Synthesis of a novel Boc-protected cyclopropane-modified proline analogue

Tetrahedron Letters 53 (2012) 3847–3849

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Synthesis of a novel Boc-protected cyclopropane-modified proline analogue Andriy V. Tymtsunik a,b, Vitaliy A. Bilenko a, Yevhen M. Ivon a,b, Oleksandr O. Grygorenko a,b,⇑, Igor V. Komarov a,b a b

Enamine Ltd, Alexandra Matrosova Street, 23, Kyiv 01103, Ukraine Kyiv National Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01601, Ukraine

a r t i c l e

i n f o

Article history: Received 20 February 2012 Revised 26 April 2012 Accepted 3 May 2012 Available online 19 May 2012 Keywords: Unnatural amino acids Proline analogues Cyclopropane Spiro compounds Simmons–Smith reaction

a b s t r a c t The synthesis of the Boc derivative of a novel member of the cyclopropane-modified proline library, Bocprotected 5-azaspiro[2.4]heptane-6-carboxylic acid, is reported. The synthesis was performed in six steps starting from (2S,4R)-4-hydroxyproline using a modified Simmons–Smith reaction as the key step. The reaction conditions for all the steps were carefully selected to avoid racemization at the chiral centers in the intermediates and the final product. Ó 2012 Elsevier Ltd. All rights reserved.

Incorporation of a cyclopropane ring into biologically active molecules might severely alter their conformational behavior and electronic properties, which can be advantageous in medicinal chemistry in the search for potential drug candidates and for model studies in bioorganic chemistry.1 It is noteworthy, that these alterations can be achieved by minimal structural changes to the parent scaffolds (addition of a C–C bond, –CH2–, or –CH2–CH2– units) and could be attributed to the intrinsic rigidity and peculiar electronic properties of the cyclopropane fragment. For example, a number of cyclopropane-containing analogues of the amino acid Lproline (scaffold structure 1) were synthesized (compounds 2–8) ( Fig. 1) and used for structure–activity relationship (SAR) studies, as model compounds for elucidating mechanisms of enzyme action, and as building blocks for drug design.2,3 The known compounds 2–8 comprise an incomplete set of all theoretically possible cyclopropane-modified L-proline analogues; some of them have not been synthesized, namely, compounds 9–12.4 In this Letter, we report a short and scalable synthesis of an unknown member of the cyclopropane-modified L-proline family, (6S)-5-azaspiro[2.4]heptane-6-carboxylic acid (9), obtained as the Boc derivative. This compound increases the arsenal of the available conformationally constrained proline analogues which might be used in medicinal chemistry. For example, the isomers of 9, compounds 7 and 8 are already used as mechanistic probes of prolyl-4-hydroxylase.5,6

⇑ Corresponding author. Tel.: +380 44 239 33 15; fax: +380 44 502 48 32. E-mail address: [email protected] (O.O. Grygorenko). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.05.020

Retrosynthetic analysis of 9 proved quite simple and relied on (2S,4R)-4-hydroxyproline (13) as a chiral pool starting compound (Scheme 1). The key transformations involve cyclopropanation of the C@C double bond, which in turn can be obtained by the ketone olefination.

COOH

N H

COOH

N H

1

N H

2

COOH 4

7

10

N H

COOH

COOH

COOH

N H 8

COOH

3

6

N H

COOH

COOH

N H

5

N H

N H

COOH

N H

N H

9 COOH

11

N H

COOH 12

Figure 1. Proline and its cyclopropane-containing analogues.

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A. V. Tymtsunik et al. / Tetrahedron Letters 53 (2012) 3847–3849

N H

COOR

N

COOH

conditions, namely, using trifluoroacetic acid as a promoter for the reaction between 15, diethylzinc, and diiodomethane.12 In this reaction, the Boc protecting group was partially cleaved, and a mixture of (S)-17 and (S)-18 was obtained. This mixture was subjected to Boc-derivatization to give (S)-1713 which was used in the next step without purification. Hydrolysis of (S)-17 led to the Boc derivative (S)-19 of the target amino acid 9 (34% yield from 15).14 To determine the optical purity of (S)-19, it was transformed into methyloxycarbonyl derivative (S)-20 using a standard protocol.15 A racemic sample of 20 was also prepared from 15 to be used as a reference. Chiral stationary phase HPLC analysis16 showed that no racemization occurred during the cyclopropanation step, and the final compound was obtained as a single enantiomer. In conclusion, an approach to the synthesis of (6S)-5-azaspiro[2.4]heptane-6-carboxylic acid, a novel member of the cyclopropane-modified proline library, has been developed. The synthetic scheme consisted of six steps starting from (2S,4R)-4-hydroxyproline and resulted in a 5% total yield of the title compound. The drawback of this scheme is the methylenation of the corresponding 4-ketoproline derivative 14 with Tebbe’s reagent, which proceeded in a modest 25% yield; further optimization of this step might include using alternative olefination conditions.17 In principle, the approach used in the presented synthesis – cyclopropanation of an appropriate unsaturated amino acid derivative – might be extended to the remaining members of the cyclopropane-modified proline library, namely, compounds 10–12.

PG

9

O

HO

N H

COOH

COOR

N PG

13

Scheme 1. Retrosynthetic analysis of 9.

Although the described retrosynthesis took advantage of wellknown reactions, the correct choice of specific synthetic methods to carry out these transformations required some experimentation. The starting material, (2S,4R)-4-hydroxyproline (13) was easily converted into ketone 14 using procedures reported previously (Scheme 2).7 Next, we employed the Wittig reaction for the olefination of 14; the corresponding transformation has been described for analogous substrates in a number of previous reports.8 In our hands, almost complete racemization occurred under the conditions described in the literature, and the alkene 15 was obtained in 38% yield with only 3% ee.9 Hence, we considered Tebbe’s reagent (16) as a possible alternative for the olefination.8d,10 Under these conditions, the reaction proceeded smoothly to give (S)-15 as a single enantiomer in 25% yield (after column chromatography) with >98% ee.11 The following reaction of 15 with the carbene generated catalytically from diazomethane gave disappointing results, the best yield of 17 was ca. 25% (measured by 1H NMR spectroscopy), with CuCl as the catalyst. Classical Simmons–Smith reaction (ZnEt2, CH2I2) gave better yields of the desired products, however, the cyclopropanation proceeded very slowly. Satisfactory yields and acceptable reaction rates were achieved only under modified

Acknowledgments The authors thank Olga V. Manoylenko for the chromatographic separations and Vitaly Polovinko for NMR spectral measurements. References and notes 1. Salaun, J. Cyclopropane Derivatives and Their Diverse Biological Activities. In Small Ring Compounds in Organic Synthesis VI; Springer-Verlag: Berlin, 1999; p p. 240. 2. (a) Stammer, C. H. Tetrahedron 1990, 46, 2231–2254; (b) Komarov, I. V.; Grigorenko, A. O.; Turov, A. V.; Khilya, V. P. Russ. Chem. Rev. 2004, 73, 785–810; (c) Medda, A. K.; Lee, H.-S. Synlett 2009, 921–924; (d) Hercouet, A.; Bessieres, B.; Le Corre, M. Tetrahedron: Asymmetry 1996, 7, 1267–1268; (e) Hanessian, S.;

HO

HO

HO

.HCl

SOCl2/MeOH OH

N H 13

100%

N H

O

Boc2O/Et3N O

100%

O

Boc

Cp2Ti O N Boc (S)-17

O

+ N H

O

O

ZnEt2

O

CH2I2 TFA

O Boc (S)-15

(S)-18

16

+

Cl Al 25%

N

O

N O

NaIO4, RuCl3 82% O

Boc

N Boc (S)-19

O

O 14 Ph3P+-CH2-

1. Boc2O, Et3N 34% (from 15) 2. NaOH

OH

O

N

38%

1. MeOH, SOCl2 2. MeOC(O)Cl, Et 3N 92%

O N O

O OMe (S)-20

Scheme 2. Synthesis of (S)-19.

O N Boc

O 15

A. V. Tymtsunik et al. / Tetrahedron Letters 53 (2012) 3847–3849

3.

4.

5. 6. 7.

8.

9.

10. 11.

Reinhold, U.; Saulnier, M.; Claridge, S. Bioorg. Med. Chem. Lett. 1998, 8, 2123– 2128; (f) Mori, M.; Kubo, Y.; Ban, Y. Tetrahedron 1988, 44, 4321–4330. For some recent reviews on conformationally restricted molecules, see: (a) Cativiela, C.; Ordóñez, M. Tetrahedron: Asymmetry 2009, 20, 1–63; (b) Trabocchi, A.; Scarpi, D.; Guarna, A. Amino Acids 2008, 34, 1–24; (c) Grygorenko, O. O.; Radchenko, D. S.; Volochnyuk, D. M.; Tolmachev, A. A.; Komarov, I. V. Chem. Rev. 2011, 111, 5506–5568; (d) Soloshonok, V. A. Curr. Org. Chem. 2002, 6, 341–364. The proline analogue 11 was described in the literature as an antibiotic isolated from the culture filtrate of Streptomyces zaomiceticus: (a) Shimura, M.; Iwata, M.; Omoto, S.; Sekizawa, Y. Agric. Biol. Chem. 1979, 43, 2271–2279; (b) Kodama, Y.; Ito, T. Agric. Biol. Chem. 1980, 44, 73–76. Its synthesis, to the best of our knowledge, is still not reported.. Tandon, M.; Wu, M.; Begley, T. P. Bioorg. Med. Chem. Lett. 1998, 8, 1139–1144. Petter, R. C. Tetrahedron Lett. 1989, 30, 399–402. (a) Cheng, M.; De, B.; Almstead, N. G.; Pikul, S.; Dowty, M. E.; Dietsch, C. R.; Dunaway, C. M.; Gu, F.; Hsieh, L. C.; Janusz, M. J.; Taiwo, Y. O.; Natchus, M. G. J. Med. Chem. 1999, 42, 5426–5436; (b) Qiu, X.-l.; Qing, F.-l. J. Org. Chem. 2002, 67, 7162–7164; (c) Schumacher, K. K.; Jiang, J.; Joullié, M. M. Tetrahedron: Asymmetry 1998, 17, 47–53; (d) Grygorenko, O. O.; Komarov, I. V.; Cativiela, C. Tetrahedron: Asymmetry 2009, 20, 1433–1436. (a) Manfré, F.; Kern, J.-M.; Biellmann, J.-F. J. Org. Chem. 1992, 57, 2060–2065; (b) Cheng, M.; De, B.; Pikul, S.; Almstead, N. G.; Natchus, M. G.; Anastasio, M. V.; McPhail, S. J.; Snider, C. E.; Taiwo, Y. O.; Chen, L.; Dunaway, C. M.; Gu, F.; Dowty, M. E.; Mieling, G. E.; Janusz, M. J.; Wang-Weigand, S. J. Med. Chem. 1999, 42, 5426–5436; (c) Shi, W.; Ma, H.; Duan, Y.; Yang, L.; Hu, W.; Aubart, K.; Fang, Y.; Zonis, R. Bioorg. Med. Chem. Lett. 2011, 21, 1060–1063; (d) Arakawa, Y.; Yagi, N.; Arakawa, Y.; Tanaka, K.-I.; Yoshifuji, S. Chem. Pharm. Bull. 2009, 57, 167–176; (e) Herdewijn, P.; Claes, P. J.; Vanderhaeghe, H. Can. J. Chem. 1982, 60, 2903– 2907. The enantiomeric excess of 15 was determined by HPLC analysis which was carried out by injection of 2 lL of a 1 g/L solution into a 4.6  250 mm ChiralPack IAÒ column using hexane-2-propanol (95:5) as eluent (flow rate: 0.6 mL/min) with UV monitoring performed at 215 nm. Resolution parameters: Rt [(R)-15] = 9.3 min, Rt [(S)-15] = 10.8 min. Murphy, A. C.; Mitova, M. I.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod. 2008, 71, 806–809. Procedure for the preparation of 1-tert-butyl-2-methyl-(2S)-4-methylenepyrrolidine-1,2-dicarboxylate [(S)-15]: To a suspension of Cp2TiCl2 (10.5 g, 42 mmol) in dry toluene (10 mL), Me3Al (46.4 mL, 2 M in toluene, 93 mmol) was added at rt. The mixture was stirred for 3 d at rt under an argon atmosphere, and then an additional portion of Me3Al (17 mL, 2 M in toluene, 34 mmol) was added. The resulting mixture was stirred overnight at rt and evaporated to dryness in vacuo without external heating. The residue was dissolved in toluene (120 mL). The resulting solution of Tebbe’s reagent18 was added dropwise to a solution of (S)-14 (13.2 g, 54 mmol) in dry THF (150 mL) under an argon atmosphere at 78 °C. The resulting mixture was stirred at 78 °C for 2 h and at rt for 1 d. Next, dry THF (50 mL) was added, and the resulting mixture was stirred vigorously for 15 min, and then cooled to 10 °C. A 10% aq K2CO3 solution (150 mL) was added with vigorous stirring. The resulting mixture was filtered through a silica gel pad and washed with THF (3  50 mL). The filtrate was evaporated in vacuo, and the residue diluted with Et2O (250 mL). The resulting suspension was dried over Na2SO4 overnight, filtered, and evaporated in vacuo. The residue was purified by column chromatography (hexanes-EtOAc, 5:1) as eluent, Rf = 0.56) to give (S)-15 (2.56 g, 25% from Cp2TiCl2; 19% from (S)-14). ½a20 D = 29.4 (c 1.0, MeOH). Anal. Calcd for C12H19NO4 C 59.73, H 7.94, N 5.80. Found C 59.38, H 8.25, N 5.94. 1H NMR (500 MHz, CDCl3, d): 5.01 (s, 0.5H), 4.98 (s, 1.5H), 4.49 (d, J = 9.1 Hz, 0.5H),

12. 13.

14.

15. 16.

17.

18.

3849

4.38 (dd, J = 9.1 Hz and 2.5 Hz, 0.5H), 4.08 (br s, 1H), 4.04 (br s, 1H), 3.71 (s, 3H), 2.88–3.01 (s, 1H), 2.65 (br s, 0.5H), 2.59 (br s, 0.5H), 1.46 (s, 4.5H), 1.41 (s, 4.5H). 13C NMR (125 MHz, CDCl3, d): 173.1 and 172.8 (C), 154.4 and 153.7 (C), 143.5 and 142.4 (C), 107.9 and 107.7 (CH2), 80.1 (C), 59.1 and 58.6 (CH), 52.1 and 52.0 (CH3), 50.8 and 50.6 (CH2), 36.8 and 36.0 (CH2), 28.4 and 28.3 (CH3). Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 8621–8624. (6S)-5-tert-Butyl-6-methyl-5-azaspiro[2.4]heptane-5,6-dicarboxylate (17): 1H NMR (500 MHz, CDCl3, d): 4.46 (dd, J = 3.0 and 8.5 Hz, 0.5H), 4.36 (dd, J = 3.0 and 8.5 Hz, 0.5H), 3.72 (s, 3H), 3.37 (m, 1H), 3.30 (m, 1H), 2.22 (m, 1H), 1.75 (m, 1H), 1.45 (s, 4.5H), 1.41 (s, 4.5H), 0.3–0.6 (m, 4H). 13C NMR (125 MHz, CDCl3, d): 174.2 and 173.1, 79.9, 59.6 and 59.2, 54.1 and 53.7, 52.0 and 51.8, 39.1 and 38.3, 28.4, 21.4, 20.7, 20.1, 12.4, 11.6, 9.6, 8.9, 1.0. Procedure for the preparation of (6S)-5-(tert-butoxycarbonyl)-5azaspiro[2.4]heptane-6-carboxylic acid [(S)-19]: Et2Zn (48 mL, 15% in hexane, 41 mmol) was added to dry CH2Cl2 (40 mL) under an argon atmosphere. The solution was cooled to 5 °C, and TFA (3.03 mL, 41 mmol) was added dropwise slowly and carefully. The resulting mixture was stirred at this temperature for 30 min. A solution of CH2I2 (3.28 mL, 41 mmol) in dry CH2Cl2 was added dropwise at 5 °C, and the mixture stirred at this temperature for 1 h. Next, a solution of (S)-15 (0.82 g, 3.4 mmol) in absolute CH2Cl2 (30 mL) was added dropwise at 5 °C. The resulting mixture was stirred at 30 °C for 3 d, and then cooled to 0 °C. Saturated aq NH4Cl (50 mL) was added dropwise at this temperature, and the resulting mixture stirred for 1 h. The organic phase was separated, and the aqueous phase washed with CH2Cl2 (4  20 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give a crude mixture (1.58 g) containing (S)-17 and (S)-18 which was dissolved in EtOAc (30 mL). Et3N (1.6 mL) and Boc2O (1.6 g) were added, and the mixture stirred at rt for 1 d, then filtered and acidified with 0.3 M aq NaHSO4 to pH = 1–2. The organic phase was separated, and the product extracted from the aqueous phase with EtOAc (4  20 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give crude (S)-17 (1.85 g).13 Attempts to purify the residue by column chromatography led to a considerable loss of the product. Therefore crude (S)-17 was dissolved in EtOH (20 mL), and a solution of NaOH (1 g) in H2O (20 mL) was added. The resulting mixture was stirred for 1 d and then evaporated to dryness. The residue was triturated with Et2O (40 mL) and filtered. The precipitate was washed with Et2O (25 mL), and then dissolved in H2O (50 mL). The solution was acidified with 1 M aq KHSO4 to pH = 2, extracted with CH2Cl2 (4  30 mL), dried over Na2SO4 and evaporated in vacuo to give (S)-19 (0.28 g, 34% from (S)-15, >95% by NMR). Anal. Calcd for C12H19NO4 C 59.73, H 7.94, N 5.80. Found C 60.02, H 8.36, N 5.63. 1H NMR (500 MHz, CDCl3, d): 9.76 (br s, 1H), 4.48 (br s, 0.5H), 4.39 (br s, 0.5H), 3.44 (d, J = 9.2 Hz, 0.5H), 3.39 (br s, 1H), 3.16 (d, J = 9.2 Hz, 0.5H), 2.25–2.31 (m, 1H), 2.00 (d, J = 12.2 Hz, 0.5H), 1.93 (d, J = 12.2 Hz, 0.5H), 1.47 (s, 4.5H), 1.43 (s, 4.5H), 0.55–0.67 (m, 4H). 13C NMR (125 MHz, CDCl3, d): 178.4 and 174.8, 156.2 and 153.8, 81.4 and 80.4, 59.6 and 59.4, 54.4 and 53.6, 38.9 and 36.5, 28.39 and 28.32, 20.6 and 20.1, 13.1 and 11.7, 9.3 and 7.7. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd; John Wiley & Sons Inc: New York, 1991. p. 779. The enantiomeric excess of 20 was determined by HPLC analysis which was carried out by injection of 3 lL of a 1 g/L solution into a 4.6  250 mm Ò ChiralPack IB column using hexane-2-propanol (80:20) as eluent (flow rate: 0.5 mL/min) with UV monitoring performed at 225 nm. Resolution parameters: Rt [(R)-20] = 24.4 min, Rt [(S)-20] = 10.7 min. (a)Modern carbonyl olefination: methods and applications; Takeda, T., Ed.; WileyVCH: Weinheim, 2004. p. 365; (b) Korotchenko, V. N.; Nenajdenko, V. G.; Balenkova, E. S.; Shastin, A. V. Russ. Chem. Rev. 2004, 73, 957–989. Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386–2387.