a (Table 1, entry 2) could be increasedup to 60%. These encouraging results suggested that not onlythe lithium acetylides were more adapted than Grignard reagentsfor this transformation, but also that the reactivity of the UNCAsneeded to be modulated also as a function of the temperature.Different UNCAs were tested in the reaction with various substi-tuted lithium acetylides bearing an aryl or alkyl group and aselection of data is given in Table 1. α-Amino-ynones 2 wereobtained exclusively, in good to excellent yields, in a range oftemperature between −60 °C and −78 °C and as expected, thetemperature played a crucial role also in terms of the control ofthe enantiomeric excess (Table 1, entries 7 and 8). Chiral HPLCanalysis of α-amino-ynones 2 showed moderate erosion of theenantiomeric excess for the Boc-Ala-NCA derivatives (e.e.90–94%; Table 1, entries 4–6) while a minimal decrease of thestereochemical purity was observed for Boc-Val-NCA deriva-tives (e.e. 96–100%; Table 1, entries 7–10).

However, contrasting results were observed with Boc-Phe-NCA: the enantiomeric excess of the α-amino-ynones 2h and 2ibeing 18% and 95% respectively (Table 1, entries 11 and 12).The decrease of stereochemical purity could be explained by afaster epimerization occurring via a direct enolization mechan-ism5 during the reaction of addition of UNCAs to organolithiumcompounds, favoured when an aromatic group was present in theside chain of the amino acid derivative, as shown by comparisonof data in entries 6, 10 and 11.

Having succeeded in the ring opening of UNCAs with orga-nolithiums leading only to the mono addition product 2 in goodyields and enantiomeric excess, with the full conversion ofN-protected carboxyanhydrides, the α-amino-ynone derivatives2 were exploited to access highly substituted heterocyclesincorporating a halogen atom into the ring systems for furtherfunctionalization by transition-metal-catalyzed cross-couplingreactions. In view of the various functionalizing abilities ofiodine, its operational simplicity and low cost, it is an attractivereagent from an environmental point of view for organic func-tional group conversions. Iodine is involved in many appli-cations such as the introduction of protecting groups anddeprotection reactions,6 iodocyclization and synthesis ofheterocycles.7,8

We report herein the first example of direct iodocyclization ofα-amino-ynones 2 leading to β-iodinated pyrrolin-4-ones 3(Table 2), heterocyclic structures finding direct applications inthe pharmaceutical field.9 The obtention of iodinated pyrroli-dones has been reported starting from the pre-formed heterocyclevia indirect methods using N-halogenosuccinimides under stan-dard ‘electrophilic’ conditions.10 The use of α-iodopyrrolin-4-one derivatives as a starting material for cross-coupling reactions,such as Suzuki and Stille, has been previously mentioned,9c butthe preparation of substrates has not been reported. To the best ofour knowledge no examples of one-pot direct iodination leadingto β-iodinated pyrrolin-4-ones from α-amino-ynones 2 (Tables 2and 3) have been reported.

We have shown recently11 that the microwave-assisted iodo-cyclization of alkynyl diols or alkynyl aminoalcohols could beefficiently performed using poly(ethylene glycol) 3400(PEG-3400) as a solvent to provide the corresponding iodofuransand iodopyrroles (Scheme 1).

In view of these positive results, we investigated the corre-sponding iodocyclization of various α-amino-ynones in solidPEG-3400, using first 2 equiv. of I2 and sodium bicarbonate.The mixture was heated up under microwave activation for10 min at 50 °C. The reaction mixture was cooled down, dis-solved in a small amount of CH2Cl2 and precipitated in Et2O.The product was recovered after precipitation–filtration asreported previously.11 The organic phase was washed with asaturated solution of thiosulphate (Na2S2O3) to neutralize theexcess of iodine. Results are presented in Table 2.

In the case of the reaction of 2e, the analysis of the filtrateshowed partial conversion of the substrate and the expectedproduct 3e was obtained in a poor yield (34%, entry 1). Whenthe reaction time was extended to 15 min, the quantity of iodineand base increased (3 equiv.) (entry 2), substrate 2e was comple-tely converted but 3e was obtained in only 65% yield. A muchbetter result was obtained when the iodocyclization reaction wascarried out using substrate 2f (80% yield, entry 3). Under thesame conditions substrates 2g and 2c did not give satisfactoryresults (entries 4 and 5). One problem with this method mayarise from the fact that heating, even gently at 50 °C, is necess-ary to melt the polymer used as the solvent and for the reactionto occur. This may generate side-products including directaddition of iodine on the alkyne. Since this method did notprove to be general under these conditions, the iodocyclizationreaction was investigated in more classical solvents in which thereaction could be carried out at room temperature (Table 3).

α-Amino-ynone 2b was selected as the model substrate tostudy the electrophilic iodine-mediated cyclization reaction inCH3CN and CH2Cl2 at room temperature, in a basic medium.12

The best results were obtained in acetonitrile, with the full

Scheme 1 Iodocyclization in PEG.

9086 | Org. Biomol. Chem., 2012, 10, 9085–9089 This journal is © The Royal Society of Chemistry 2012

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conversion of substrate 2b in 2 h at room temperature, affordingthe corresponding β-iodopyrrolin-4-ones 3b in excellent isolatedyield (98%). When the solvent was dichloromethane, total con-version was reached after 75 min, but the analysis of crudeshowed the presence of many signals of degradation anddecomposition, and the expected product 3b was recovered inonly 32% of 1H NMR yield. Consequently the use of CH3CNwas preferred as a solvent for the iodocyclization reaction. Theoptimized conditions were applied to various α-amino-ynonesbearing an aromatic or alkyl group at the end of the acetylenefunctionality. Excellent isolated yields were obtained in all cases(Table 2). Compounds 3 were analyzed by chiral HPLC showingthat minimal epimerization had occurred during the synthesis(Table 2). The described method allowed rapid access to enantio-enriched iodinated penta-substituted skeletons, never reported inthe literature before. Then, β-iodopyrrolin-4-ones 3 were testedas substrates in Pd-catalyzed cross-coupling reactions, in Suzuki

and Heck conditions, using PEG-3400 as the reaction solvent,13

under microwave irradiation. Preliminary tests showed that thecorresponding cross-coupling products 4e and 5e were obtainedin good, non-optimized, isolated yields (Scheme 2), with highE-stereoselectivity in the case of the Heck reaction. In thesetransformations, the harsh reaction conditions led to theracemization of the asymmetric center, affording 4e and 5e as aracemic mixture. Milder conditions are currently under investi-gation to avoid this side reaction.

In conclusion we propose herein an original route to the prep-aration of iodopyrrolin-4-ones in mild conditions and excellentyields, starting from α-amino-ynone derivatives 2 obtained bydirect addition of commercially available UNCAs to organo-lithium compounds. In some cases, the chirality of startingmaterials decreased during the two consecutive steps. Cross-coupling reactions were explored in order to open up the way tonew substrates for further derivatizations.

Experimental section

All commercially available compounds were used as receivedfrom commercial suppliers (Aldrich, Fluka, Chem, ISOCHEM).Boc-Ala-NCA and Boc-Phe-NCA were diluted in AcOEt andwashed with a saturated solution of NaHCO3 to remove traces ofthe corresponding acid derivative. The solvents were purified bydistillation over a drying agent. NMR spectra were recorded atroom temperature with the appropriate deuterated solvent(CDCl3, CD3OD or d6-DMSO). Chemical shifts (δ) of 1H NMRand 13C NMR spectra are reported in ppm relative to residualsolvent signals (CHCl3 in CDCl3: δ = 7.27 ppm for 1H andCDCl3: δ = 77.04 ppm for 13C NMR). J values are given in Hz.1H and 13C NMR spectra were registered on a Bruker Avance-300 MHz and a Bruker Avance 400 MHz. Microwave-assistedreactions were performed in a sealed vessel with a BiotageInitiator 60 EXP® instrument. The temperature was measuredwith an IR sensor on the outer surface of the reaction vial.Analytical high performance liquid chromatography (HPLC)was performed on a Waters Millenium 717 equipped with anAutosampler, with a variable wavelength diode detector using a

Table 3 Synthesis of a library of β-iodopyrrolin-4-ones 3 by directiodocyclization of α-amino-ynones 2

Entry R1 R2

Yield 3a

(%)e.e. 3b

(%)e.e.2b

(%)

1 1b Me Ph 67 3b 60 652 1c n-Bu 76 3c 78 943 1d c-Pr 98 3d 84 904 1e i-Pr Ph 98 3e 80 815 1f n-Bu 96 3f 93 966 1g c-Pr 95 3g 99 1007 CH2Ph p-NMe2C6H4 94 3i 86 95

a Isolated yields. b e.e. determined by chiral HPLC analyses (see ESI†).

Table 2 Iodocyclization of α-amino-ynones 2 in PEG-3400 undermicrowaves

Entry R1 R2

Time(min)

Conversiona

(%)Yielda

(%)

1 2e i-Pr Ph 3eb 10 70 342 2e i-Pr Ph 3e 15 100 653 2f i-Pr n-Bu 3f 15 100 804 2g i-Pr c-Pr 3g 15 100 645 2c Me n-Bu 3c 15 60 29

aConversion and yields were determined by 1H NMR using CH2Br2 asan internal standard. b In this case, 2 equiv. of I2 and NaHCO3 wereused. Scheme 2 Pd-catalyzed cross-coupling reactions in PEG.

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CHROMOLITH RP18 column (50 × 4.6 mm), flow 5 mLmin−1, linear gradient CH3CN in water 0–100% (+0.1% TFA) in4.5 min. LC-MS analysis was performed with an HPLC WatersAlliance 2695 (UV Waters 2489), column Onyx C18 (25 ×4.6 mm), flow 3 mL min−1, linear gradient CH3CN in water0–100% (+0.1% HCO2H) in 2.5 min. HRMS analysis was per-formed on a Q-Tof (Waters, 2001) with ESI ionization mode.Chiral HPLC analysis was performed with a Beckman CoulterSystem Gold 126 Solvent Module and a Beckman CoulterSystem Gold 168 Detector. Columns: Chiralpak AD-H (0.46 ×25 cm), Chiralcel OD-H (0.46 × 25 cm); chiral HPLC reversephase: Chiralcel OD-RH (0.46 × 25 cm). [α]D measurementswere performed on a Perkin Elmer Instrument Polarimeter,model 341 Polarimeter, OROT 589 nm, 20 °C [10 mg mL−1];solvent: dichloromethane.

Representative procedure for the preparation of 2

(1-Methyl-2-oxo-oct-3-ynyl)-carbamic acid tert-butyl ester(2c). A solution of hexyne (254 mg, 3.09 mmol) in anhydrousTHF was added dropwise to a stirred solution of BuLi (1.9 mLof a 1.6 M solution in hexane, 3.09 mmol) in anhydrous THF at−78 °C. To the resulting mixture, maintained at −78 °C, understirring, a solution of LiBr (190 g, 2.18 mmol) in THF (3 mL)was added. After 0.5 h, Boc-Ala-NCA (500 mg, 2.32 mmol),diluted in anhydrous THF, was slowly added under nitrogen atthe same temperature. The resulting mixture was stirred for anadditional 4 h and then allowed to warm up to room temperature.After quenching with a saturated solution of NH4Cl, the mixturewas extracted with ethyl acetate. The combined organic layerswere washed with brine and then dried over MgSO4. After fil-tration, the solvent was evaporated to afford the pure product 2c(560 mg, 95%) of the title compound. Pale oil, e.e. 94%; [α]D =+0.026° (10 mg mL−1 CH2Cl2);

1H NMR (CDCl3, 400 MHz),δ (ppm): 5.20 (d, J = 7.5 Hz, 1H), 4.42–4.35 (m, 1H), 2.40 (t,J = 6.8 Hz, 2H), 1.62–1.40 (m, 4H), 1.45 (s, 9H), 0.93 (t, J =7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz), δ (ppm): 187.1,155.0, 98.3, 79.8, 78.8, 57.0, 29.6, 28.3, 28.0, 22.0, 17.9, 13.5;ESI-MS m/z 254.1 (M + H)+, 276.2 (M + Na)+, 198.1 (M + H-t-Bu)+, 154.1 (M + H-Boc)+, 529.3 (2M + Na)+; HMRS (ESI)calcd for C14H24NO3 (M + H)+: 254.1756, found: 254.1756;HPLC Chiralpak AD-H, i-propanol–hexane = 2 : 98, flow rate1.0 mL min−1, λ = 214 nm, tmajor = 13.017 min, tminor =11.65 min.

Typical procedure for the iodocyclization

To a stirred solution of substrate 2 (0.1 mmol), NaHCO3

(25.2 mg, 0.3 mmol) in 0.5 mL of CH3CN, a solution of I2(0.3 mmol, 76.2 mg) in 0.5 mL of CH3CN was added. After 2 hat r.t., the organic phase was evaporated under vacuum, dissolvedin AcOEt, washed with a saturated solution of thiosulphate(Na2S2O3) to neutralize the excess of iodine, dried over MgSO4,filtered and evaporated to afford product 3.

β-Iodopyrrolin-4-one (3c). Based on the typical procedure,and starting from 25.7 mg of 2c, 27.9 mg (76% isolated yield) of3c were obtained: Yellow oil, e.e. 78%. 1H NMR (CDCl3,400 MHz), δ (ppm): 4.20 (q, J = 7.0 Hz, 1H), 3.16–3.03 (m,

2H), 1.68–1.44 (m, 4H), 1.49 (s, 9H), 1.44 (d, J = 7.0 Hz, 3H),0.98 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz), δ (ppm):196.7, 175.3, 148.3, 83.5, 76.8, 76.0, 61.8, 32.0, 29.8, 28.1,22.8, 17.8, 13.9. ESI-MS m/z 380.1 (M + H)+, 402.0 (M + Na)+,324.0 (M + H-t-Bu)+. Confirmed by chiral LC/MS. HMRS (ESI)calcd for C14H23NO3I (M + H)+: 380.0723, found: 380.0731.HPLC Chiralcel OD-RH, ACN–H2O (+0.01% TFA) = 60 : 40,flow rate 1.0 mL min−1, λ = 214 nm, tmajor = 7.267 min, tminor =6.933 min.

Acknowledgements

We thank the CNRS, the MESR, the Università della Calabria(Italy) for financial support. We thank ISOCHEM (Vert le Petit,France) for a gift of UNCAs.

Notes and references

1 (a) J.-A. Fehrentz, C. Genu-Dellac, M. Amblard, F. Winternitz, A. Loffetand J. Martinez, J. Pept. Sci., 1995, 1, 124; (b) W. D. Fuller,M. Goodman, F. R. Naider and Y. F. Zhu, Biopolymers, 1996, 40, 183;(c) V. Declerck, P. Nun, J. Martinez and F. Lamaty, Angew. Chem., Int.Ed., 2009, 48, 9318; (d) J.-A. Fehrentz, C. Pothion, J. C. Califano,A. Loffet and J. Martinez, Tetrahedron Lett., 1994, 35, 9031;(e) P. Audin, C. Pothion, J. A. Fehrentz, A. Loffet, J. Martinez andJ. Paris, J. Chem. Res. Synop., 1999, 282; (f ) M. Paris, J. A. Fehrentz,A. Heitz, A. Loffet and J. Martinez, Tetrahedron Lett., 1996, 37, 8489;(g) C. Pothion, J. A. Fehrentz, A. Aumelas, A. Loffet and J. Martinez,Tetrahedron Lett., 1996, 37, 1027; (h) Y. Ishii, R. Fujimoto, M. Mikami,S. Murakami, Y. Miki and Y. Furukawa, Org. Process Res. Dev., 2007,11, 609; (i) J. F. Hang, H. M. Li and L. Deng, Org. Lett., 2002, 4, 3321;( j) H. Bruckner and M. Lüpke, Chromatographia, 1995, 40, 601.

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9 (a) A. B. Smith, S. D. Knight, P. A. Sprengeler and R. Hirschmann,Bioorg. Med. Chem., 1996, 4, 1021; (b) A. B. Smith, L. D. Cantin,A. Pasternak, L. Guise-Zawacki, W. Q. Yao, A. K. Charnley, J. Barbosa,P. A. Sprengeler, R. Hirschmann, S. Munshi, D. B. Olsen, W. A. Schleifand L. C. Kuo, J. Med. Chem., 2003, 46, 1831; (c) A. B. Smith,A. K. Charnley and R. Hirschmann, Acc. Chem. Res., 2011, 44, 180.

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