Accepted Manuscript Base-dependent formation of cis and trans olefins and their application in the synthesis of 5-oxo-ETE receptor antagonists Vivek Gore, Shishir Chourey, Qiuji Ye, Pranav Patel, Yannick Ouedraogo, Sylvie Gravel, William S. Powell, Joshua Rokach PII: DOI: Reference:

S0960-894X(14)00599-X http://dx.doi.org/10.1016/j.bmcl.2014.05.090 BMCL 21704

To appear in:

Bioorganic & Medicinal Chemistry Letters

Received Date: Revised Date: Accepted Date:

13 March 2014 21 May 2014 23 May 2014

Please cite this article as: Gore, V., Chourey, S., Ye, Q., Patel, P., Ouedraogo, Y., Gravel, S., Powell, W.S., Rokach, J., Base-dependent formation of cis and trans olefins and their application in the synthesis of 5-oxo-ETE receptor antagonists, Bioorganic & Medicinal Chemistry Letters (2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.05.090

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.

Leave this area blank for abstract info.

Base-dependent formation of cis and trans olefins and their application in the synthesis of 5-oxo-ETE receptor antagonists Vivek Gore, Shishir Chourey, Qiuji Ye, Pranav Patel, Yannick Ouedraogo, Sylvie Gravel, William S. Powell, and Joshua Rokach

5-Oxo-ETE is the most potent eosinophil chemoattractant among lipid mediators. We have developed two 5-oxo-ETE receptor antagonists. In the course of the work, we have developed a procedure to selectively introduce a cis and trans double bond in an alkyl side chain. Reacting indolecarboxaldehydes with alkyl ylides using the Li base affords the trans olefins, whereas using the K base yields the cis olefins.

Bioorganic & Medicinal Chemistry Letters j o ur n al h om e p a g e : w w w . e l s e v i er . c o m

Base-dependent formation of cis and trans olefins and their application in the synthesis of 5-oxo-ETE receptor antagonists Vivek Gorea, Shishir Choureya, Qiuji Yea, Pranav Patela, Yannick Ouedraogoa, Sylvie Gravelb, William S. Powellb, and Joshua Rokacha∗ a b

Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 West University Boulevard, Melbourne, Florida 32901, USA Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, H2X 2P2, Canada

A R T IC LE IN F O

A B S TR A C T

Article history: Received Received in revised form Accepted Available online

5-Oxo-ETE is the most potent eosinophil chemoattractant among lipid mediators. We have developed two 5-oxo-ETE receptor antagonists. In the course of the work, we have developed a procedure to selectively introduce a cis and trans double bond in an alkyl side chain. Reacting indolecarboxaldehydes with alkyl ylides using the Li base affords the trans olefins, whereas using the K base yields the cis olefins.

Keywords: 5-Oxo-ETE Antagonist Indolecarboxaldehyde Wittig reaction LiHMDS KHMDS

2009 Elsevier Ltd. All rights reserved.

5-Oxo-ETE is the most potent eosinophil chemotactic factor among lipid mediators.1 It is formed by the biotransformation of arachidonic acid (AA) (Fig. 1). Its actions are mediated by the selective OXE receptor.2 Its potent effects on eosinophil migration suggest that it may play a role in allergic diseases such asthma. One of the hallmarks of asthma is the accumulation of eosinophils in the lungs during the onset of an asthma attack. Eosinophil accumulation in the lungs is responsible for the late phase asthma and is associated with inflammation, tissue damage, and airway narrowing. Therefore, OXE receptor is an attractive therapeutic target for drugs that would prevent eosinophil migration to the lung.3 For this reason, we designed and synthesized two selective OXE receptor antagonists.4,5 As part of our study on the structure-activity relationship (SAR), we generated an alkyl side chain at the C2 position of the indole ring, which was further modified to a series of antagonists such as 5, 6 and 7 (Fig. 2). CO2 H 5-LO OOH

1 AA

CO2H Peroxidase

2 5S-HPETE

OH

CO2H 5-HEDH

3 5-HETE

ylide (Scheme 1). The synthesis of 5 was described by us in detail previously, 5 whereas the syntheses of novel compounds 6 and 7 as reported here are shown in Scheme 1.

Cl

N O

Cl

OH

N

OH

O

O

5

Cl

N

O

OH O

6

O

7

Figure 2. 5-Oxo-ETE receptor antagonists

To accomplish this we investigated a series of reactions between indolecarboxaldehydes and pentylphosphonium ylide (Scheme 1). We discovered that the outcome of the Wittig reaction could be altered by the choice of the base used in the reaction. The Wittig reaction is widely used as a coupling reaction in synthetic chemistry and several modifications have been reported in the literature.6-12 In the present study, we found (ii)

O

CO2H

(i)

4 5-oxo-ETE

Figure 1. Biochemical formation of 5-oxo-ETE

N H

Cl

10

N

CHO

Cl

Ph3P

N H

O

Br

9

O

O

O

68%

9

(iii) Ph3P

O

OH

6

12

Br

8

We wanted to determine whether the introduction of some rigidity in the alkenyl side chain (e.g. compounds 6 and 7) would affect antagonist potency compared to the corresponding saturated compound (5), which is one of our most potent antagonists. These alkenyl side chains at the C2 position were introduced by reacting the carboxaldehydes with a phosphonium

Cl

(iv)

Cl

N

Cl N H

11

12 O

O

O

OH

7 O

O

47%

Scheme 1. Synthesis of 6 and 7. Reagents & Conditions: (i) 9, LiHMDS, 8, THF, -78 °C-rt; (ii) 10, tBuOK, 12, THF, rt; (iii) 9, KHMDS, 8, THF, -78 °Crt; (iv) 11, KOH, DMSO, rt.

———

∗ Corresponding author. Tel.: +1-321-674-7329; fax: +1-321-674-7743; e-mail: [email protected]

that the use of lithium bis(trimethylsilyl)amide (LiHMDS) led to the formation of the trans isomer as the major product. In contrast, when potassium bis(trimethylsilyl)amide (KHMDS) was used under the same conditions the cis isomer was formed predominantly (Table 1).

Figure 3. Trans/cis ratios of hexenylyindoles obtained in the Wittig reactions between indolecarboxaldehydes and pentylphosphonium ylide using different bases.

Figure 3 shows the ratio of trans to cis isomers formed following the reaction of different indolecarboxaldehydes with pentylphosphonium ylide in the presence of LiHMDS, KHMDS, or NaHMDS (5). As can be seen, selectivity is best with the 2, 5, and 6-indolecarboxaldehydes. Since we were primarily interested in 2-alkylindoles we investigated this reaction in detail. We have previously shown that the 2-alkyl indole with 1 or 3 carboxy side chains led to much higher activity than other configurations.4 Table 1. Trans/cis ratios resulting from the reaction of indolecarboxaldehydes and other aldehydes with pentylphosphonium bromide Entry #

Substrate

1

Base

CHO

N H

13

Ratio trans/Cis

Yield* (%)

A

LiHMDS

95:05

85

B

KHMDS

05:95

99

C

KHMDS/ LiBr**

97:03

84

A

LiHMDS

95:05

73

B

KHMDS

02:98

97

A

LiHMDS

99:01

77

B

KHMDS

0:100

77

A

LiHMDS

100:0

94

B

KHMDS

38:62

77

A

LiHMDS

97:03

92

B

KHMDS

06:94

96

A

LiHMDS

99:01

93

B

KHMDS

12:88

97

A

LiHMDS

46:54

90

B

KHMDS

17:83

81

A

LiHMDS

07:93

85

B

KHMDS

12:88

80

A

LiHMDS

33:66

99

B

KHMDS

05:95

99

Cl

2

CHO

N H

14

3

Cl N H

CHO

8

4

CHO

N H

15 MeO

5

N H

CHO

16

6

MeO N H

CHO

17

7

N

CHO

18

8

O

CHO

19 CHO

9 20

*All yields are isolated yields, and THF was the solvent for all the reactions. **LiBr (3eq) was added to the reaction mixture.

The trans to cis ratios for various substrates are summarized in Table 1. Unprotected indole-2-carboxaldehydes gave primarily the trans product with LiHMDS and the cis isomer with KHMDS (Entries 1-6). However, methylation of the indole nitrogen inverted the trans/cis ratio (Entry 7). Substrates lacking a nitrogen atom in the ring were converted predominantly to the cis isomer in the presence of both bases (Entries 8-9). A typical procedure for the synthesis of the olefins is described below. To a stirred solution of pentylphosphonium bromide (13.4 g, 32 mmol) in THF (15 ml) was added LiHMDS (29.2 ml, 1.0 M in THF, 29.2 mmol) at -78 °C. After 30 min, 8 (2.238 g, 12.5 mmol) in THF (25 ml) was added dropwise at -78 °C over a period of 10 min. The reaction mixture was brought to rt and stirred for 3 h. Saturated NH4Cl solution was added and the organic layer extracted with EtOAc. The combined organic extracts were washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and the crude was purified by flash chromatography to obtain 10. 15 The same procedure was used in the case of KHMDS (Entry 3B).16 The olefins 10 & 11 were further coupled with 3-methyl glutaric anhydride (12) to yield the final unsaturated compounds 6 and 7, respectively (Scheme 1). The trans compound 6 contained minute (

Base-dependent formation of cis and trans olefins and their application in the synthesis of 5-oxo-ETE receptor antagonists.

5-Oxo-ETE is the most potent eosinophil chemoattractant among lipid mediators. We have developed two 5-oxo-ETE receptor antagonists. In the course of ...
423KB Sizes 3 Downloads 3 Views