Isocoumarins in Medicinal Chemistry and Organic Synthesis

Chapter 5

Isocoumarins in Medicinal Chemistry and Organic Synthesis 5.1 SYNTHESIS OF ISOCOUMARINS OF PHARMACOLOGICAL INTEREST As mentioned earlier, isocoumarins display remarkable pharmacological properties in a broad range of therapeutic areas. Thus isocoumarin framework represents an attractive scaffold or pharmacophore for the design and development of new chemical entities in the area of drug discovery and pharmaceutical research. Few representative examples on the preparation of isocoumarins of pharmacological interest are presented here.

5.1.1 Various Enzyme Inhibitors 4-Chloro-3-alkoxyisocoumarins, a class of haloenol lactones, have been reported to be potent and reversible inhibitors of pancreatic cholesterol esterase (CEase).1 CEase secreted from the exocrine pancreas is a serine hydrolase that has three proposed functions in the intestine, i.e., (1) controlling the bioavailability of cholesterol from dietary cholesterol esters; (2) contributing to incorporation of cholesterol into mixed micelles; and (3) aiding in transport of free cholesterol to the enterocyte. Studies also indicated a pathological role(s) for CEase in the circulation where CEase accumulates in atherosclerotic lesions and triggers proliferation of smooth muscle cells. Thus, CEase has attracted particular attention as a potential drug target, and inhibitors of CEase are anticipated to limit the absorption of dietary cholesterol. As potential inhibitors of CEase a series of 4-chloro-3-alkoxyisocoumarins were synthesized and evaluated. Synthesis of this class of compounds (Scheme 5.1) involved monoesterification of homophthalic acid (380) followed by cyclization of the resulting mono-ester (381) with phosphorus pentachloride in toluene to give 3-alkoxy-4-chloroisocoumarins 382. Catalytic hydrogenation of 382 (when X ¼ nitro) followed by treating the resulting amine 383 with acid chloride afforded the amide derivative of isocoumarin 384. Among the Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin. https://doi.org/10.1016/B978-0-12-815411-3.00005-9 Copyright © 2019 Elsevier Inc. All rights reserved.

153

154 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin (when X = NO2 R = Me)

O X

CO2 H

380

X

ROH

H 2 SO 4 CH 2CO2 H benzene

CO2 H CH 2CO2 R

OR 382

Cl

H 2 , Pd/C MeOH

O R'COCl

O

R'OCHN

O

Et3N, THF

OMe 383

O

toluene

381

O H2 N

X

PCl5

Cl

OMe 384

Cl

O

O

O

O O

O Cl

Cl 382a

382b

SCHEME 5.1 Synthesis of 4-chloro-3-alkoxyisocoumarin-based inhibitors of CEase.

compounds synthesized, the 4-chloro-3-(4-cyclohexylbutoxy)isocoumarin (382a) and 4-chloro-3-(3-cyclopentylpropoxy)isocoumarin (382b) were identified as potent reversible inhibitors of CEase, with dissociation constants of 11 and 19 nM, respectively. The kinetic results were supported by predictions from molecular modeling studies. Notably, 3-alkoxy-7-amino-4-chloroisocoumarin derivatives have shown to inhibit the secretion of b-amyloid peptide, a major component of the senile plaques involved in the Alzheimer’s disease.2 This class of compounds, especially their acyl, urea, and carbamate derivatives have also been reported as potent inhibitors of human leukocyte elastase (HLE).3 In case of 4-chloro-3(2-bromoethoxy)isocoumarin series, a substituent, e.g., PhNHCONH at C-7 provided a selective and potent inhibitor. A number of isocoumarin-based compounds, e.g., 2,8-disubstituted-benzo [c]chromen-6-ones, have been explored as inhibitors of various enzymes such as serine proteases (trypsin and a-chymotrypsin), HIV aspartyl protease, nitric oxide synthase, and a panel of protein kinases.4 Notably, among the protein kinases, glycogen synthase kinase (GSK-3) has been an attractive therapeutic target for the treatment of numerous serious pathologies, including Alzheimer’s disease, stroke, bipolar disorders, chronic inflammatory processes, cancer, and type II diabetes. The synthesis of a representative compound (Scheme 5.2) involved Suzuki coupling of bromoarene 385 with boronic acid derivative 386 to give the biaryl compound 387. The reduction of aldehyde 387 and then the nitro group of the resulting alcohol 388 afforded the corresponding amine 389. The intramolecular cyclization of 389 involving the proximate methoxy and the ester group provided the benzo[c]chromen-6-one

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

O 2N O2N

COOMe

(HO)2 B

+

Br

COOMe

PdCl2 dppf,

CHO

CHO

dppf, KOAc, dioxane, ref lux

MeO

MeO

386

385 O 2N

387

COOMe

BH 3/DMS

155

H 2N

COOMe

CH 2OH H 2/Pd/C

THF, rt, 1h

CH 2OH

THF, r t, 1h

MeO

MeO

388

389 O

H 2N

O

BBr 3, CH 2Cl2, -78 0C, 2h then CH 3 OH 390

CH 2Br

H-Z (chemical or enzymatic nucleophile) O

O O H 2N

HBr

Z

H 2N

CH 2

CH 2Br HO

H 2N

Z

Z

H-Z

CH 2Z HO

H-Br O E-5.1 Proposed compound - chemical / enzyme interaction

SCHEME 5.2 Synthesis of a 2,8-disubstituted-benzo[c]chromen-6-one and its proposed interaction with chemical or enzymatic nucleophiles.

derivative 390 containing a bromomethyl and amino group. Indeed the presence of bromomethyl group at the C-2 position of 390 was thought to be interesting because upon chemical or enzymatic attack the compound 390 or its analogs could provide very reactive intermediate E-5.1 (Scheme 5.2). This is interesting particularly from the view point of medicinal chemistry as intermediate E-5.1 could trap or inactivate enzyme and therefore could be useful for the design of enzyme inhibitors. Nevertheless, some of the synthesized compounds including 390 exhibited modest inhibitory activities when tested using the enzyme models. The toxic metabolite of the basidiomycete Gloeophyllum abietinum, i.e., oosponol or 4-hydroxymethylketone-8-hydroxyisocoumarin (391; R ¼ H) (Fig. 5.1), is produced by dehydrogenation of the nontoxic precursor oospoglycol in nature. Oosponol and its structural analogs (391, R ¼ OH, OAc) (Fig. 5.1) were synthesized to investigate the structural features responsible for their biological activities, particularly antibiotic activities.5

156 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin COCH 2OH

O R

O

391; R = H, OH, OAc

FIGURE 5.1 Oosponol and its structural analogs.

5.1.2 Phosphodiesterase 4 Inhibitors To explore the pyranone ring fused with a pyrazolopyrimidine moiety as a potential template for PDE4 (phosphodiesterase 4) inhibitors, various related compounds were prepared and evaluated for their PDE4 inhibitory properties.6 It is known that PDE4, one of the 11 isozymes, exists in four different isoforms, e.g., PDE4A, B, C and D, and is specific for the hydrolysis of cAMP to AMP.7 The elevated levels of cAMP in inflammatory and immune cells are associated with the inhibition of cellular responses, including the production and/or release of proinflammatory mediators, cytokines, and active oxygen species. Thus inhibition of PDE4 is beneficial for the treatment of inflammatory and immunological diseases including asthma and chronic obstructive pulmonary disease (COPD). The synthesis of target compounds (397) was carried out via the construction of pyranone ring using iodocyclization followed by Sonogashira/Heck/Suzuki reactions (Scheme 5.3).6,7 R1

EtO2C Br

N H

+

N

R1

N

NH 2

H3 PO3 EtOH

N N

Reflux

R2 O

Br

N CO2Et

393

392

R1

R1

N N N

R

I2 R3

Pd/C, TEA, PPh3 , CuI, DMF

394 (70-75%)

R1

R2

R 3 (4) R2

2

N N

CH 2 Cl2

I

Sonogashira or Suzuki R 2 or Heck R3

N O

CO2 Et

O 396 (85-92%)

395 (60-70%)

R4

N N

R3

N O O 397 (80-93%)

(R1 = H, CH 3 , R 2 = H, CO2 Et, R 3 = alkyl, aryl, alkyl alcohol, R 4 = alkynyl,aryl, alkenyl)

CONH2 N

N

N

O O

397a

SCHEME 5.3 Synthesis of pyranones fused with a pyrazolopyrimidine moiety.

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

157

The key precursor, i.e., the bromo compound (394) was prepared via the H3PO3- mediated condensation reaction of a bromo pyrazole derivative (392) with the enone (393). Upon coupling with various terminal alkynes under Sonogashira conditions, the bromo derivative (394) afforded the required alkyne esters (395). The iodocyclization of compound 395 gave the iodo derivative (396) that was converted to the target compound (397). The iodocyclization step was found to be regioselective as only six-membered ring product was obtained in this step. One of the synthesized compounds (397a) was found to be a safer inhibitor of PDE4B (one of the four subtypes of PDE4) with IC50 ¼ 1.33  0.64 mM (Rolipram IC50 ¼ 0.94  0.24 mM) and could be useful for the potential treatment of COPD and asthma.

5.1.3 Potential Anticancer Agents A similar strategy was adopted to prepare novel thieno[3,2-c]pyran-4-onebased small molecules that were designed as potential anticancer agents. These compounds (403) were synthesized via a multistep sequence consisting of iodocyclization and then Pd-mediated various CeC bond forming reactions as key steps (Scheme 5.4).8 The overall strategy involved the construction of thiophene-fused pyranone moiety and then functionalization at C-7 position of the resultant thieno[3,2-c]pyran-4-one framework. Some of the compounds synthesized showed selective growth inhibition of cancer cells in vitro among which two compounds (402a and 403a) showed IC50 values in the range of 2.0e2.5 mM.

O

O 398

S, morpholine EtOH, 90 °C 3-8h

S

NH 2

t

CuI, MeCN 0 oC, 5 min

S

O

S R1

R1

O

I

O S

or Heck

R1 R2

403 (52-72%)

402 (58-80%)

401 (60-72%)

CuI, Et3 N, EtOH, 60 o C 2-3 h

Sonogashira or Suzuki

O

I2 , CH2 Cl2 rt, 5-15 min

I

400 (50-54%)

O OEt

OEt 10% Pd/C, PPh3

BuONO

399

S

R1

O OEt

CNCH 2 CO2 Et

(R 1 = aryl; R 2 = alkynyl, aryl, alkenyl) O

O

O

O S

S 402a

I

Me

403a

C 4H 9

SCHEME 5.4 Synthesis of compounds based on thieno[3,2-c]pyran-4-one framework.

158 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin O

O

R1

O

O R2

N

F

N F

404

404a

(R1 , R 2 = H, F, Cl, Me, OMe)

FIGURE 5.2 6H-1-benzopyrano[4,3-b]quinolin-6-one derivatives.

The 6H-1-benzopyrano[4,3-b]quinolin-6-ones (404) (Fig. 5.2) designed as potential anticancer agents were prepared via the reaction of 4-chloro-2oxo-2H-chromene-3-carbaldehyde with various aromatic amines under ultrasound irradiation.9 Some of these compounds showed anti-proliferative properties in vitro (IC50 w 8e18 mM) when tested against four cancer cell lines, e.g., human chronic myeloid leukemia cells (K562), human colon carcinoma cells (Colo-205), breast cancer cells (MDA-MB 231), and human neuroblastoma cells (IMR32). Further in vitro studies suggested that inhibition of sirtuins could be the possible mechanism of action of these molecules. Sirtuins (class III NADedependent deacetylases) are shown to be upregulated in various types of cancers and therefore are considered as important targets for this disease.10 Indeed, inhibition of sirtuins allows reexpression of silenced tumor suppressor genes, leading to reduced growth of cancer cells. At the concentration of 10 mM, compound 404a (Fig. 5.2) showed 48% inhibition of Sirt1 compared with suramin’s 79% inhibition.

5.1.4 Potential Antibacterial/Antifungal Agents The 4-alkyl-3-aroyl and 4-alkyl-3-aminocarbonyl isocoumarin derivatives prepared via the classical method (i.e., condensing different o-acyl benzoic acids with bromoacetophenone derivatives or bromoacetylbromide in presence of K2CO3) showed interesting antibacterial, antifungal, and analgesic activities.11 Notably, a strategy similar to that used in synthesizing these isocoumarin derivatives was explored to develop a microwave-assisted method recently.12 Thus, a small library of isocoumarin derivatives was synthesized via K2CO3-catalyzed domino reactions of 2-carboxybenzaldehyde and a-bromoacetophenones under microwave irradiation. The antifungal potential of 3-substituted isocoumarins with or without additional substituents on the aryl ring has also been studied intensively.13 Indeed, this class of compounds (406, 407, and 408) prepared via various Pdcatalyzed coupling reactions (e.g., Sonogashira-, Heck-, or Buchwald-type reactions) was screened in vitro for antifungal activity against Candida species (Scheme 5.5).14 The key precursor, i.e., the 3-bromo isocoumarin (405) required for the synthesis of this class of compounds was prepared in 20% yield via bromination of homophthalic anhydride using PBr3. Thus a

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

R

R Br O

O 406 (60-96%)

Pd(PPh 3)2 CuI, Et3 N 60 o C

(R = H, TMS, CH 2 OBn, CH 2OAc, CH 2CH2 OBz)

R

Pd(OAc) 2

R O

O

PPh 3, Et3 N MeCN, 85 o C

O

O 407 (40-65%)

405

(R = CO2 Me, CO 2tBu, COMe) Pd2 (dba) 3 Xantphos K2CO3 80 o C

NH

N N

N O O 408 (25-96%) N

159

Cl

O O

408a

= imidazol-1-yl, pyrazol-1-yl, 1,2,4-triazol-1-yl, tetrazol-1-yl, 4-carbethoxyimidazol-1-yl, benzimidazol-1-yl, 2-trifluoromethylbenzimidazol-1-yl, benzotriazol-1-yl, 4-chloropyrazol-1-yl

SCHEME 5.5 Pd-catalyzed functionalization of 3-bromo isocoumarin.

diverse range of isocoumarin derivatives, e.g., alkynyl (406)-, alkenyl (407)and azole (408)-substituted compounds were prepared from the bromo compound (405) under various reaction conditions. These compounds were screened in vitro for antifungal activity against Candida species. Among the tested compounds, the azole-substituted isocoumarins showed the most promising activity, in some cases equal to that of clinically used voriconazole (MIC ¼ 7.8 mg/mL). Additionally, these compounds were appeared to be capable of inhibiting hyphal formation of Candida albicans (although for some of them the opposite effect was observed) and showed potential to act against azole-resistant strains such as Candida krusei and Candida parapsilosis. Notably, both Candida krusei and Candida parapsilosis strains were recognized as fungal nosocomial pathogens primarily found in the immunocompromised patients, which could be responsible for sepsis. Overall, the compound 408a (Scheme 5.5) showed activities against C. albicans (MIC ¼ 5.0 mg/mL), C. krusei ATCC 6258 (MIC ¼ 125 mg/mL), and C. parapsilosis clinical strain CA-27 (MIC > 500 mg/mL). Although this compound also showed significant cytotoxicity (antiproliferative activity) toward a normal human lung fibroblast cell line (MRC5) (IC50 ¼ 15  0.6 mg/ mL) in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay because of its promising antifungal activities, the compound 408a emerged as an initial lead for further studies.

5.1.5 5-Lipoxygenase Inhibitors Several 3-arylisocoumarins (411) and 8-hydroxy-3-arylisocoumarins (413) were synthesized using acyl anion chemistry for the initial CeC bond

160 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

formation followed by base (e.g., DBU or NaOMe)-promoted intramolecular cyclization of resulting keto esters (410) and keto lactones (412), respectively (Scheme 5.6).15 The 2-morpholino-2-arylacetonitrile (409) was used as a key reactant for the introduction of acyl group in the first step. The methodology was used for the synthesis of naturally occurring thunberginol A and cajanolactone A. Subsequently, a series of 3-arylisocoumarin derivatives were tested against 5-LOX (5-lipoxygenase) enzyme in vitro and PGE2 production in HeLa cells.16 Notably, the 5-LOX and microsomal prostaglandin E2 synthase 1 (mPGES1), the two key downstream enzymes in the leukotriene (LT) and prostaglandin (PG) pathways, respectively, are considered as important targets in combating inflammation. The 5-LOX (a crucial nonheme ironcontaining enzyme in the biosynthesis of leukotrienes) catalyzes arachidonic acid (AA) to 5(S)-hydroperoxyeicosatetraenoic acid (5-HPETE) and further to LTA4. The enzyme mPGES1 converts PGH2 to PGE2 that exerts its effect through its receptors, EP1eEP4, and is known to be involved in the etiology of tumorigenesis, cancer survival, epithelial mesenchymal transition (EMT), regulation of vascular tone, fever, and pain. So, inhibition of PGE2 synthesis is viewed as an important strategy to limit the growth and spread of several types of cancers. Overall, development of dual inhibitors that target both 5-LOX and PGE2 is beneficial to fight against inflammatory diseases as well as cancer. Nevertheless, while most of the synthesized isocoumarin derivatives showed

R' CO2 Me

R' CO2 Me

N Ar

CN

dry CH2 Cl2 O

R

Ar

2)CuSO4.5H 2 O MeOH:H 2O (7:3) 60 o C, 90 min

R = H, OH, OMe R' = H, OH Ar = Ph, aryl

O

O

409

OH

O O

NaOMe

O

O O

dry MeOH O Br

O

Ar

Ar

412

413 (Ar = Ph, aryl)

OH O

O

O

O

OMe

OH

411a

Ar 411

410

1) NaH, DMF -20 oC-rt, 2h

O

O O

R

Br

R

R'

DBU

OH

OMe 413a

OMe

SCHEME 5.6 Synthesis of 3-arylisocoumarin derivatives.

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

161

high activity,16 one of these compounds, e.g., 411a was found to be a dual inhibitor [IC50 ¼ 4.6  0.26 mM against 5-LOX and 6.3  0.13 mM against PGE2] with mixed and competitive modes of action (redox mechanism of action) against 5-LOX. Another compound 413, exhibited an IC50 of 12.4  0.14 mM against 5-LOX with nonredox mechanism. Notably, thunberginol [413b; Ar ¼ 3,4-(OH)2C6H3] exhibited IC50 of 15.8  0.03 mM against PGE2 production, whereas both 411a and thunberginol inhibited the mRNA expression of mPGES1 and COX-2 (cyclooxygenase-2). In other words, the molecular mechanism of action of compounds such as 411a could be due to the activation of several antiinflammatory and apoptotic cytokines and transcription factors. However, further optimization of this molecule may be necessary to afford a potent agent comparable with licofelone [IC50 ¼ 0.2 mM for 5-LOX and 6.0 mM for mPGES1], currently in clinical trial. The strategy of base-promoted intramolecular cyclization of keto esters and keto lactones was also used for the preparation of 3-glycosylated isocoumarins17 (414e418, Fig. 5.3) that are rare in nature. These compounds belong to C-aryl glucoside class, in which the gluco-configured pyranosyl unit is directly attached to the aromatic ring. The importance of C-aryl glucoside class of compounds has been realized through the discovery and development of antidiabetic drug Dapagliflozin. Indeed, Dapagliflozin is a potent and selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2) that reduces blood glucose levels in a dose-dependent manner via blocking glucose reabsorption in kidneys.18 Nevertheless, a modified Julia olefination for initial CeC bond formation between aldehydes and benzylic sulfones was used as the key step for the preparation of required starting materials. Additionally, Pd-catalyzed Meinwald rearrangement was used as a key step for the access to keto ester intermediates. R

R

O

O

R

O

O

O

O

O

O

O O

O O

414

O

O BnO 416

415

R OBn O BnO BnO

OBn

O O

O O

R 418

417

O

O

OBn OBn

BnO BnO

(R = H, OH)

FIGURE 5.3 3-Glycosylated isocoumarin derivatives.

162 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

5.2 ISOCOUMARINS IN ORGANIC SYNTHESIS: SYNTHETIC APPLICATIONS Utility of isocoumarins in organic synthesis has been demonstrated not only in the preparation of various natural products such as nitidine, tazettine, and ()-ochratoxin a19e21 but also in their frequent use as intermediates in the synthesis of isocarbostyrils, isoquinolines, isochromenes, and various aromatic compounds.22 Additionally, isocoumarins are used in the synthesis of a number of drug-like small molecules. For example, a series of isocoumarin derivatives of potential pharmacological interest was prepared from the 4-iodoisocoumarin (419) via transition metalecatalyzed cross-coupling followed by further chemical transformations (Scheme 5.7).23 Thus several different substituents were introduced at the C-4 position of the isocoumarin 419 via displacement of the iodine group. The 4-methyl derivative 420 was prepared through the Stille coupling of 419 with Me4Sn that on demethylation of OMe groups afforded hydroxyl derivative 421. A similar strategy was used for the preparation of 4-ethyl analog via 422 and 423. For the synthesis of 4-CF3 analog 425 an unusual fluorosulfonylfluoroacetate reagent was used as a precursor for the in situ generation of the trifluoromethide species that replaced the iodo group of 419. Demethylation of 425 afforded the corresponding phenol derivative 426.

OMe

Me

BBr 3

O

MeO

CH 2Cl2

O

420

OH

Me

OH

O

O

HO 421

HO

O

424

Me4Sn Pd2 (dba) 3 PtBu3 CsF, Dioxane

BBr 3 CH 2Cl2 OMe

I

OMe SnBu3 O

Pd 2(dba)3 MeO PBu 3, CsF Dioxane

O

OMe

H 2 , Pd/C

O MeO 419

O

422

EtOH

O

O

MeO 423

O

FSO 2CF2 CO 2Me CuI, DMF OMe

F3 C

OH

F3 C

BBr 3 O

MeO 425

O

O CH 2Cl2

HO 426

O

SCHEME 5.7 Derivatization of isocoumarins bearing iodo and methoxy groups.

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

163

In 2009, the solution phase synthesis of a 167-member library of isocoumarins (80%e99% yields) using Pd(PPh3)4-ZnCl2-Et3N as the catalyst system in DMF at 75 C has been described.24 Apart from the use of 4-iodoisocoumarins for library generation (via Sonogashira, Suzuki-Miyura, and Heck reactions), isocoumarins bearing hydroxyl (Scheme 5.8) or bromo functionalities (Scheme 5.9) were used to prepare diversified compounds by derivatization of the hydroxyl or bromine groups. Consequently, the hydroxylbearing isocoumarin, e.g., 427, was acylated using various acid chlorides, acid anhydrides, and carbamoyl chlorides to give the corresponding products, e.g., 428, 429, and 430 (Scheme 5.8). The reason for using cyclic anhydrides was to introduce a polar carboxylic acid functionality in the final product (429). In general, the reactions with acid chlorides and acid anhydrides were more efficient than those with carbamoyl chlorides. Although triethylamine was

O

O O

RCOCl

OCOR

O

O

OH

OCO(CH2 )mCO2 H

O

Et 3N, CH 2Cl2 0 o C - rt

428

O

Toluene 100 o C

427

429

(CH 2) m O R 1R 2 NCOCl cat DMAP, Et 3 N CH 2Cl2 0 o C - 50 oC

O

O O

OCONR 1R 2

430

SCHEME 5.8 Derivatization of isocoumarins bearing hydroxyl group.

O

O Ar

O R 432

R1

Br

ArB(OH) 2

Pd(PPh3 )4 Cs 2CO3 , DMF EtOH, H 2O microwave, 120 oC

R1

O

O

O (PPh3 )2 PdCl2 CuI, Et3 N, DMF 60 o C

R 431

R 433

CH 2=CHAr Pd(OAc)2 , TBAC Na 2CO3 ,DMF,80 o C O

Ar

O R 434

SCHEME 5.9 Derivatization of isocoumarins bearing bromo group.

164 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

found to be effective in most acylation reactions, a combination of DMAP and triethylamine was used in case of reactions with acid chlorides in some cases, especially for the more sluggish reactions. The 7-bromoisocoumarins (431) were used to expand the diversity present in the aromatic core of the isocoumarin ring (Scheme 5.9). Thus 7-aryl-/alkynyl-/alkenyl-substituted isocoumarins (432, 433, and 434) were prepared from 431 through Sonogashira, Suzuki-Miyaura, and Heck reactions. Overall, most of the isocoumarin library members prepared via further functionalization of isocoumarin framework was found to have drug-like properties in terms of Lipinski’s rules, c log P values, molecular weight, etc. 3-Substituted isocoumarins have been used as synthetic precursors for a series of 2-substituted benzophenones 139,25,26 fluorinated 3,4-dihydroisocoumarins,27 3-aryl-1H-isochromene-1-thiones (or 1-thio-isocoumarins),28 benzimidazo[2,1-a] isoquinoline, and related compounds.29

5.2.1 Precursor of NM-3 NM-3 [i.e., 2-(8-hydroxy-6- methoxy-1-oxo-1H-2-benzopyran-3-yl)propionic acid], a synthetic isocoumarin derivative not only identified as an orally active antiangiogenic agent with low toxicity but also reported to possess significant antiarthritic activity. However, NM-3 did not inhibit the activities of enzymes such as COX-1, COX-2, or phospholipase A2 associated with inflammation. The study30 of NM-3 in conjunction with ionizing radiotherapy (IR) suggested that NM-3 is selectively cytotoxic to endothelial cells (human umbilical vein endothelial cells or HUVEC) but had no detectable effects on HUVEC migration. Combination therapy with IR and NM-3 inhibited HUVEC migration and significantly reduced tumor volume to a greater extent compared with either therapy alone. NM-3 in combination with other chemotherapeutic agents, such as 5-fluorouracil, was also found to be effective.31 Although different methods have been reported for the synthesis of NM-3, two representative methods, i.e., orsellinic acidebased syntheses are presented here. One of these methods32 reported in 2003 involved preparation of the isocoumarin intermediate 437 (Scheme 5.10) from the orsellinic acid dimethylether (435) via the generation of 3,5-dimethoxy homopthalic acid (436). On reaction with ethyl methylmalonyl chloride, the acid 436 afforded the desired precursor, i.e., the protected NM-3 intermediate 437. Indeed, the isocoumarin ring was constructed in this step. The selective demethylation of 437 afforded the 8-hydroxyisocoumarin derivative (438) that on ester hydrolysis afforded the NM-3 (14). According to another report published in the next year, i.e., 2004, NM-3 (14) was prepared from the isocoumarin 443 (Scheme 5.11), which in turn was prepared from ethyl orsellinate (439) via a four-step method.33 Thus selective methylation followed by the hydroxy group protection of 439

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

CO2 Et 1) LDA/THF MeO -70 o C

Me

MeO

OH

CO2 H OH

2) CO(OMe)2 -30 o C

OMe O 435

Me

Me MeO CO2 Et

COCl

O

Et3 N, CH 2Cl2 0 oC

OMe O

MeO

Me

Me

MeO CO2 Et

MeO NaOH

CO2 H

O THF, reflux

HO

O MeCN: MeOH (1:1) 0 oC

O

438 (97%)

SCHEME 5.10

HO

1. MeI, K2 CO3

CO2 Et

2. EtOCH2 Cl, i-Pr2 NEt

OH

MeO

O 14 (quantitative)

Me CO 2Et

LDA

MeO CO2 H

CO2

CO 2Et EtOCH 2O

EtOCH 2O

441

440

439

tBuOH, PhH ref lux

HO

Preparation of NM-3 from the orsellinic acid dimethylether.

Me

Meldrum's acid DCC

O

437 (89%)

436 (92%)

MgCl2 , KI

MeO

MeO

CO 2tBu

EtOCH 2O

O CO 2Et

CO2 tBu

LDA O THF

EtOCH 2 O

442

O

443 Me

Me

MeO CO2 tBu

LDA CH 3I

165

O EtOCH 2 O

O 444

MeO CO2 H

1) HCl, i-PrOH 2) TFA, CH 2Cl2

O HO

O 14

SCHEME 5.11 Preparation of NM-3 from ethyl orsellinate.

afforded the compound 440, which was then converted to the homophthalic acid derivative (441). On coupling with Meldrum’s acid, the compound 441 afforded the ketone 442 that was subsequently converted to the isocoumarin derivative 443. Methylation of 443 afforded 444, which on deprotection and ester hydrolysis afforded the desired product (14). The use of LDA in this reaction sequence including the key step where the construction of isocoumarin ring was carried out was remarkable.

5.2.2 Precursor of Nitidine Synthesis of nitidine (450) that belongs to the fully aromatized benzo[c] phenanthridine alkaloid class of compounds was carried out from an isoquinolone intermediate (449) that in turn was prepared from the corresponding isocoumarin derivative (448) (Scheme 5.12).34 The isocoumarin

166 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

MeO MeO

OMe

MeO

OMe O

OMe

O

(EtO)Me2Si

O

+ O

O

I 445

MeO MeO

O

(EtO)Me 2Si

PdCl2(PPh 3) 2 Et3 N, 90 o C, 12h

OMe

MeO

OMe

I O

MeO

CO2 Me MeO

[(allyl)2 PdCl]2 (EtO) 3P, Bu 4NF THF, 60 oC, 2h 76%

O Hydrolysis

O MeO

O

OMe

MeO

OH

MeO O

MeO

446

447

O

OMe

MeO

OMe

O PdCl2(MeCN) 2

MeO

1,4-benzoquinone THF, 30 oC, 1h 48%

MeO

O

O 1, NH 3, EtOH 120 oC, 12h MeO

O

O O

4 48

2. NaH, MeI 56%

N

MeO O

Me 4 49

O 3 steps

MeO MeO

O N

Me

450 (Nitidine)

SCHEME 5.12 Preparation of nitidine.

precursor (448) was prepared from the iodoarene (445) via a double Heck-type coupling in a single pot followed by hydrolysis of the ester formed (446) and then a palladium-catalyzed cyclization of the resultant o-styrylbenzoic acid derivative (447).34 The double Heck-type coupling in a single pot was performed using two iodoarenes in a sequence to avoid the loss of yield at this step. However, the product yield (i.e., the yield 448) in the cyclization step was not particularly high and the regioisomeric fivemembered ring product, i.e., the corresponding 3-arylidine phthalide derivative was isolated in low yield as a side product. Moreover, this step was found to be sensitive towards the reaction conditions employed, e.g., the use of lower quantity of Pd catalyst at room temperature for longer reaction time (18 h) afforded a benzo[d]naphtho[l,2-b]pyran-6-one derivative instead of the desired isocoumarin precursor. Nevertheless, the isocoumarin derivative (448) on treatment with ammonia followed by methylation afforded the corresponding isoquinolone derivative that was converted to nitidine (450) according to a reported method. Apart from accomplishing the total synthesis of nitidine, this effort also provided a methodology for the construction of benzo[c]phenanthridine framework.

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

167

5.2.3 Bromo Isocoumarins Isocoumarins possessing a bromo group have been used generally as precursors for the preparation of isocoumarin analogs having various substituents. As presented in the previous sections that the bromo group could be used for further functionalization, particularly via Pd or other transition metalecatalyzed reactions, e.g., Sonogashira, Heck, Suzuki, or Buchwald reactions (Schemes 5.5 and 5.9). Accordingly, the bromo group could be replaced by substituents such as alkenyl, alkynyl, aryl, or amine moieties on an isocoumarin ring. Two interesting 7-substituted isocoumarin derivatives (452 and 453) were prepared from the bromo derivative 451 using this strategy (Scheme 5.13).35 Notably, apart from their utility on organic synthesis a 7-bromo isocoumarin derivative itself has been found to have biological activity. Thus the bromo derivative (455) prepared via bromination of the corresponding isocoumarin (454) (Scheme 5.14) showed relaxation of tracheal smooth muscle of guinea pig when tested in the same animal model.36 A regioselective monobromination was achieved successfully using N-bromo succinamide in the presence of a radical initiator AIBN (azobisisobutyronitrile) in this case.

MeO

MeO

O

Me

O

B(OH) 2

N Bn

N Bn

Me

Pd(PPh3 )4 , PPh3 CsF, 1,4-dioxane 100 o C, 3h

O Br

O

Ts

452 (88%)

Ts O

451

O (PPh3 )2 PdCl2 CuI, Et3 N, DMF 60 o C, 16h

Me

N Bn

Ts

453 (91%)

SCHEME 5.13 Bromoisocoumarins: functionalization via Pd-catalyzed reactions.

MeO

Me

NBS, CH2 Cl2

O OH 454

O

CCl4, AIBN 50o C, 2h

MeO

Me O

Br OH

O

455

SCHEME 5.14 Preparation of 7-bromo isocoumarin derivative.

168 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

5.2.4 Precursor of (D)-Sescandelin A 4-acetylisocoumarin derivative, e.g., AGI-7 (6,8-dihydroxy-4-acetylisocoumarin) (464), was used to prepare (þ)-sescandelin (465), isolated from the fungus Sesquicillium candelabrum (Scheme 5.15).37 Indeed, the AGI-7 was also isolated along with sescandelin from an unidentified fungal strain by bioassay-guided fractionation and isolation. The enantioselective reduction of AGI-7 (464) by borane in the presence of Corey’s (S)-oxazaborolidine reagent afforded the desired product (465) with a 93% ee. The synthesis of AGI-7 (464) involved the DielseAlder reaction of diene (456) with allenedicarboxylate (457) followed by aromatization with Et3NHþF to give the known homophthalate (458). The protection of its phenolic hydroxyl groups of 458 as benzylether followed by hydrolysis of the resulting compound 459 provided the homophthalic acid (460). Transforming the homophthalate (460) to the vinylogous amide ester (462 via the ketone 461) upon treatment with refluxing aqueous acetic acid afforded the 4-acetylisocoumarin derivative (463) as a major product along with its regioisomer, i.e., 3-methyl-4-formylisocoumarin in a 3:1 ratio. On further refluxing with 70% aqueous formic acid the ether groups of 463 was cleaved to provide the desired product AGI-7 (464). The enantioselective reduction of AGI-7 (464)

OTMS

CO 2Me

Neat, 0-25 o C HO 70 min

MeO 2C

TMSO

+ C

CO 2Me

Et3 N.HF, EtOH CO2 Me rt, 40 min 69% 457

OMe 456

OH 458

O

aqAcOH reflux 5h

COMe CO2Me OBn 462

Me2 NCH(OMe)2 BnO PhMe, reflux 5h, 87%

HO

CO 2H OBn 461

aqNaOH H2 O, 60 o C 1h, 76%

HO O

O CO2Me OBn

95% (mixture)

459

Ac2 O, Py Et2 O, rt overnight BnO

aq HCO 2H

COMe

OBn

COCH 3

COCH 3 BnO

BnO

CO 2Me

reflux 2days 87% KOH EtOH H2 O

Me2N BnO

CO 2Me BnBr, K2CO3 BnO Acetone, KI

reflux, 1d OBn O

OH

O

464 (AGI-7) Corey’s oxazaborolidine-catalyzed reduction

463 HO HO O

88% yield with a 93% ee

OH O 465; (+)-sescandelin

SCHEME 5.15 Preparation of (þ)-sescandelin.

reflux 24h 93% CO 2H

CO 2H OBn 460

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

169

was carried out after its separation from the unwanted minor isomer. Notably, the reduction of AGI-7 (464) under Luche conditions afforded ()-sescandelin as a racemate in 96% yield.

5.2.5 Precursor of 5-Aminoisoquinolin-1-One Analogs Isocoumarins have been used to prepare 3-substituted analogs of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs [poly(ADP-ribose)polymerases].38 PARP-1, one of the two isoforms of this superfamily, is an important target for drug design for several therapeutic applications including cancer. Indeed, inhibitors of PARP-1 have been in clinical trial for the treatment of cancer. The 5-AIQs were synthesized from their corresponding isocoumarin precursors that were initially prepared using different routes. The first one involved condensation of methyl 2-methyl-3-nitro benzoate with dimethyl formamide dimethyl acetal (DMFDMA) to afford the 5-nitroisocoumarin that on treatment with ammonia and then reduction of nitro group afforded a 3-unsubstituted 5-AIQ. However, this method could not be extended to the 3-methyl/3-aryl substituted analogs because of the difficulty in accessing the required benzamide acetals. In an alternative approach (Scheme 5.16), 3-aryl-5-nitroisocoumarins (467) were synthesized by CastroeStevens coupling of 2-iodo-3-nitrobenzoic acid (466; R1 ¼ H) with arylethynes, followed by cyclization in situ. However, this method was limited to three examples only. The Sonogashira coupling (Scheme 5.16) of methyl 2-iodo-3methylbenzoate (466; R1 ¼ Me) with phenylethynes followed by Hg2þ-catalyzed cyclization of the resulting alkyne (468) was also investigated, but that was only effective for one example (R2 ¼ Ph). The FriedeleCrafts acylation (Scheme 5.16) of 5-nitroisocoumarin (469) with aroyl chlorides under forcing conditions in nitrobenzene, followed by in situ rearrangement and decarboxylation afforded the desired product. But this low-yielding method was

O

O CO2 R 1

(R 1 = H)

NH

O

CuC CR2 R2 Pyridine NO2 NO2 467 reflux 466 (R 2 = Ph, 4-MePh, 4-MeOPh) HgSO4 H 2SO4 (R 1 = Me) CO2 R 1 acetone reflux Ph (PPh 3)2 PdCl2 NO2 Ph CuI, Pr i2NH, THF 468

R2

I

NH 2 R 2COCl, SnCl4 PhNO2 , 130 oC

5-AIQs

O O

NO2

469

SCHEME 5.16 Synthesis of analogs of 5-aminoisoquinolin-1-one (5-AIQ): earlier preparation of isocoumarin precursors.

170 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

CO2 H Br NO2

O

O

R

1) NH3

O R

Cu powder, KOBu t Bu tOH, reflux

O

NO2 471

470

O

MeO(CH 2) 2OH ref lux

NH

R 2) SnCl2, H2 Pd/C, EtOH aq HCl

R NH 2

472

R = Ph, aryl, Me, Et, pentyl, Bn, CH 2CHMe2

SCHEME 5.17 Synthesis of analogs of 5-aminoisoquinolin-1-one (5-AIQ): alternative preparation of isocoumarin precursors.

limited to benzoyl chloride and aroyl chlorides carrying electron-withdrawing para-substituents. Thus a more general method was developed for the synthesis of isocoumarin precursors (471) (Scheme 5.17) that involved a tandem Hurtley coupling of b-diketones with 2-bromo-3-nitrobenzoic acid (470) followed by retro-Claisen acyl cleavage and finally cyclization to afford the required 3-substituted 5-nitroisocoumarins (471) as starting materials. These isocoumarins (471) on treatment with ammonia at high temperature and reduction with tin(II) chloride afforded the target 3-substituted 5-AIQs (472), that in the form of their HCl salts were found to be soluble in water (>1% w/v).

5.2.6 Precursor of Fused Heterocycles The synthesis of 1,2-diaryl[2]benzopyrano[3,4-d]imidazole-5(1H)-one derivatives39 (476) has been achieved by using diaminoisocoumarin derivatives (474) as starting compounds (Scheme 5.18). The synthesis of diaminoisocoumarin derivatives (474) involved a strategy that was based on the combination of the Strecker and Ugi reactions.40 Nevertheless, treating diaminoisocoumarins (474), obtained from 2-formylbenzoic acid (473), with aromatic aldehydes followed by CAN-mediated cyclization of the resulting

ArHN CO2 H

ArNH 2

CHO

KCN/AcOH MeOH, ref lux

473

N

Ar'CHO

O 474

O

Ar'

ArHN NH2

O AcOH 70 o C

475

O

Ar'

Ar N CAN

N

THF room temp

O 476

O

SCHEME 5.18 Synthesis of 1,2-diaryl[2]benzopyrano[3,4-d]imidazole-5(1H)-one derivatives.

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

O

R

CO 2H

O

SOCl2

CO2 H

Cl

X

O OH

O O

dry CH2 Cl2 reflux, 98%

O

477

171

O

O

Et3 N, - 5 oC 1h

O

478

E-5.2

(X = Nphth, Cl; R = alkyl) O

O

O

NEt 3 O

O

O O O

O

O

O CO2 H

OH CO2 H

HO2 C

O E-5.3

O O O O O HO

R

O X

479 (60-79%)

SCHEME 5.19 Chiral pool based synthesis of naphtho-fused isocoumarins.

imine (475) afforded the products (476) containing tricyclic system, that is, fused isocoumarin with imidazole rings. The role of the CAN appeared to be important because it acted as a Lewis catalyst. The synthesis of naphtho-fused isocoumarin derivatives has been achieved by several methods. For example, the reaction of homophthalic acid with ethyl chloroformate in the presence of Et3N and NaN3 at 5  C afforded benzo[d] naphtha[1,2-b]pyran-6-one.41 Similarly, a variety of chiral derivatives of benzo [d]naphtho[1,2-b]pyran-6-one (479) were prepared in a single step via Et3Nmediated condensation of homophthalic anhydride (478), obtained from homophthalic acid (477), with different (S)-amino acid chlorides at 5  C (Scheme 5.19).42 The reaction proceeds via several steps involving isocoumarin E-5.2 and E-5.3 as key intermediates.

5.2.7 Precursor of Sparstolonin B Sparstolonin B (SsnB) containing both xanthone and isocoumarin core is a novel bioactive natural small molecule, isolated from a Chinese herb, Sparganium stoloniferum.43 This compound selectively blocks toll-like receptors 2 (TLR2) and TLR4-mediated inflammatory signaling by inhibiting the recruitment of MyD88 to the Toll/Il-1 receptor homologue domains of TLR2 and TLR4. Blockade of excessive TLR signaling is a therapeutic approach being actively pursued for many chronic inflammatory diseases

172 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin OH OH OMe

480

OMe O

OMe

O

Br CuI, PPh3

OMe

HO2 C

OMe MeO

PdCl2, piperidine 80 o C, 12h 80%

1) Bromobenzene Cs2 CO 3, Pd(OAc) 2 P(1-Naph)3 , o-xylene 160 oC, 36h 2) BBr 3, DCM -78 oC - rt 69%

OMe 481

OH

OMe

[Cp*RhCl2 ]2 Ag2 CO3, DMF 120 oC, 12h 86%

482

O

OH

PPTs, O2 OH

HO

Mesitylene 160 oC, 6h 75%

O

HO

OH O Sparstolonin B 484

483

SCHEME 5.20

OMe

MeO

O O

OH

Synthesis of SsnB.

such as diabetes, Alzheimer’s disease, autoimmune colitis, and heart and brain ischemia/reperfusion injury. Thus SsnB has been identified as a promising lead for the development of selective TLR antagonist for inflammation control. One of the syntheses of this compound (484) has been achieved via constructing the isocoumarin core first (Scheme 5.20). Thus Sonogashira coupling of 1-bromo-2,5-dimethoxybenzene (480) with 2-methylbut-3-yn-2-ol afforded the required alkyne (481), which was then coupled with 2,5-dimethoxybenzoic acid in the presence of an Rh-catalyst to give the corresponding 3,4-disubstituted isocoumarin derivative (482). The compound 482 on Pd-catalyzed removal of 2-hydroxyporp-2-yl substituent followed by demethylation of the OMe groups afforded the required 3-aryl substituted isocoumarin (483) that was converted to the target compound (484) via an oxidative cyclization method.

5.2.8 Precursor of Polyheterocyclic Compounds Some interesting polyheterocyclic compounds, e.g., 490 and 491 (Scheme 5.21), containing an isocoumarin ring as one of the heterocyclic moieties have been synthesized by using the alkyne coupling and then cyclization strategy. This multistep approach involved the sequential construction of benzofuran and isocoumarin ring of 487 and 489, respectively, followed by other heteroarene ring (Scheme 5.21).44 The reaction based on iodocyclization strategy was used as a key step in this multistep sequence, and the presence of iodo group in the product 487 (obtained from 1-iodo-2methoxybenzene 485 via the alkyne 486) and 489 (obtained from alkyne 488) formed allowed subsequent and desired transformations.

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

OMe

I

Ph Cat Pd/Cu 72%

485

Ph

OMe

Ph

I

OMe

O O

I

81% 486

487

Ph

Ph

I

O

173

Cat Pd/Cu 98%

XMe O

I O

91% OMe O

Cat Pd/Cu 55-79%

O

488

(X = NMe, O, S)

489 O

XMe O Ph

I

O O

O

91-96% O

490

Ph X

I 491

SCHEME 5.21 Generation of polyheterocyclic compounds.

5.3 CONCLUSIONS Although the utility and usefulness of isocoumarin framework has been explored in different areas, the focus of this chapter was particularly on their uses in medicinal/pharmaceutical chemistry, drug discovery, and organic synthesis. As mentioned earlier, isocoumarins display remarkable pharmacological properties in a broad range of therapeutic areas. Thus isocoumarin framework represents an attractive scaffold or pharmacophore for the design and development of new chemical entities in the area of drug discovery and pharmaceutical research. This is exemplified by the fact that compounds based on isocoumarin scaffold have been evaluated as PDE4 and various enzyme inhibitors, 5-LOX inhibitors, potential anticancer agents, antibacterial/antifungal agents, etc. Several examples on the preparation of isocoumarins of pharmacological interest are presented in this chapter. The utility of isocoumarins in organic synthesis has been demonstrated not only in the preparation of various natural products such as nitidin, tazettine, and ()-ochratoxin a but also in their frequent uses as intermediates in the synthesis of isocarbostyrils, isoquinolines, isochromenes, and various aromatic compounds. Indeed, isocoumarin-based compounds have been specifically used as a precursor of NM-3, (þ)-sescandelin, 5-AIQ analogs, Sparstolonin B, polyheterocyclic compounds, etc. Additionally, isocoumarins are used in the synthesis of a number of druglike small molecules.

174 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin

For example, a series of isocoumarin derivatives of potential pharmacological interest was prepared from the 4-haloisocoumarin via palladiumcatalyzed cross-coupling reactions. Several examples on the synthetic applications of isocoumarin or cases, where isocoumarin has been a synthetic precursor, are listed in this chapter.

REFERENCES 1. Heynekamp, J. J.; Hunsaker, L. A.; Jagt, T. A. V.; Royer, R. E.; Deck, L. M.; Jagt, D. L. V. Isocoumarin-Based Inhibitors of Pancreatic Cholesterol Esterase. Bioorg. Med. Chem. 2008, 16, 5285e5294. 2. Garino, C.; Bihel, F.; Souard, F.; Que lever, G.; Kraus, J.-L. N-Acyl Substituted 7-Amino-4Chloroisocoumarin: A Peptide Degradation Model Via an Imide Mechanism. Bioorg. Med. Chem. Lett 2004, 14, 1771e1774. 3. Kerrigan, J. E.; Oleksyszyn, J.; Kam, C.-M.; Selzler, J.; Powers, J. C. Mechanism-Based Isocoumarin Inhibitors for Human Leukocyte Elastase. Effect of the 7-Amino Substituent and 3-Alkoxy Group in 3-Alkoxy-7-Amino-4-Chloroisocoumarins on Inhibitory Potency. J. Med. Chem. 1995, 38, 544e552. 4. Garino, C.; Bihel, F.; Pietrancosta, N.; Laras, Y.; Quelever, G.; Woo, I.; Klein, P.; Bain, J.; Boucherd, J.-L.; Kraus, J.-L. New 2-Bromomethyl-8-Substituted-Benzo[c]chromen-6-Ones. Synthesis and Biological Properties. Bioorg. Med. Chem. Lett 2005, 15, 135e138. 5. Kovacs, T.; Sonnenbichler, I.; Sonnenbichler, J. Total Synthesis of the Toxin Oosponol and of Structural Analogs and Investigation of Their Antibiotic Activities. Liebigs Annalen 1997, 4, 773e777. 6. Kumar, P. M.; Kumar, K. S.; Meda, C. L. T.; Reddy, G. R.; Mohakhud, P. K.; Mukkanti, K.; Krishna, G. R.; Reddy, C. M.; Rambabu, D.; Kumar, K. S.; Priya, K. K.; Chennubhotla, K. S.; Banote, R. K.; Kulkarni, P.; Parsa, K. V. L.; Pal, M. (Pd/C-Mediated)couplinge IodocyclizationeCoupling Strategy in Discovery of Novel PDE4 Inhibitors: A New Synthesis of Pyrazolopyrimidines. Med. Chem. Commun. 2012, 3, 667e672. 7. Kodimuthali, A.; Jabaris, S.; Pal, M. Recent Advances on Phosphodiesterase 4 Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease. J. Med. Chem. 2008, 51, 5471e5489. 8. Nakhi, A.; Adepu, R.; Rambabu, D.; Kishore, R.; Vanaja, G. R.; Kalle, A. M.; Pal, M. Thieno [3,2-c]pyran-4-one Based Novel Small Molecules: Their Synthesis, Crystal Structure Analysis and In Vitro Evaluation as Potential Anticancer Agents. Bioorg. Med. Chem. Lett 2012, 22, 4418e4427. 9. Mulakayala, N.; Rambabu, D.; Raja, M. R.; Chaitanya, M.; Kumar, C. S.; Kalle, A. M.; Krishna, G. R.; Reddy, C. M.; Rao, M. V. B.; Pal, M. Ultrasound Mediated Catalyst Free Synthesis of 6H-1-Benzopyrano[4,3-b]Quinolin-6-Ones Leading to Novel Quinoline Derivtives: Their Evaluation as Potential Anti-cancer Agents. Bioorg. Med. Chem. 2012, 20, 759e768. 10. Li, K.; Luo, J. The Role of SIRT1 in Tumorigenesis. N. Am. J. Med. Sci. 2011, 4, 104e106. 11. Yadav, P.; Purohit, N. V. Synthesis and Biological Evaluation of Some Novel 3,4-Disubstituted Isocoumarins. Indian J. Pharm. Sci. 2011, 73, 171. 12. Zhao, Y.-H.; Luo, M.-J.; Liu, H.-W.; Wu, L.-H. K2CO3-Promoted Domino Reactions for Synthesis of Isocoumarins Under Microwave Irradiation. Synth. Commun. 2015, 45, 857e862.

Isocoumarins in Medicinal Chemistry and Organic Synthesis Chapter | 5

175

13. Wang, Q.-X.; Bao, L.; Yang, X.-L.; Guo, H.; Yang, R.-N.; Ren, B.; Zhang, L.-X.; Dai, H.-Q.; Guo, L.-D.; Liu, H.-W. Polyketides with Antimicrobial Activity from the Solid Culture of an Endolichenic Fungus Ulocladium sp. Fitoterapia 2012, 83, 209e214. 14. Simic, M.; Paunovic, N.; Boric, I.; Randjelovic, J.; Vojnovic, S.; Nikodinovic-Runic, J.; Pekmezovic, M.; Savic, V. Functionalised Isocoumarins as Antifungal Compounds: Synthesis and Biological Studies. Bioorg. Med. Chem. Lett 2016, 26, 235e239. 15. Sudarshan, K.; Manna, M. K.; Aidhen, I. S. Synthesis of 3-Arylisocoumarins by Using Acyl Anion Chemistry and Synthesis of Thunberginol A and Cajanolactone A. Eur. J. Org Chem. 2015, 1797e1803. 16. Ramanan, M.; Sinha, S.; Sudarshan, K.; Aidhen, I. S.; Doble, M. Inhibition of the Enzymes in the Leukotriene and Prostaglandin Pathways in Inflammation by 3-Aryl Isocoumarins. Eur. J. Med. Chem. 2016, 124, 428e434. 17. Sudarshan, K.; Aidhen, I. S. Convenient Synthesis of 3-Glycosylated Isocoumarins. Eur. J. Org Chem. 2017, 34e38. 18. Washburn, W. N. Development of the Renal Glucose Reabsorption Inhibitors: A New Mechanism for the Pharmacotherapy of Diabetes Mellitus Type 2. J. Med. Chem. 2009, 52, 1785e1794. 19. Napolitano, E. Synthesis of Isocoumarins over the Last Decade: A Review. Org. Prepn. Procedures Intl. 1997, 29, 631e664. 20. Azumi, M.; Ogawa, K.-I.; Fujita, T.; Takeshita, M.; Yoshida, R.; Furumai, T.; Igarashi, Y. Bacilosarcins A and B, Novel Bioactive Isocoumarins With Unusual Heterocyclic Cores From the Marine-Derived Bacterium Bacillus subtilis. Tetrahedron 2008, 64, 6420e6425. 21. Saeed, A. Isocoumarins, Miraculous Natural Products Blessed With Diverse Pharmacological Activities. Eur. J. Med. Chem. 2016, 116, 290e317. 22. Barry, R. D. Isocoumarins. Development Since 1950. Chem. Rev. 1964, 64, 229e260. 23. Angelis, M. D.; Stossi, F.; Waibel, M.; Katzenellenbogen, B. S.; Katzenellenbogena, J. A. Isocoumarins as Estrogen Receptor Beta Selective Ligands: Isomers of Isoflavone Phytoestrogens and Their Metabolites. Bioorg. Med. Chem. 2005, 13, 6529e6542. 24. Roy, S.; Roy, S.; Neuenswander, B.; Hill, D.; Larock, R. C. J. Solution-Phase Synthesis of a Diverse Isocoumarin Library. Comb. Chem. 2009, 11, 1128e1135. 25. Manivel, P.; Roopan, S. M.; Khan, F. N. Synthesis of O-Substituted Benzophenones and 1,2Phenylethanones From Isocoumarins. Indian J. Heterocycl. Chem. 2008, 18, 21e24. 26. Manivel, P.; Roopan, S. M.; Khan, F. N. Synthesis of O-Substituted Benzophenones by Grignard Reaction of 3-Substituted Isocoumarins. J. Chil. Chem. Soc. 2008, 53, 1609e1610. 27. Qadeer, G.; Rama, N. H.; Gardun˜o-Ramı´rez, M. L. Synthesis and Anti-inflammatory Activity of Fluorinated Isocoumarins and 3,4-Dihydroisocoumarins. J. Fluorine Chem. 2007, 128, 641e646. 28. Saeed, A.; Ashraf, Z. Synthesis of Some 3-Aryl-1H-Isochromene-1-Thiones. J. Heterocycl. Chem. 2009, 45, 679e682. 29. Deady, L. W.; Loria, P. M.; Rodemann, T. Studies on the Synthesis of Benzimidazo[2,1-a] isoquinolines. Aust. J. Chem. 1998, 51, 941e946. 30. Salloum, R.; Jaskowiak, N.; Mauceri, H.; Seetharam, S.; Beckett, M.; Koons, A.; Hari, D.; Gupta, V.; Reimer, C.; Kalluri, R.; Posner, M.; Hellman, S.; Kufe, D.; Weichselbaum, R. NM3, an Isocoumarin, Increases the Antitumor Effects of Radiotherapy Without Toxicity. Cancer Res. 2000, 60, 6958e6963.

176 Isocoumarin, Thiaisocoumarin and Phosphaisocoumarin 31. Reimer, C. L.; Agata, N.; Tammam, J. G.; Bamberg, M.; Dickerson, W. M.; Kamphaus, G. D.; Rook, S. L.; Milhollen, M.; Fram, R.; Kalluri, R.; Kharbanda, S. Antineoplastic Effects of Chemotherapeutic Agents Are Potentiated by NM-3, an Inhibitor of Angiogenesis. Cancer Res. 2002, 62, 789e795. 32. Tsuchida, T.; Kuroda, A.; Nagai, H.; Yoshida, M.; Nakashima, T.; Konuki, K.; Isshiki, K.; Nakamura, H.; Takeuchi, T. Convenient Total Synthesis of NM-3, an Antiangiogenesis Agent, and Its Optical Resolution. J. Antibiot. 2003, 56, 38e41. 33. Yuan, H.; Junker, B.; Helquist, P.; Taylor, R. E. Synthesis of Anti-angiogenic Isocoumarins. Curr. Org. Synth. 2004, 1, 1e9. 34. Minami, T.; Nishimoto, A.; Hanaoka, M. Formal Synthesis of Nitidine Through PalladiumCatalyzed Isocoumarin Synthesis. Tetrahedron Lett. 1995, 36, 9505e9508. 35. Liu, H.; Yang, Y.; Wu, J.; Wang, X. N.; Chang, J. Regioselective Synthesis of 3,4Disubstituted Isocoumarins Through the Pd-Catalyzed Annulation of 2-Iodoaromatic Acids With Ynamides. Chem. Commun. 2016, 52, 6801e6804. 36. Nakajima, T.; Kuroda, A.; Tsuji, E.; Yoshida, M.; Tsuchida, T.; Agata, N.; Isshiki, K.; Takeuchi, T. Isocoumarins and Bronchodilators Containing Them. JP 2002161091 Chem. Abstr. No. 137:731. 37. Kim, S.; Fan, G.-J.; Lee, J.; Lee, J. J.; Kim, D. Synthesis of 4-Acetylisocoumarin: First Total Syntheses of AGI-7 and Sescandelin. J. Org. Chem. 2002, 67, 3127e3130. 38. Woon, E. C. Y.; Sunderland, P. T.; Paine, H. A.; Lloyd, M. D.; Thompson, A. S.; Threadgill, M. D. One-Pot Tandem HurtleyeRetro-ClaiseneCyclisation Reactions in the Synthesis of 3-Substituted Analogues of 5-Aminoisoquinolin-1-One (5-AIQ), A WaterSoluble Inhibitor of PARPs. Bioorg. Med. Chem. 2013, 21, 5218e5227. 39. Rodrı´guez, R.; Vicentes, D. E.; Cobo, J.; Nogueras, M. Synthesis of New 1,2-Diaryl[2] Benzopyrano[3,4-d]Imidazole-5(1H)-One Derivatives Mediated by Ceric Ammonium Nitrate. Tetrahedron Lett. 2017, 58, 1487e1489. 40. Opatz, T.; Ferenc, D. Facile Preparation of 3-Amino-4-(Arylamino)-1H-Isochromen-1-Ones by a New Multicomponent Reaction. Eur. J. Org Chem. 2005, 5, 817e821. ¨ zcan, S.; Balci, M. The Chemistry of Homophthalic Acid: A New Synthetic Strategy for 41. O Construction of Substituted Isocoumarin and Indole Skeletons. Tetrahedron 2008, 64, 5531e5540. 42. Raza, A. R.; Saddiqa, A.; C¸akmak, O. Chiral Pool-Based Synthesis of Naphtho-Fused Isocoumarins. Chirality 2015, 27, 951e957. https://doi.org/10.1002/chir.22530. 43. Wang, Y.; Wang, C.; Wang, Y.; Dong, L.; Sun, J. Total Synthesis of Sparstolonin B, A Potent Anti-inflammatory Agent. RSC Adv. 2015, 5, 12354e12357. 44. Mehta, S.; Larock, R. C. Iodine/palladium Approaches to the Synthesis of Polyheterocyclic Compounds. J. Org. Chem. 2010, 75, 1652e1658.