Solid-Phase Synthesis of 2,3-Dihydrobenzo[

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Solid-phase synthesis of 2,3-dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)one 1,1-dioxides with three diversity positions Patricia Trapani, Tereza Volna, and Miroslav Soural ACS Comb. Sci., Just Accepted Manuscript • Publication Date (Web): 10 May 2016 Downloaded from http://pubs.acs.org on May 10, 2016

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ACS Combinatorial Science

Solid-phase synthesis of 2,3-dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)-one 1,1dioxides with three diversity positions Patricia Trapania, Tereza Volnáa and Miroslav Soural a,b* a

Department of Organic Chemistry, Faculty of Science, Palacký University, 771 46 Olomouc, Czech Republic

b

Institute of Molecular and Translation Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 779 00, Olomouc, Czech Republic

*Corresponding author. E-mail: [email protected] *Corresponding author. Phone: +420 585632196, fax: +420 585634465

TOC

Abstract Synthesis of 2,3-dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)-one 1,1-dioxides from polymer-supported α-amino acids is described herein. Different α-amino acids immobilized on Wang resin were sulfonylated with various 2-nitrobenzenesulfonyl chlorides. The resulting 2-nitrobenzenesulfonamides were alkylated with alcohols according to the FukuyamaMitsunobu procedure. After reduction of the nitro group and cleavage from the polymer support, the final intermediates were reacted with thionyl chloride, and target compounds of good crude purity and acceptable overall yields were obtained. The chiral HPLC studies revealed the impact of the cyclization step on the resulting stereochemistry. The developed strategy allows for simple production of desired compounds with the application of parallel/combinatorial solid-phase synthesis using commercially available building blocks.

Introduction

ACS Paragon Plus Environment


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Polymer-supported 2/4-nitrobenzensulfonamides represent excellent intermediates for the preparation of various substances. In the past, different strategies have been used to obtain number of diverse heterocyclic moieties, including “privileged scaffolds”.1 In the case of immobilized 2-nitrobenzenesulfonamides, the nitro group was reduced followed by subsequent inter/intramolecular cyclization with aldehydes,2 ketones3 or isothiocyanates.4 In this way, three types of cyclic benzenesulfonamides based on 6 or 7-membered rings have been synthesized (Figure 1). Figure

1:

Cyclic

benzenesulfonamides

accessible

from

polymer-supported

2-

polymer-supported

2-

nitrobenzenesulfonamides

Our

intention

was

to

further

extend

the

chemistry

of

nitrobenzenesulfonamides to prepare selected benzothiadiazepine 1,1-dioxides. Although compounds based on the benzo[f][1,2,5]thiadiazepine 1,1-dioxide scaffold have been rarely studied, their antiarrhythmic,5 anti-HIV6,7 and anticancer8 activity (Figure 2) make these molecules attractive for medicinal chemistry. Further, the target scaffold is closely related to to acyl sulfams, the unnatural compounds that have been reported to encompass a variety of activities and recently, their seven-memebred analogues were described.9 Figure 2: Known benzo[f][1,2,5]thiadiazepine 1,1-dioxides with biological properties

In the past, the synthesis of 2,3-dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)-one 1,1dioxides (with R1 limited to H or CH3) was described with the application of traditional solution-phase chemistry.5-7,10 Methylesters of glycine or alanine were used as the starting material. The substituent R3 (see the target scaffold in Figure 1) was introduced by alkylation with alkyl iodides. Our goal was to develop a more versatile approach for the diversification


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of individual positions R1-3. For this purpose, easily available Fmoc-α-amino acids were selected as the starting compounds and Fukuyama-Mitsunobu alkylation11 employing alcohols was chosen to extend the number of available reagents for the R3 position. Taking the large number of available building blocks into account, the solid-phase synthesis concept, which is easily applicable for chemical library production,12 was selected. Results and discussion

The synthetic approach leading to the target compounds is depicted in Scheme 1. To test its applicability, three representative building blocks were selected: Fmoc-Ala, 2nitrobenzenesulfonyl chloride and benzyl alcohol. In the first step, Wang resin was acylated with Fmoc-Ala followed by deprotection with piperidine to obtain the immobilized amino acid 1(1). After sulfonylation with 2-nitrobenzenesulfonyl chloride, polymer supported 2nitrobenzenesulfonamide 2(1,1) was isolated. With use of the standard Fukuyama-Mitsunobu procedure,11 the sulfonamide 2(1,1) was alkylated with benzyl alcohol to yield the resin 3(1,1,1). After nitro group reduction with sodium dithionite,13 the final intermediate 4(1,1,1) of high crude purity (above 95%, characterized by LC-UV-MS after cleavage from the polymer support) was obtained. For the final cyclization, several methods were tested. The first strategy was based on the direct “cyclative cleavage” reported for the traceless synthesis of various heterocycles.14 Unfortunately, we were not able to perform the reaction even under very harsh conditions in high-boiling solvents (dimethylsulfoxide, N,N-dimethylformamide, Nmethylpyrrolidone or 2-methoxyethanol) including catalysis with acetic acid, p-toluenesulfonic acid or DIPEA at temperatures ranging from 100 to 200 ºC (both conventional and microwave heating). In each case, only the starting material 4(1,1,1) was recovered, accompanied by numerous unknown side-products. To increase the reactivity towards intramolecular aminolysis, a different attachment was also tested (see resins 8 and 10, Scheme 2) but the reaction afforded the desired compound 6(1,1,1) only as part of a complex mixture. The second strategy was based on the cleavage of the intermediate 4(1,1,1), its subsequent transformation to methylester 4(1,1,1) and aminolysis in solution-phase. Whereas the esterification was successful and provided the methylester 5(1,1,1) in very good crude purity, the following cyclization was difficult to perform. Although different conditions were used, the final compound 6(1,1,1) was obtained in low purity. Additionally, the reaction was not reproducible on a larger scale. Taking the low reactivity of the amino group into account, we developed a novel strategy based on the in situ preparation of the corresponding acyl chloride and its spontaneous cyclization to a 7-membered scaffold. For this purpose, cleaved intermediate 4(1,1,1) was heated at 50 ºC with 20% thionylchloride in chloroform for 60 minutes. The final compound 6(1,1,1) was obtained as the main product with only minor



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impurities (crude purity 80%, calculated from LC-UV traces). After semipreparative HPLC purification, the product was isolated in 35% yield. Although the final step of the reaction sequence had to be performed in solution-phase, the protocol was still fully compatible with the high-throughput concept due to the volatility of all reagents. To avoid a two-step procedure (cleavage with TFA and cyclization with SOCl2), we also tested the direct use of thionylchloride. However, when the resin 4(1,1,1) was heated with SOCl2, the required product was obtained in very low crude purity. Scheme 1. General synthetic pathway leading to target compounds 6a

a

Reagents:

(i)

Fmoc-amino

acid,

1-hydroxybenzotriazole

(HOBt),

N,N-

diisopropylcarbodiimide (DIC), dimethylformamide (DMF), dichloromethane (DCM), N,Ndimethylpyridin-4-amine (DMAP), rt, 16 hours; (ii) piperidine, DMF, rt, 30 min; (iii) 2nitrobenzenesulfonyl chlorides (Nos-Cls), 2,6-lutidine, DCM, rt, 16 hrs; (iv) alcohols, diisopropyl azodicarboxylate (DIAD), triphenylphosphine (TPP), anhydrous THF, -20 ºC to rt, 16 hrs; (v) Na2S2O4, K2CO3, tetrabutylammonium hydrogen sulfate (TBAHS), DCM, H2O, rt, 16 hours; (vi) 50% trifluoroacetic acid (TFA) in DCM, rt, 1 hour; (vii) 10%TFA in MeOH, reflux, 16 hours; (viii) 20% thionylchloride in chloroform, 50 ºC, 1 hour.

Scheme 2. Unsuccessful attempt to increase the reactivity towards the cyclative cleavagea


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a

Reagents: (i) iodoacetic acid, DIC, DMF, rt, 16 h; (ii) Fmoc-Ala-OH, DIPEA, DMF, DCM rt,

16 h, then piperidine, DMF, rt, 30 min; (iii) a) carbonyldiimidazol (CDI), pyridine, DCM, rt, 3 h, b) ethanolamine, DMSO, rt, 3 h; (iv) Fmoc-Ala-OH, HOBt, DIC, DMF, DCM, DMAP, rt, 16 h, then piperidine, DMF, rt, 30 min. To evaluate the limitation and scope of the method, we subsequently tested various starting materials for each diversity position: Fmoc-amino acids with a different substitution on the side chain to give R1 and 2-nitrobenzenesulfonyl chlorides with electron donating and electron withdrawing groups to give R2. To diversify the R3 position, benzyl alcohol, ethanol, 2-(diethylamino)ethanol, 3-(pyridin-4-yl)propan-1-ol, 2-methoxyethanol and methanol were selected as representative alcohols. All tested building blocks are depicted in Figure 3, and the synthesized derivatives are summarized in Table 1. In each case, the reaction sequence afforded the final compound as the major product of good crude purity accompanied by minor impurities. The exception was detected for methoxy derivative 6(1,3,1), which was obtained after the cyclization step only as a part of a complex mixture, thus giving low overall yield. Limited yields were detected for compounds with basic functional groups (derivatives 6(1,1,4), 6(1,1,3) and 6(5,1,1)) due to the formation of the corresponding salts leading to more demanding purification. The NMR analysis of numerous final compounds purified by semipreparative HPLC revealed contamination originating from the use of TBAHS for the reduction step. To remove the impurity, resins 4(R1,R2,R3) were extensively washed with various solvents without any effect. However, if the resin was heated in DMSO at 100 ºC for 16 hours, the contamination decreased sufficiently and it was completely removed during the final reverse phase HPLC purification. Alternatively, HPLC purified compounds were dissolved in 2 ml of ethyl acetate and filtered through a silicagel column (diameter 1 cm, length 2 cm) to obtain pure compounds. For representative derivatives we have also tested the reduction with tin(II) chloride dihydrate. In the case of compound 6(4,1,1), the reduction afforded the required product.



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However, the resin was strongly contaminated with insoluble tin salts. The removal of the tin salts after cleavage from the polymer support by solid-phase extraction (to avoid clogging of the HPLC semiprep column) was time-consuming and significantly diminished the overall yield. In other cases, the reduction with tin chloride dihydride was successful, but the subsequent cyclization led to mixtures of compounds due to the presence of tin salts.

Figure 3: List of successfully tested building blocks Trt N O 1

Fmoc-amino acids (R )

O

CH3

HO

O

O

HO

OtBu

NHFmoc

HO

FmocN

NHFmoc

HO

N

O

O

NHFmoc 1

OH

NHFmoc

3

4

5

2

SO2Cl

SO2Cl Nos-Cls (R2)

F3C

NO2

NO2

O

2

1

SO2Cl NO2

SO2Cl Cl

NO2 4

3 N O

Alcohols (R3)

N HO

HO

HO

HO

HO 2

1

3

5

HO 4

6

Table 1: Synthesized derivatives 6

Compound

R

1

2

R

3

R

Crude Purity (%)a

Final Purity (%)b

Yield (%)c

Ratio of enantio mersd (%)

6(1,1,1)

H

80

99

35

99:1

6(1,1,2)

H

60

95

52

50:50 or 97:3


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a

6(1,2,1)

7-CF3

75

99

26

83:17

6(1,4,1)

7-Cl

70

92

41

50:50

6(1,1,4)

H

70

90

8

57:43

6(1,1,3)

H

60

99

12

NT

6(1,1,5)

H

70

99

25

99:1

6(1,3,1)

7-MeO

40

90

10

93:7

6(2,1,1)

H

70

99

21

80:20

6(1,1,6)

H

71

96

25

69:31

6(4,1,1)

H

74

97

16

99:1

6(3a,1,1)

H

73

99

23

99:1

6(3b,1,1)

H

60

98

23

50:50

6(3c,1,1)

H

80

99

26

93:7

6(5,1,1)

H

68

95

10

64:36

e

Crude purity after seven reaction steps according to the integrated HPLC-UV

chromatograms (PDA, 200-500 nm) b

Purity after semipreparative HPLC purification according to the integrated HPLC-UV

chromatograms (PDA, 200-500 nm) c

Overall yields after seven reaction steps and HPLC purification.

d

Enantiomeric purity according to the integrated HPLC-UV chromatograms determined with

use of the chiral separation of purified compounds (PDA, 200-500 nm) e

Peak originating from the trityl protecting group was not included in the integration

NT – not tested. In the case of derivative 4(3,1,1) synthesized from glutamic acid, the treatment with thionyl chloride led to parallel chlorination of the side chain carboxylate. We used this reaction for further diversification. After evaporation of the thionyl chloride, the crude product was treated with methanol, propylamine or morpholine. The reaction yielded the corresponding methylester or amides (Scheme 3).



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Scheme 3. Further diversification of intermediates synthesized from polymer-supported glutamic acida

a

Reagents: (i) 50% trifluoroacetic acid (TFA) in DCM, rt, 1 h; (ii) 20% thionylchloride in

chloroform, 50 ºC, 1 h; (iii) methanol or 20% propylamine in chloroform or 20% morpholine in chloroform, rt, 30 min.

Although we began the synthetic route with enantiomerically pure α-amino acids (Lisomers), we considered possible racemization within the reaction sequence. In our recent article, it was demonstrated that the configuration remains untouched if the amino acid is immobilized with use of HOBt/DIC strategy.14 In contrast, full15 or partial4 racemization of the α-amino acid stereocenter can occur during the acylation that yields the heterocyclic moiety. To evaluate the stereochemical outcome of the synthetic method, compound 6DL(1,1,1) was prepared as the racemic standard. For this purpose, an equimolar mixture of Fmoc-L-Ala-OH and Fmoc-D-Ala-OH was used for the acylation of Wang resin and the target derivative was synthesized according to Scheme 1. For the racemic sample, a method for the separation of enantiomers by chiral HPLC was developed. Analysis of the corresponding product 6(1,1,1) by this method (Figure 4) confirmed that the amino acid stereocenter configuration was not influenced by the reaction sequence conditions. In contrast, the analysis of other synthesized compounds by the same method revealed the presence of the second enantiomers (see Table 1). Our investigation showed that different compounds synthesized from the same batch of resin 1(1) had different enantiomeric purity (e.g., 99% for compound 6(1,1,1) and 50% for compound 6(1,4,1)). Therefore, the full/partial racemization undoubtedly occured during the cyclization step to the seven-membered ring. To support this theory, we cleaved and analyzed the intermediate 4(1,1,2) along with its racemic standard 4DL(1,1,2). The chiral HPLC analysis proved that the compound 4(1,1,2) was enantiomerically pure. On the other hand, when the cyclization of intermediate 4(1,1,2) to the corresponding product 6(1,1,2) was repeated, the previous full racemization was not observed (see Table 1), although exactly the same reaction conditions were used. This irreproducibility showed that the stereocenter conversion was not structure-dependent and it explained the different stereochemical outcome for structurally very similar compounds (see Table 1, compare compounds 6(3a,1,1) and 6(3b,1,1), or 6(1,1,2) and 6(1,1,1)). Finally, to address the potential racemization, we


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tested the cyclization with oxalyl chloride which is known for its ability to yield acyl chlorides at mild conditions. However, the reaction of intermediate 4(1,1,2) with oxalyl chloride at room temperature gave no conversion. Heating to 50 oC afforded the desired compound, but only as a part of a complex mixture. For these reasons, the cyclization with the thionyl chloride seemed to be a method of choice although the relationship between the stereochemistry and reaction conditions was not fully clear. A detailed studies on this phenomenon will be reported in a due course. Figure 4: Chiral separation of the sample 6(1,1,1) and analysis of the corresponding racemate 6DL(1,1,1) a

a

Conditions: Chiralpak® HSA (150 × 4.0 mm i.d.; particle size: 5 µm; Chiral, Illkirch

Cedex, France). Mobile phase: aqueous ammonium acetate buffer 90% (25 mM) and isopropylalcohol 10%, flow 0.8 ml/min.

In conclusion, we have developed a simple method for the solid-phase synthesis of 2,3dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)-one 1,1-dioxides with three diversity positions. The target compounds were obtained in good crude purity and acceptable overall yields influenced by the need of double purification procedure. The stereochemical outcome of the synthetic route was influenced by the cyclization step. We reported a suitable method for the determination of the enantiomeric purity. Considering the large number of commercially available starting materials (Fmoc-amino acids, alcohols and 2-nitrobenzenesulfonyl chlorides), this method can be used for the simple preparation of collections of diversely substituted compounds. The versatility of this synthetic route was highlighted using a variety



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of starting materials and was demonstrated by the preparation and full characterization of 15 representative compounds.

Acknowledgements The authors are grateful to project CZ.1.07/2.3.00/20.0009 from the European Social Fund and internal project of Palacky University Olomouc (IGA-PrF-2016-020). The infrastructure of this project (Institute of Molecular and Translation Medicine) was supported by the National Program of Sustainability (project LO1304).

Supporting Information Available Supporting information contains details of experimental, synthetic and analytical procedures along with spectroscopic data for synthesized compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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Solid-Phase Synthesis of 2,3-Dihydrobenzo[

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