Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade reaction

Bioorganic & Medicinal Chemistry xxx (2015) xxx–xxx

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Synthesis of 1,4,5 trisubstituted c-lactams via a 3-component cascade reaction Michael Åxman Petersen a, Michael A. Mortensen a, A. Emil Cohrt a, Rico Petersen a, Peng Wu a, Nicolas Fleury-Brégeot c, Rémy Morgentin c, Claude Lardy c, Thomas E. Nielsen a,b,⇑, Mads H. Clausen a,d,⇑ a

Department of Chemistry, Technical University of Denmark, Kemitorvet 207, DK-2800 Kgs. Lyngby, Denmark Singapore Centre on Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore EDELRIS, 115 Avenue Lacassagne, F-69003, France d Center for Nanomedicine and Theranostics, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark b c

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 10 November 2014 Revised 21 January 2015 Accepted 22 January 2015 Available online xxxx

A three component one-pot cascade reaction was developed for the synthesis of 1,4,5-trisubstituted c-lactams. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. The phases of building block generation, scaffold synthesis and subsequent appendage modification were adapted to library production, which resulted in a screening library of 500 compounds. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: c-Lactams Cascade reaction One-pot reaction Molecular diversity Library production

1. Introduction

R1

O

R3

N

Independently, c-lactams1 and indoles2 are structural motifs that are widely present in natural and synthetic bioactive compounds. One prominent example, the kinase inhibitor Staurosporine and derivatives hereof, incorporates both of these motifs.3 In our pursuit of new scaffolds suitable for library production, we have developed an easy and efficient procedure to access indole-containing compounds with a 1,4,5-trisubstituted c-lactam scaffold (1). The unique molecular structure has a high fraction of sp3-hybridized carbon atoms and contains two stereogenic centers. In addition to three positions that can be varied independently in library synthesis, the scaffold also offers a promising distribution of molecular weight against c log P. There are examples of effective synthetic pathways to c-lactams via acyclic intermediates4 but often the lactam forming step involves formation of the cyclic N-acyliminium ion followed by nucleophilic attack (Fig. 1). There are several methods for generation of the N-acyliminium ion which often includes treatment of the corresponding hydroxy-, alkoxy-, or acetoxy-lactam with Lewis or Brønsted acids.5 The stereochemical outcome of a reaction ⇑ Corresponding authors. E-mail addresses: (M.H. Clausen).

[email protected]

(T.E.

Nielsen),

[email protected]

R''

O NH

N

±1

R'' N Nu

R'

R2

O Nucleophile

R' (Racemic)

Figure 1. General target structure and formation of scaffold via nucleophilic attack on N-acyliminium ion.

between the nucleophile and N-acyliminium ion is dependent on the nature of the substituent adjacent to the reactive center: when R0 (Fig. 1) is equal to aryl or alkyl the resulting racemic c-lactam is expected to exhibit trans stereochemistry.6 2. Results and discussion Our first approach to the synthesis of 1 was a stepwise strategy starting from aldehyde 2, which could be synthesized from commercially available phenylacetaldehyde on multigram scale (30 g) following the procedure of Kenda et al.7 The aldehyde was converted to the corresponding acetal 3, followed by basic hydrolysis of the ester to give the free carboxylic acid 4. This was

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M. Åxman Petersen et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx

O

O

O

O

O

a

OH

Table 1 One-pot reaction with different amines

b O

O

O

2

O

O 3

O

O

O

+

AcOH 50 °C

N H

±1b

O

O

O

NR1

N H

+ HN

NH

±1a-e

a b c d

NR 1

+

N H

Scheme 1. Stepwise synthesis of c-lactam 1b. Reagents and conditions: (a) HC(OCH3)3, p-TsOH (cat.), MeOH, 20 °C, 5 h, 83%. (b) KOH, EtOH, 20 °C, 16 h, 89%. (c) HATU, i-Pr2NEt, H2N(CH2)5CH3, NMP, 20 °C, 4 h, 78%. (d) BF3Et2O, indol, CH2Cl2, reflux, 16 h, 54%. R = –(CH2)5CH3.

then coupled with hexylamine to give the corresponding amide 5 in good yield. Treatment of a mixture of 5 and indole with BF3Et2O in refluxing CH2Cl2 overnight resulted in deprotection of the masked aldehyde followed by formation of the desired substituted c-lactam 1b in 54% yield (Scheme 1) with the expected trans stereochemistry (vide infra). By lowering the temperature to 21 °C the yield could be improved to 81%, but the reaction time was extended to 3 days. Although the desired c-lactam scaffold could be obtained in an acceptable yield (overall yield 31–46% from aldehyde 2), we wanted to improve the overall efficiency of the synthesis. Therefore, we explored the possibility of a one-pot reaction between aldehyde 2, an amine, and a nucleophile to give the desired c-lactam scaffold directly. This transformation is most likely to proceed via a three-step cascade reaction: (1) imine formation; (2) nucleophilic attack; (3) formation of the lactam. Attempting the one-pot reaction under neutral conditions in the presence of Lewis or Brønsted acids proved unsuccessful. Likewise for attempts to pre-form the hydroxylactam before subjecting it to the nucleophile. Gratifyingly, it was found that the desired c-lactam 1 could be obtained when the reaction was performed in AcOH, but unfortunately accompanied by the formation of byproducts (Table 1). LCMS suggested that acyclic intermediate 6 was formed during the reaction, but eventually consumed. The resulting crude contained a mixture of lactam 1, unsaturated c-lactam 8, and bisindole 7. The latter can originate from a nucleophilic attack on an extended iminium ion formed by elimination of amine 6. Bisindole 7 can also be formed by reaction between the nucleophile and the aldehyde 2,8 evidence of which was obtained when the reaction was performed in the absence of the amine, where only the bisindole 7 was isolated. If on the other hand, the reaction is performed without a nucleophile present, only unsaturated c-lactam 8 could be isolated. Excess of nucleophile (2 equiv) was used to insure full conversion of the aldehyde. To minimize the formation of the bisindole byproduct from direct reaction with the aldehyde, excess of amine (4 equiv) was applied to favor the formation of imine intermediate. To explore the scope the reaction, a selection of different amines was tested, see Table 1. The nature of the amine was found to have a major influence on the outcome of the reaction: sterically unhindered amines such as hexylamine (1b) and glycine (1d) resulted in acceptable product yields, comparable to the results of the stepwise synthesis, although formation of bisindole could not be fully suppressed. When more bulky isopropylamine (1c) was used, a significant decrease in yield was observed, accompanied by increased bisindole formation. Aniline (1e) gave only trace amount of product, which we ascribe to its reduced nucleophilicity. Ammonia (1a)

NH 6

O

O 5

N H

NR

d

O

R

O 2

NHR

c

R1 NH2

+

4 O

O

O

7

8

Compound

R1

1:7a

Yieldb,c (%)

1a 1b 1c 1d 1e

–H –(CH2)5CH3 –CH(CH3)2 –CH2COOH –Ph

1:1 4:1 1:2 3:2 —

36 43 21 47 Traced

Determined by 1H NMR. Isolated yield after chromatography. dr >95/5. Detected by LCMS.

Table 2 One-pot reaction with varying nucleophiles O

O

O +

Glycine, AcOH 50 °C, 16 h

HR1

OH

R1

O

±1f-n

2

Compound

O

N

R

1

Yield (%)

1d

a,b

47

Compound

R

1

Yielda,b (%)

1k

N H

O Cl

1f

44

1l

N H

1g

—

N O

27

1m

S

38

1n

S

56

1o

—

N H

1h N

O

29

O

1i

1j a b

N N H N N

— O

32

Isolated yield after chromatography. dr >95/5.

gave slightly lower yield than that of the primary unhindered amines. A selection of different nucleophiles was evaluated in the onepot reaction together with glycine. These results are summarized in Table 2. In general, indole derivatives, together with indazole and pyrazole were successful, whereas reactions with benzofuran and benzisoxazole did not lead to the formation of the desired

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M. Åxman Petersen et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx

product. Thiophene also did not react, but the more electron-rich methoxythiophene did. Electron-rich 1,3-dimethoxy benzene failed to react. We found the glycine derivative especially interesting for further study, because the free carboxylic acid offers a handle for functionalization via amide coupling. As proof-of-concept, a small series of amides were produced via reaction with a selection of primary, secondary, aryl-, and heterocyclic-amines. The final products are shown in Figure 2. The indole nitrogen could be further derivatized, which was demonstrated by arylation of the glycine derivative 1d using reported conditions,9 affording the corresponding N-arylated compound in 50% yield (see supporting info, Scheme S1). The third point of diversity was introduced by modification of the aldehyde component. This was realized using substituted benzaldehydes as starting materials, which are widely commercially available. Treatment of halide substituted benzaldehydes 8a/b with vinyl Grignard afforded the allylic alcohols 9a/b. These were rearranged to the corresponding cinnamyl alcohols 10a/b, using catalytic amounts of O3ReOH.10 Subsequently, cinnamyl alcohols 10a/b were subjected to a Johnson–Claisen11 rearrangement by treatment with trimethyl orthoacetate and catalytic amounts of propanoic acid, giving olefins 11a/b in good yields. Oxidative cleavage12 of the olefin afforded the corresponding aldehydes, which were subjected to the one-pot conditions described above to give the desired c-lactams 12a/b in acceptable yields. One advantage of this synthetic route is the ease of purification: column chromatography is only necessary for the final compounds since intermediates are of sufficient purity after simple extractive workup. There are unfortunately limitations to this synthetic strategy: electron-rich aryls afforded byproduct formation in both the rhenium catalyzed rearrangement as well as the Johnson–Claisen reaction. Byproduct formation in the rhenium catalyzed rearrangement could be reduced by lowering the temperature (Scheme 2).

O

3

3. Structure determination To verify the stereochemistry of the c-lactam scaffold, compound 1c was subjected to NOE NMR studies, which indicated the expected trans relationship between the phenyl and indolyl groups (Fig. 3a). X-ray crystallography conducted on single crystals of compound 1c (CCDC 1032424) grown from acetonitrile confirmed the trans-configuration (Fig. 3b). 4. Library production In order to synthesize 400–600 compounds in compliance with the ELF specifications, the validated chemistry routes were carried out on larger scales and adjusted if needed. For the production phase, all the three validated diversity points were exploited. In particular, it was decided to focus the library on several nucleophilic heterocycles (indoles, thiophenes and pyrazoles). In order to maximize diversity and to exploit the scope of the method fully, production was divided into 3 sub-libraries: the first one with the 3-CR used directly as a final step, and the other two relying on peptidic couplings after the lactam formation with either glycine or 4amino butyric acid. Varying the length of the linker between the lactam moiety and other functional groups allowed us to cover a wider range of properties as depicted by the c log P versus MW graph of the synthesized compounds (Fig. 4). For this library 476 screening compounds have been produced in 15 production campaigns over 9 weeks. The one-pot procedure allowed a production success rate up to 73%, and the peptidic

S

O N

O

O

O

O

N

O

NH

N Ph

Cl

N H

N

Ph

±7b

Figure 3. (a) Observed NOE correlations of c-lactam 1c. (b) X-ray crystal structure of c-lactam 1c (racemic mixture—only one isomer displayed).

Ph N H

N H ±7a

O NH

N

N

Ph

O

NH

N ±7c

±7d

Figure 2. Amides 7a–d synthesized from corresponding glycine derivatives 1d, 1f, 1g, and 1h.

R2

R2

R2

OH

a

O

b OH

R1 R

1

1

8a/b

R 9a/b

10a/b

R2

c

OH O

2

N

R

d

R1

R1 11a/b

O

O

O

±12a/b

N H

Scheme 2. Reagents and conditions: (a) BrMgCHCH2, THF, 0 °C to 20 °C, 1 h, 9a: 80%, 9b: 96%. (b) O3ReOH (2 mol %), Et2O, 20 °C, 2 h, 10a: 80%, 10b: 86%. (c) CH3C(OCH3)3, CH3CH2COOH (cat.), toluene, reflux, 16 h, 11a: 91%, 11b: 87%. (d) (1) K2OsO4, NaIO4, 2,6-lutidine, dioxane/H2O (3/1), 20 °C, 1 h; (2) glycine, indole, AcOH, 50 °C, 16 h, 12a: 36%, 12b: 22%. a: R1 = H, R2 = F. b: R1 = Br, R2 = H.

Figure 4. Library synthesized and its predicted properties (ChemBioDraw).

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coupling provided up to 96% success rate. All obtained compounds were purified by mass-directed preparative HPLC.

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmc.2015.01.041.

5. Conclusion and summary

References and notes

Stepwise and one-pot procedures for the synthesis of 1,4,5 substituted c-lactams have been developed. With the overall yields of the two procedures being comparable, the one-pot procedure offers a faster and more economic approach. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. In the end, a 500-membered library of 1,4,5-trisubstituted c-lactams was produced. Acknowledgements The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115489, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. Supplementary data Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail: [email protected]).

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