Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile building block

Tetrahedron 71 (2015) 5597e5601

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Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile building block €rstner, Alicia M. Dilmac Hartmut Schirok *, Nils Griebenow, Chantal Fu Bayer HealthCare Pharmaceuticals AG, Global Drug Discovery, Medicinal Chemistry Wuppertal, Building 460, D-42096 Wuppertal, Germany

a r t i c l e i n f o

a b s t r a c t

Article history: Received 2 March 2015 Received in revised form 10 June 2015 Accepted 12 June 2015 Available online 23 June 2015

A one-pot multigram synthesis of 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine starting from 2fluoropyridine using directed ortho metallation (DoM) technique is described. The compound contains an anionically activatable trifluoromethyl group and is a versatile building block for the microwave assisted synthesis of 3-substituted 1H-pyrazolo[3,4-b]pyridines. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Directed ortho metallation Pyrazolopyridine Trifluoromethyl Anionic activation Microwave assisted synthesis

O

1. Introduction The discovery of new synthetic methods to further expand the toolbox that allows for the rapid exploration and customization of the pharmaceutical diversity space is one major focus for organic chemists. Within this context, the synthesis of so-called ‘privileged structures’1 is of considerable interest, because such structures combine drug-like properties with the ability to address various biological targets, depending on their substitution pattern. Examples include the synthesis of benzodiazepines,2 benzopyrans,3 biphenyls,4 phenyl piperazines,5 and spiro-piperidines.6 In the course of our ongoing efforts directed towards the synthesis of novel scaffolds for medicinal chemistry purposes, we were interested in the diversification of the 1H-pyrazolo[3,4-b]pyridine scaffold, another example of a ‘privileged structure’. 1H-Pyrazolo[3,4-b]pyridines, when appropriately substituted, exert potent and selective actions at diverse sets of protein targets, including G proteincoupled receptors, lyases and DNA polymerases. Besides their well-known vasodilatatory activity found in therapeutics such as Riociguat (A)7 1H-pyrazolo[3,4-b]pyridines have also demonstrated activities as reverse transcriptase inhibitors represented by B,8 phosphodiesterase IV inhibitors such as C,9 and adenosine A2B receptor antagonists exemplified by D.10

* Corresponding author. Tel.: þ49 202 363926; fax: þ49 202 368149; e-mail address: [email protected] (H. Schirok). http://dx.doi.org/10.1016/j.tet.2015.06.050 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

N

H2N N

Cl O

O NH2

Cl

N

O N

N N

N

H2N

N

N H

N

F Riociguat (A)

O

O HN

N

O O

H2N

N N

(B)

N

(C)

N

N

O

NH2 N N

N H

(D)

In one of our drug discovery projects we required 1H-pyrazolo [3,4-b]pyridine-3-carbonitrile (4) as a key building block.11 Initially, the synthesis was established via 3-amino-pyrazolo-pyridine 2, prepared from commercially available 2-chloro-3-cyanopyridine (1) and hydrazine hydrate (Scheme 1).12 Diazotation followed by treatment with sodium iodide in acetone provided 3-iodo-1Hpyrazolo[3,4-b]pyridine (3),13 which was further transformed into nitrile 4 with copper(I) cyanide in DMF. This synthetic route suffered from moderate to low yields of 39% and 26% in the final two

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steps. Alternatively, we demonstrated the possibility to convert aminoderivative 2 directly into the desired cyanide 4. However, the overall yield remained low (15e35%). Thus, alternative synthetic routes were considered.

Scheme 1. Reagents and conditions: (a) N2H4H2O, EtOH, reflux. (b) 1. BF3OEt2, isoamylnitrite, THF, 10  C; 2. NaI, acetone, 0e5  C / rt. (c) CuCN, DMF, 135  C. (d) 1. BF3OEt2, isoamylnitrite, THF, 10  C; 2. CuCN, acetonitrile, 0  C / rt.

Recently, we developed a high-yielding synthesis of a 3-cyano7-azaindole 8 based on anionic activation14 of trifluoromethyl analog 6, which undergoes rapid aminolysis via highly reactive methide intermediate 7 (Scheme 2).15 An analogous pathway to nitrile 4 would start from the trifluoromethyl substituted pyrazolopyridine 12 (Scheme 3). On the basis of our work on CF3azaindoles,16 we prepared 3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridine in a one-pot procedure from 2-fluoropyridine (5).11

charcoal, the trifluoromethyl compound 12 was essentially pure and needed no further purification. The trifluoromethyl substituted pyrazolopyridine 12 proved to be much less reactive than the corresponding azaindole 6. Stirring in aqueous ammonia at 60  C led to a clean conversion of 3trifluoromethyl substituted 7-azaindole 6 to the 3-cyano derivative within hours, whereas the reaction of pyrazolopyridine 12 was still not complete after heating overnight. With sodium amide in toluene at room temperature and even at 100  C, 12 remained unchanged. A direct comparison of the stability of 3-trifluoromethyl-7azaindole (6, R¼H) and 3-(trifluoromethyl)-1H-pyrazolo[3,4-b] pyridine (12) in aqueous solution at pH 10 and 37  C demonstrated impressively the difference in reactivity of both compounds (Fig. 1). Whilst the azaindole 6 was completely hydrolyzed to the acid within less than 4 h, the pyrazolopyridine 12 remained unchanged under these conditions. These results are in concordance with the recent report by Ermolenko et al., according to which the hydrolysis

Scheme 2. Synthesis of 3-cyano-7-azaindole 8.15,16

Fig. 1. Stability of 6 and 12 at pH 10 and 37  C. Scheme 3. Reagents and conditions: (a) LDA, THF, 78 N2H4H2O, reflux.

 C;

then CF3COOEt; then

The ortho lithiation of 2-fluoropyridine (5) is based on the acidifying effect of the halogen atom and is a powerful method of introducing functional groups to an aromatic nucleus. As shown in guiner17 and extensive investigations mainly done by Que 18 Schlosser, lithium-bases, commonly lithium diisopropylamide, promote a hydrogen/metal exchange at the 3-position. The reaction conditions of the deprotonation reported in the literature vary from 78  C to 0  C and from 1 to 4 h. When we warmed the lithiation reaction mixture to temperatures above 40  C, the mixture turned brownish and increasing amounts of o-diisopropylaminopyridine could be identified as byproduct.19 This aromatic substitution reaction20 could best be avoided by performing the deprotonation at 78  C for 4 h. Subsequently, trifluoroacetic acid ethyl ester was added as an electrophile and reacted instantaneously. After aqueous work-up, we isolated the hydrate of the trifluoroacetyl compound (Scheme 3) rather than the carbonyl compound 9 itself.21 This hydrate could be purified by sublimation and dehydrated by azeotropic distillation with toluene.22 Later-on we discovered that the isolation of intermediate 9 was dispensable. When we added hydrazine hydrate to the reaction mixture and stirred it at slightly elevated temperatures for several hours, the desired bicyclic compound 12 was formed (Scheme 3). The work-up was very simple, since all components of the crude mixture except the target compound are water soluble. After treatment of the crude product with

of 5-substituted-3-trifluoromethylpyrazoles requires microwave heating.23 Yang et al. prepared 3-cyanopyrazoles from 3trifluoromethyl analogs in aqueous ammonia in sealed tubes.24 Similarly, when 12 was heated in aqueous ammonia to 140  C in sealed tubes in a microwave oven the desired nitrile 4 was formed in 90% yield (Scheme 4). Concomitant ammonium fluoride was separated by trituration with hot ethyl acetate/tert-butyl methyl ether and filtration. The product contained up to 10% of the corresponding primary amide, which could be separated by chromatography.

Scheme 4. Reagents and conditions: (a) aq NH3-solution, mW, 140  C. (b) BnBr, Cs2CO3, DMF, rt.

H. Schirok et al. / Tetrahedron 71 (2015) 5597e5601

To gain further insight into the mechanism of this transformation, we protected the acidic nitrogen in 12 by benzylation (Scheme 4). According to the assumption that the reactivity of 12 relies on the push-pull system present in the molecule, and that Ndeprotonation is required previous to the reaction with a nucleophile, the N-benzylated compound 14 did not react under the described reaction conditions in the microwave oven. In addition, we examined the stability of compounds 12 and 14 in 1 N sodium hydroxide solution at 50  C. We found the N-benzylated compound 14 stable under these conditions, whilst 80% of the unprotected pyrazolopyridine 12 was consumed after the same period of time (see Fig. 2).

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Table 1 Reaction of 12 with different nucleophiles

CF3

R

150 °C μW

N N H

N 12 Entry

Nucleophile

1

aq NH3

N nucleophile (Table 1) aq. NaOH

N

N H

4, 16-21

Product

Yield %

CN N N

O

O

2

N H

16

95

17

42

18

82

19

63

20

40

21

64

N N H

N

N

H2N NH2

N N

N H

O

4

90

O

N

HN

3

4

N H

N

HO NH2

N N

N H

N

5

O

N

HO

NH2

Fig. 2. Stability of 12 and 14 in 1 N NaOH at 50  C.

N N

We previously reported on the syntheses of heterocycle substituted 1H-pyrazolo[3,4-b]pyridines in 3e4 steps starting from 4.11c Herein, we show that such compounds are also easily accessible in a single synthetic step from 12. Indeed, applying microwave heating, the trifluoromethyl compound 12 reacts with other nucleophiles, and several heterocycle substituted 1H-pyrazolo[3,4-b] pyridines were synthesized (Table 1). In aqueous sodium hydroxide solution as solvent and with an amine present, amides were isolated, as for example the morpholide 16 (entry 2), which was isolated in 95% yield. Binucleophilic reagents gave heteroaromatics:25 1,2-diaminobenzene yielded benzimidazole 17 (entry 3), and 2aminophenol reacted to benzoxazole 18 (entry 4). Hydrazinocarbothiamides afforded thiadiazoles 20 and 21 (entry 6 and 7). In summary we have developed an efficient one-pot synthesis of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine from 2-fluoro pyridine. It was shown to be much less reactive than its carbon analog, 3-trifluoromethyl-7-azaindole. However, we demonstrated its use as a versatile building block under microwave assisted heating giving rapid access to various 3-substituted 1H-pyrazolo[3,4-b]pyridines in moderate to high yields.

2. Experimental Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. Flash chromatography was done on silica gel 60 (0.063e0.200 mm) from Merck KgaA, Darmstadt, Germany. Preparative HPLC chromatography was done on a 250 mm30 mm column packed with YMC gel ODS-AQ S5/15 mM, with acetonitrile/water as eluent and UV-

N

N H Me2N

6

H N

Me2N

N N

S

NH2

S

N N

N H

MeNPh

7

Ph MeN

H N

N N

S NH2

S

N N

N H

detection. All 1H NMR and 13C NMR spectra were recorded in DMSO-d6. Spin multiplicities are given as s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet) as well as br (broad). All microwave irradiation experiments were carried out using the EmrysÔ optimizer microwave from Biotage. The reactions were performed in Biotage microwave vials (for 0.5e2 mL or 2e5 mL) sealed with a septum. The power range was up to 300 W at 2.45 GHz. 2.1. 3-(Trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (12) To a solution of freshly prepared LDA (108 mmol) in THF (180 mL) at 75  C was added 2-fluoropyridine (7.00 g, 72.1 mmol), and the mixture was stirred for 4 h at this temperature. Ethyl trifluoroacetate (18.4 g, 130 mmol) was added quickly.

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The internal temperature raised to 40  C. The mixture was cooled again to 75  C, and hydrazine hydrate (28.9 g, 577 mmol) was added. The reaction was heated to 70  C for 6 h. Subsequently, volatile components were removed in vacuo. Water (300 mL) was added, and the mixture was heated to reflux and filtered. The residue was dissolved in ethyl acetate (300 mL) and this solution was dried over sodium sulfate, stirred with charcoal and filtrated. After evaporation of the solvent, 7.86 g (55%) of the title compound was obtained as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): d 7.43 (dd, J¼8.1, 4.4 Hz, 1H), 8.34 (d, J¼8.1 Hz, 1H), 8.72 (dd, J¼4.4, 1.5 Hz, 1H), 14.67 (br s, 1H). 13C NMR (125 MHz, DMSOd6): d 110.7, 119.1, 121.5 (q, 1JC,F¼269 Hz), 128.7, 132.5 (q, 2 JC,F¼38.2 Hz), 150.6, 151.7. HRMS m/z calcd for C7H4F3N3: 187.0357; found: 187.0357. 2.2. 1H-Pyrazolo[3,4-b]pyridine-3-carbonitrile (4) Compound 12 (500 mg, 2.67 mmol) was suspended in aqueous ammonia solution (33%, 10 mL). The mixture was heated in a sealed tube in the microwave oven to 140  C for 10 min. Volatiles were evaporated. To the residue was added ethyl acetate (100 mL) and tert-butyl methyl ether (25 mL), and the mixture was heated to 70  C. The hot mixture was filtered, and the residue was washed with tert-butyl methyl ether. The combined filtrates were evaporated to yield the title compound as slightly yellow residue (389 mg, 90%), which contained traces of corresponding primary amide. 1H NMR (400 MHz, DMSO-d6): d 7.47 (dd, J¼8.2, 4.5 Hz, 1H), 8.46 (dd, J¼8.2, 1.5 Hz, 1H), 8.73 (dd, J¼4.5, 1.5 Hz, 1H), 15.02 (br s, 1H). 13C NMR (125 MHz, DMSO-d6): d 113.5, 115.5, 116.9, 119.6, 128.7, 150.9, 151.0. HRMS m/z calcd for C7H4N4: 144.0436; found: 144.0430. 2.3. 1-Benzyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (14) A mixture of compound 12 (50 mg, 0.27 mmol), benzylbromide (50 mg, 0.29 mmol) and caesiumcarbonate (104 mg, 0.32 mmol) was stirred overnight at room temperature in DMF (1.0 mL). It was then diluted with tert-butyl methyl ether and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated. The crude product was purified by column chromatography (eluent: cyclohexane/ethyl acetate 3:1) to yield 50 mg (67%) of the title compound. 1H NMR (400 MHz, DMSO-d6): d 5.82 (s, 2H), 7.26e7.37 (m, 5H), 7.50 (dd, J¼8.2, 4.5 Hz, 1H), 8.39 (d, J¼8.2 Hz, 1H), 8.79 (dd, J¼4.5, 1.2 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): d 50.8, 111.4 (q, 1JC,F¼1.4 Hz), 119.7, 121.4 (q, 1 JC,F¼269 Hz), 127.7, 127.9, 128.7, 129.3, 131.5 (q, 2JC,F¼38.6 Hz), 136.2, 149.8, 151.0. HRMS m/z calcd for C14H10F3N3: 277.0827; found: 277.0825. 2.4. 3-(Morpholin-4-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridine (16) To compound 12 (100 mg, 0.53 mmol) and morpholine (93 mg, 1.07 mmol) was added a 1 N aqueous sodium hydroxide solution (2.0 mL), and the mixture was heated in a microwave oven to 150  C for 10 min. The mixture was extracted with ethyl acetate, neutralized with 4 N HCl solution and again extracted. The combined organic layers were dried over sodium sulfate, and the solvent was evaporated to yield 117 mg (95%) of the title compound. 1H NMR (400 MHz, DMSO-d6): d 3.63e3.75 (m, 6H), 4.07e4.15 (m, 2H), 7.32 (dd, J¼8.1, 4.5 Hz, 1H), 8.42 (dd, J¼8.1, 1.5 Hz, 1H), 8.60 (dd, J¼4.5, 1.5 Hz, 1H), 14.15 (br s, 1H). 13C NMR (125 MHz, DMSO-d6): d 42.3, 46.9, 66.1, 66.4, 114.8, 118.2, 131.1, 138.1, 149.5, 151.6, 161.0. HRMS m/ z calcd for C11H12N4O2: 232.0960; found: 232.0962.

2.5. 3-(1H-Benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine (17) To compound 12 (150 mg, 0.80 mmol) and benzene-1,2-diamine (104 mg, 0.96 mmol) was added a 1 N aqueous sodium hydroxide solution (3.0 mL), and the mixture was heated in a microwave oven to 150  C for 10 min. The mixture was diluted with water and extracted twice with ethyl acetate. The solvent was evaporated, and the residue was purified by preparative HPLC to yield 80 mg (42%) of the title compound as a white solid. 1H NMR (400 MHz, DMSOd6): d 7.19e7.29 (m, 2H), 7.39 (dd, J¼8.1, 4.4 Hz, 1H), 7.53 (d, J¼7.1 Hz, 1H), 7.74 (d, J¼7.1 Hz, 1H), 8.65 (dd, J¼4.4, 1.0 Hz, 1H), 8.85 (dd, J¼7.8, 1.0 Hz, 1H), 13.12 (br s, 1H), 14.19 (br s, 1H). 13C NMR (125 MHz, DMSO-d6): d 111.5, 112.8, 118.2, 119.0, 121.6, 122.9, 131.3, 134.2, 135.6, 143.8, 146.5, 149.7, 152.7. HRMS m/z calcd for C13H9N5 þ [Hþ]: 236.0931; found: 236.0936. 2.6. 3-(1,3-Benzoxazol-2-yl)-1H-pyrazolo[3,4-b]pyridine (18) To compound 12 (50 mg, 0.27 mmol) and 2-aminophenol (35 mg, 0.32 mmol) was added a 1 N aqueous sodium hydroxide solution (0.75 mL), and the mixture was heated in a microwave oven to 150  C for 10 min. It was then diluted with water and extracted twice with ethyl acetate. 4 N HCl solution was added (pH 4), and the mixture was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, and the solvent was evaporated. The residue was purified by preparative HPLC to yield 52 mg (82%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): d 7.44e7.52 (m, 3H), 7.89 (t, J¼8.4 Hz, 2H), 8.71 (d, J¼4.4 Hz, 1H), 8.76 (d, J¼8.1 Hz, 1H), 14.42 (br s, 1H). 13C NMR (125 MHz, DMSOd6): d 111.0, 113.3, 118.9, 119.8, 125.0, 125.8, 130.4, 131.9, 141.1, 149.5, 150.1, 152.3, 157.4. HRMS m/z calcd for C13H8N4O: 236.0698; found: 236.0698. 2.7. 2-(1H-Pyrazolo[3,4-b]pyridin-3-yl)[1,3]oxazolo[4,5-b]pyridine (19) To compound 12 (150 mg, 0.80 mmol) and 2-amino-pyridin-3ol (106 mg, 0.32 mmol) was added a 1 N aqueous sodium hydroxide solution (3.0 mL), and the mixture was heated in a microwave oven to 150  C for 10 min. The precipitate was collected by suction filtration and washed with methanol to yield 120 mg (63%) of the title compound. 1H NMR (400 MHz, DMSO-d6): d 7.51 (dd, J¼8.1, 4.6 Hz, 1H), 7.52 (dd, J¼8.3, 4.9 Hz, 1H), 8.33 (dd, J¼8.3, 1.2 Hz, 1H), 8.61 (dd, J¼4.9, 1.2 Hz, 1H), 8.73 (dd, J¼4.6, 1.5 Hz, 1H), 8.78 (dd, J¼8.1, 1.5 Hz, 1H), 14.72 (br s, 1H). 13C NMR (125 MHz, DMSO-d6): d 113.6, 119.2, 120.9, 130.4, 131.4, 142.0, 146.6, 150.2, 152.4, 155.2, 159.8. HRMS m/z calcd for C12H7N5O þ [Hþ]: 238.0724; found: 238.0724. 2.8. N,N-Dimethyl-5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1,3,4thiadiazol-2-amine (20) To compound 12 (200 mg, 1.07 mmol) and N,N-dimethylhydrazinecarbothioamide (153 mg, 1.28 mmol) was added a 1 N aqueous sodium hydroxide solution (4.0 mL), and the mixture was heated in a microwave oven to 150  C for 10 min. The precipitate was collected by suction filtration and washed with water to yield 106 mg (40%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): d 3.18 (s, 6H), 7.36 (dd, J¼8.0, 4.4 Hz, 1H), 8.59 (dd, J¼8.0, 1.5 Hz, 1H), 8.63 (dd, J¼4.4, 1.5 Hz, 1H), 14.08 (br s, 1H). 13 C NMR (125 MHz, DMSO-d6): d 41.1, 111.4, 118.3, 130.8, 136.3, 150.0, 151.2, 152.4, 170.4. HRMS m/z calcd for C10H10N6S: 246.0688; found: 246.0680.

H. Schirok et al. / Tetrahedron 71 (2015) 5597e5601

2.9. N-Methyl-N-phenyl-5-(1H-pyrazolo[3,4-b]pyridin-3-yl)1,3,4-thiadiazol-2-amine (21) To compound 12 (150 mg, 0.80 mmol) and N-methyl-N-phenylhydrazinecarbothioamide (174 mg, 0.96 mmol) was added a 1 N aqueous sodium hydroxide solution (3.0 mL), and the mixture was heated in a microwave oven to 150  C for 10 min. The mixture was diluted with water and extracted twice with ethyl acetate. The solvent was evaporated, and the residue was purified by preparative HPLC to yield 159 mg (64%) of the title compound as a tan solid. 1H NMR (400 MHz, DMSO-d6): d 3.60 (s, 3H), 7.35e7.40 (m, 2H), 7.52 (t, J¼7.7 Hz, 2H), 7.56e7.59 (m, 2H), 8.60 (dd, J¼7.3, 1.5 Hz, 1H), 8.64 (dd, J¼4.4, 1.5 Hz, 1H), 14.13 (s, 1H). 13C NMR (125 MHz, DMSO-d6): d 40.61, 111.6, 118.5, 124.5, 127.0, 130.0, 130.8, 136.0, 146.5, 150.1, 151.7, 152.5, 169.3. HRMS m/z calcd for C15H12N6S þ [Hþ]: 309.0917; found: 309.0908. Acknowledgements We thank Dr. P. Schmitt, C. Streich, and D. Bauer for recording NMR spectra and helpful discussions. In addition we are grateful to € bschmann and H. Musche for HRMS measurements. G. Wiefel-Hu Supplementary data Supplementary data (Spectral 1H and 13C NMR data for compounds 4, 12, 14, and 16e21.) related to this article can be found at http://dx.doi.org/10.1016/j.tet.2015.06.050. References and notes 1. (a) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem., Int. Ed. 2002, 41, 2879e2890; (b) Song, Y.; Chen, W.; Kang, D.; Zhang, Q.; Zhan, P.; Liu, X. Comb. Chem. High Throughput Screen. 2014, 17, 536e553; (c) Kim, J.; Kim, H.; Park, S. B. J. Am. Chem. Soc. 2014, 136, 14629e14638; (d) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347e361. 2. (a) Ramdas, L.; Bunnin, B. A.; Plunkett, M. J.; Sun, G.; Ellman, J. A.; Gallick, G.; Budde, R. J. A. Arch. Biochem. Biophys. 1999, 368, 394e400; (b) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555e600; (c) Herpin, T. F.; Van Kirk, K. G.; re, R. F. J. Comb. Chem. 2000, 2, 513e521. Salvino, J. M.; Yu, S. T.; Labaudinie 3. Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939e9953. 4. Neustadt, B. R.; Smith, E. M.; Lindo, N.; Nechuta, T.; Bronnenkant, A.; Wu, A.; Armstrong, L.; Kumar, C. Bioorg. Med. Chem. Lett. 1998, 8, 2395e2398.

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