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Tetrahedron 70 (2014) 8161e8167

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Tetrahedron

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Total synthesis of racemic, natural (þ) and unnatural (�)scorzocreticin

B.T.V. Srinivas, Amarnath R. Maadhur, Sreedhar Bojja *

Inorganic & Physical Chemistry Division, Indian Institute of Chemical Technology (Council of Scientific & Industrial Research), Hyderabad 500607, India

a r t i c l e i n f o

Article history:Received 28 April 2014Received in revised form 25 June 2014Accepted 15 July 2014Available online 21 August 2014

Keywords:Intramolecular carbonylationLactonizationScorzocreticinTotal synthesis

Fig. 1. Dihydroisocoumarin derivatives and the

* Corresponding author. Tel./fax: þ91 40 27160921iict.res.in (S. Bojja).

http://dx.doi.org/10.1016/j.tet.2014.07.1070040-4020/� 2014 Elsevier Ltd. All rights reserved.

a b s t r a c t

The first total synthesis of racemic scorzocreticin and its pure enantiomers is described from readilyavailable 3,5-dihydroxybenzoic acid. The key steps include Wittig olefination, asymmetric Me-CBS(CoreyeBakshieShibata) oxazaborolidine reduction, and improved Pd-catalyzed intramolecular lacto-nization reactions. Both the (S)-natural and (R)-unnatural enantiomers of scorzocreticin have beensynthesized in excellent enantioselectivities (>99% and 99% ee, respectively). In addition, 1,10-phenanthroline, a bidentate N-ligand was employed in palladium-catalyzed intramolecular carbonyla-tion/lactonization reaction for the construction of 3,4-dihydroisocoumarin ring.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction

3,4-Dihydroisocoumarin is a key structural motif found in sev-eral alkaloids and natural products that possess a wide range ofbiological activities.1 In particular, 3-substituted 3,4-dihydroisocoumarin derivatives have attracted considerable in-terest in medicinal chemistry as they show remarkable antibacte-rial, anticancer, antifungal or antimalarial properties.2 Mellein (seeFig. 1) is one of the most interesting example in such a class of

ir metabolic products.

; e-mail address: sreedharb@

compounds known for having antibacterial activity.3 Hydrangenol,an allergenic natural product4 and AI-77-B, a gastroprotectivesubstance isolated from a culture broth of Bacillus pumilus AI-77,5

are other examples of isocoumarins that have been of vast in-terest in organic synthesis.6,7 Scorzocreticin (S)-1was isolated fromMeOH extract of Scorzonera cretica, a plant commonly used in tra-ditional Cretan cuisine as an ingredient in savory meat dishes.8

Scorzocreticin possesses a single stereogenic center at the C-3position of the 3,4-dihydroisocoumarin ring. The absolute config-uration of scorzocreticinwas determined by the Skaltsounis and co-workers based on CD spectral data with that of mellein.8 In 2006,Saeed initially reported the synthesis of (�)-6-O-methyl-scorzocreticin.9 In spite of the presence of only one asymmetriccarbon no chemical synthesis of natural (S)-6,8-dihydroxy-3-(4-methoxyphenyl)isochroman-1-one, and its enantiomer, featuringan effective control of the absolute configuration has been pub-lished so far. We in particular became interested in the synthesis ofthese threemolecules, largely due to their structural similarity withvarious biological active compounds10 and at the same time findingnew leadmolecules for structureeactivity relationship studies.11 Soin this paper, we present the first total synthesis of racemic scor-zocreticin (�)-1, and its (S)-(þ)1 and (R)-(�)1 enantiomers. The keystep involves the use of 1,10-phenanthroline as a supporting ligandin Pd-catalyzed carbonylation/lactonization reaction for the con-struction of 3,4-dihydroisocoumarin ring.

Retrosynthetic analysis (Scheme 1) revealed that 3,4-dihydroisocoumarin skeleton could be synthesized via palladium-catalyzed intramolecular lactonization reaction with carbon mon-oxide. The two chiral alcohol precursors (S)-2 and (R)-2 could be

Scheme 1. Retrosynthetic analysis of (S)-1, (R)-1, and (�)-1.

B.T.V. Srinivas et al. / Tetrahedron 70 (2014) 8161e81678162

generated from a common intermediate 3 via asymmetric re-duction by using (S)-Me-CBS and (R)-Me-CBS catalysts, re-spectively.12 While, the synthesis of 3 could be achieved by anoxidation process from racemic 2whereas (�)-1was prepared from(�)-2 using carbonylation process. Alcohol (�)-2 can be retro-synthetically traced back to 5 by a sequence of oxidation, Wittigolefination, and Grignard reactions.

2. Results and discussion

To begin with we focused our attention on the synthesis of ra-cemic scorzocreticin (�)-1, which is believed to be useful for the

Scheme 2. Reagents and conditions: (a) CH3OH, H2SO4, reflux; (b) BnBr, K2CO3, DMF, rt; (c) LiAlH4, THF, rt; (d) PCC, DCM, rt; (e) Ph3P]CH2, t-BuOK, THF, 0 �C; (f) BH3$DMS, THF, rtthen NaOH, H2O2; (g) DesseMartin periodinane, DCM, rt then p-H3COeC6H4eMgBr, THF, 0 �C; (h) NIS, CHCl3, rt; (i) PdCl2(PPh3)2, 1,10-phenanthroline, K2CO3, CO, DMF, 100 �C; (j) H2,10% Pd/C, MeOH, rt.

asymmetric synthesis of optically active (S)-1 and (R)-1. The initialapproach for the synthesis of (�)-1 started from dibenzyl alcohol 6,which was prepared from 3,5-dihydroxybenzoic acid 5 througha straightforward three-step sequence of esterification, benzyl

protection, and reduction with LiAlH4 by reported procedure13

(Scheme 2). Oxidation of alcohol 6 with PCC provided 3,5-bis(benzyloxy)benzaldehyde 7.14 Witting olefination between 7and Ph3PCH3Br in THF at 0 �C afforded the stilbene 8 in 79% yield.15

Hydroboration (BH3$DMS) followed by oxidation (NaOH and H2O2)of the stilbene 8 delivered the primary alcohol 4 in 83% yield. Theoxidation of alcohol 4 with the DesseMartin periodinane (DMP)16

resulted in the corresponding aldehyde that is subsequently usedin nucleophilic addition by (4-methoxyphenyl)magnesium bro-mide, and this in turn resulted in secondary alcohol (�)-9 in 59%yield. Further, iodination of (�)-9 with N-iodosuccinimide inchloroform provided the aryl iodide (�)-2 in 91% yield.17

Subsequently, for construction of the 3,4-dihydroisocoumarinring, we used palladium-catalyzed carbonylation of aryl iodide(�)-2. It has been reported that acetoxy group serves as a goodnucleophile compared to hydroxyl group in the lactonization

B.T.V. Srinivas et al. / Tetrahedron 70 (2014) 8161e8167 8163

process.18,19 In order to minimize the number of steps and maxi-mize the atom economy of this total synthesis, we carried out thereaction keeping the hydroxyl group as such. For this (�)-2 wasexposed to CO gas in the presence of catalytic amount ofPdCl2(PPh3)2 at 60 �C furnishing (�)-10 in very low yield of 34%.18

In order to improve the yield, screening of the reaction condi-tions of the carbonylative lactonization of aromatic iodide (�)-2was carried out. The following reaction variables were examined:presence or absence of ligands, catalysts, solvents, and reactiontemperature and the results are presented in Table 1. One of our

Table 1Carbonylative lactonization of aromatic iodide (�)-2aa

Entry Catalyst Ligand Solvent Temp (�C) Yieldb (%)

1 PdCl2(PPh3)2 d DMF 60 342 PdCl2(PPh3)2 Ph3P DMF 60 383 PdCl2(PPh3)2 Xantphos DMF 60 484 PdCl2(PPh3)2 DPEPhos DMF 60 365 PdCl2(PPh3)2 dppp DMF 60 426 PdCl2(PPh3)2 2,20-Bipy DMF 60 527 PdCl2(PPh3)2 TMEDA DMF 60 548 PdCl2(PPh3)2 1,10-Phen DMF 60 619 PdCl2(PPh3)2 1,10-Phen DMF 100 6510 PdCl2(PPh3)2 1,10-Phen DMF 100 76c

11 PdCl2(PPh3)2 1,10-Phen DMSO 100 5112 PdCl2(PPh3)2 1,10-Phen Toluene 100 4613 PdCl2 1,10-Phen DMF 100 4614 Pd(OAc)2 1,10-Phen DMF 100 49

DPEPhos¼(oxydi-2,1-phenylene)bis(diphenylphosphine), TMEDA¼tetramethyle-thylenediamine, dppp¼1,3-bis(diphenylphosphino)propane.The most successful entry is highlighted in italics.

a Reaction conditions: aromatic iodide (�)-2 (1 mmol), catalyst (5 mol%), ligand(5 mol%), CO (1 atm), K2CO3 (2 mmol) in solvent (3 mL) for 6 h.

b Isolated yield.c The reaction was carried out for 24 h.

Scheme 3. Formation of prochiral ketone 3.

first considerations for optimization of this reaction was the use ofdifferent ligands. Xantphos, a bidentate phosphine ligand that hasbeen used extensively for carbonylation reaction was proved in-efficient to provide the required product in good yield (48%) (Table1, entry 3).20 Further, DPEPhos and dpppwere also examined in thisscreening investigation (Table 1, entries 4 and 5), but a decrease in

Scheme 4. Completion of the total synthesis of (S)-1 and (R)-1. Reagents and conditions: (a)100 �C; (c) H2, 10% Pd/C, MeOH, rt; (d) (R)-Me-CBS, BH3.SMe2, THF, rt.

the reaction yield of (�)-10 was observed. After the screening ofa series of phosphorous-based ligands, we next moved our atten-tion to bidentate nitrogen ligands. To our delight, addition of 1,10-phenanthroline as ligand significantly improved the yield to 61% of(�)-10 in DMF after 6 h (Table 1, entry 8). Furthermore, in com-parison to other screened ligands, the bidentate N-ligands like 2,20-bipyridine and TMEDA also gave good yields of 52 and 54% of(�)-10, respectively (Table 1, entries 6 and 7). Moreover, an increasein yield to 76% of the desired product was obtained after 24 h at100 �C (Table 1, entry 10). However, a further increase in reactiontemperature or time proved to be totally ineffective. Among thesolvents screened, best results were obtained with DMF.We furtherexamine the effect of catalyst loadings on the reaction and foundthat 5 mol% of PdCl2(PPh3)2 is efficient for carbonylation/lactoni-zation reaction.

As illustrated in Table 1, the catalytic system, (5 mol% ofPdCl2(PPh3)2, 5 mol% of 1,10-phenanthroline, K2CO3, DMF at 100 �C)proved to be highly efficient to afford the dibenzyl lactone (�)-10 ingood yield. Moreover, the added advantages of these new improvedconditions are (1) direct use of hydroxyl group for high atomeconomy without the need to convert to acetoxy group and (2)handling of moisture sensitive phosphorous ligands is avoided.

Finally, the benzyl protecting groups were removed from (�)-10by using Pd/C hydrogenolysis reaction to afford the desired racemicscorzocreticin (�)-1 in 79% yield. Starting from building block 5, theoverall yield of (�)-1 was 17.3%.

With racemic 1 in hand, we then focused our attention on theenantioselective synthesis of both the enantiomers of scorzocreti-cin. For this, alcohol 2 was oxidized with PCC to furnish the cor-responding prochiral ketone 3 (see Scheme 3).

Next, enantioselective reduction of prochiral ketone 3 wasattempted using asymmetric Me-CBS (CoreyeBakshieShibata)oxazaborolidine (Scheme 4). It was found that the best results

(S)-Me-CBS, BH3.SMe2, THF, rt; (b) PdCl2(PPh3)2, 1,10-phenanthroline, K2CO3, CO, DMF,

B.T.V. Srinivas et al. / Tetrahedron 70 (2014) 8161e81678164

were obtained using (S)-Me-CBS ((S)-2-methyl-CBS-oxazabor-olidine) as the catalyst and BH3$SMe2 as the hydride ion sourceat rt. Compound (S)-2 was obtained in 90% yield with excellentenantiomeric purity (ee >99%) by chiral HPLC analysis. Treat-ment of (S)-2 with the optimized reaction conditions resulted in76% yield of dibenzyl lactone (S)-10. Deprotection of the benzylgroup in (S)-10 is accomplished by reaction with 10% Pd/C andthe title compound (S)-(þ)1 is isolated in 86% yield with an op-tical purity of >99% ee. The proton NMR spectra and specificrotation value of natural (S)-(þ)1 were in full agreement with theliterature data8 {[a]D20 þ21.5 (c 0.2, MeOH): lit.8 [a]D20 þ23.3 (c 0.2,MeOH)}.

The unnatural enantiomer (R)-(�)1 was prepared by followingthe same procedure from prochiral ketone 3 using (R)-Me-CBS ((R)-2-methyl-CBS-oxazaborolidine) as the catalyst. The specific rota-tion of (R)-(�)1 was [a]D20 �20.8 (c 0.2, MeOH), which is consistentwith the literature data reported for (S)-enantiomer.8 Thus, startingfrom the same precursor 3, we enantioselectively synthesized boththe enantiomers of scorzocreticin. Using (�)-1 as an authenticsample, we subjected both the enantiomers (S)-(þ)1 and (R)-(�)1to chiral HPLC analysis [Chiralpak IA (250�4.6 mm) 5 mm, hexane/ethanol¼4:1, flow rate¼1mL/min]. The HPLC analysis revealed thatnatural (S)-(þ)1 (tR¼9.98 min) eluted before the unnatural (R)-(�)1(tR¼12.69 min).

Since the present manuscript describes the first total synthesisof (S)-(þ)1 and (R)-(�)1, it provides an opportunity to prove thatthe assigned stereochemistry is correct. Following a modificationof the Mosher method, the newly created stereogenic center incompound (S)-2 bearing the hydroxyl group was assigned.21 Thesynthesis of both the (S)- and (R)-MTPA esters of (S)-2 was ob-tained using MTPA acid and a carboxylic acid-activatingagentdDCC. The chemical shifts of both the (S)- and (R)-MTPAesters of (S)-2 were assigned by proton NMR spectra. From theequation given in Fig. 2, DdSR values were calculated for as manyanalogous protons as possible. The carbon chain bearing protonsshowing Dd negative values should be placed on the left hand sideof the model whilst that where Dd has positive values should beplaced on the right hand side. Using the CahneIngoldePrelogconvention, the stereochemistry of (S)-2 was assigned as S-con-figuration, which thus establishes the absolute stereochemistry of(R)-2.

OMTPA

HOI

BnO

OBn

+2

-110-130

Fig. 2. DdSR¼(dS�dR)�103 for (S)- and (R)-MTPA esters of compound (S)-2.

3. Conclusions

In summary, we have achieved the first total synthesis of(�)-scorzocreticin and its enantiomers by improving the existingpalladium-catalyzed carbonylation/lactonization and found that1,10-phenanthroline is the best supporting ligand for this trans-formation in DMF at 100 �C for 24 h. The overall yield of the natural(S)-(þ)1 and unnatural (R)-(�)1 was found to be 16.6 and 15.1%,respectively. Application of the strategies presented herein for thesynthesis of other derivatives of the 3,4-dihydroisocoumarins is inprogress in our laboratory.

4. Experimental section

4.1. General

All reactions that required anhydrous conditions were carriedby standard procedures under a nitrogen atmosphere. All chemicalswere purchased from commercial vendors and used as is, unlessotherwise specified. Ethyl acetate, hexane, and acetone were dis-tilled before use. Reactions were monitored by thin layer chroma-tography (TLC) with 250 mm precoated silica gel plates. Infraredspectrawere recorded on an FT-IR spectrophotometer and reportedin wavenumbers (cm�1). 1H NMR and 13C NMR spectra wererecorded on a 300 MHz and a 75 MHz spectrometer, respectively.Chemical shifts are reported relative to chloroform (d 7.26), orDMSO (d 2.50) for 1H NMR and chloroform (d 77.2), or DMSO (d39.5) for 13C NMR. High-resolution mass spectra were obtained byusing ESI-QTOF mass spectrometry. Enantiomeric excesses weredetermined by HPLC analysis using analytical chiral columns. Op-tical rotations were recorded on a polarimeter equipped witha sodium lamp source (589 nm).

4.2. (3,5-Bis(benzyloxy)phenyl)methanol (6)

(a) To a solution of 3,5-dihydroxybenzoic acid 5 (3.0 g,19.48 mmol) in methanol (40 mL) was added a catalytic amount ofsulfuric acid (0.3 mL). After stirring at refluxing temperature for 6 h,the mixture was cooled to rt. After concentration, the residue wasdissolved in ethyl acetate (100 mL). The solution was washed withsaturated NaHCO3, water, brine, and dried with Na2SO4 givingmethyl 3,5-dihydroxybenzoate 11 (3.20 g, 98%) (pleasesee Supplementary data) as a white solid; Rf (EtOAc/Hex, 1:1) 0.40;IR (KBr) nmax 3381, 2951, 1693, 1487, 1350, 1262, 1168, 1103,999 cm�1; 1H NMR (300 MHz, CDCl3): d 6.98 (d, J¼2.2 Hz, 2H), 6.56(t, J¼2.2 Hz, 1H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3þDMSO-d6):d 166.3, 157.7, 130.9, 107.2, 107.0, 51.2; ESI-MS m/z 169 (MþH)þ.

(b) To a solution of 11 (3 g, 17.8 mmol) in dry DMF (60 mL) wasadded anhydrous potassium carbonate (7.39 g, 53.57 mmol). After1 h, benzyl bromide (4.27mL, 35.7mmol) was added dropwise overa period of 30 min and the reaction was allowed to proceed for 8 hat rt. The reaction mixture was poured on ice-water (100 mL) andextracted with EtOAc (3�100 mL). The organic fractions werewashed with saturated brine and dried over anhydrous Na2SO4.Evaporation of the solvent gave the product, which was crystallizedfrom hexane/ether to afford the protected ester 12 (5.96 g, 96%) asa white solid; Rf (EtOAc/Hex, 1:9) 0.37; IR (KBr) nmax 2944, 1714,1598,1440,1353,1296,1166,1042 cm�1; 1H NMR (300MHz, CDCl3):d 7.45e7.31 (m, 10H), 7.30 (d, J¼2.0 Hz, 2H), 6.80 (t, J¼2.0 Hz, 1H),5.06 (s, 4H), 3.89 (s, 3H); 13C NMR (75 MHz, CDCl3): d 166.7, 159.7,136.4, 132.0, 128.6, 128.1, 127.5, 108.3, 107.1, 70.2, 52.3; ESI-MS m/z349 (MþH)þ; ESI-HRMS found: 371.12764 (MþNa)þ, forC22H20O4Na calcd 371.12538.

(c) A solution of 12 (5.8 g, 16.66 mmol) in dry THF (30 mL) wasadded dropwise to a cold suspension of LiAlH4 (0.95 g, 25 mmol) indry THF (20 mL). The reaction mixture was stirred for 2 h. Theexcess LiAlH4was decomposed by the successive dropwise additionof methanol, water and 10% NaOH. The organic layer was dried overanhydrous Na2SO4. The crude product was purified by columnchromatography to afford the dibenzyl alcohol 6 (4.85 g, 91%) asa colorless solid; Rf (EtOAc/Hex, 3:7) 0.29; IR (KBr) nmax 2864, 1728,1594,1446,1358,1284,1155,1023 cm�1; 1H NMR (300MHz, CDCl3):d 7.46e7.32 (m, 10H), 6.63 (d, J¼2.2 Hz, 2H), 6.55 (t, J¼2.2 Hz, 1H),5.04 (s, 4H), 4.63 (s, 2H); 13C NMR (75 MHz, CDCl3): d 160.0, 143.4,136.7, 128.5, 127.9, 127.4, 105.6, 101.2, 70.0, 65.2; ESI-MS m/z 321(MþH)þ; ESI-HRMS found: 321.14813 (MþH)þ, for C21H21O3 calcd321.14852.

B.T.V. Srinivas et al. / Tetrahedron 70 (2014) 8161e8167 8165

4.3. 3,5-Bis(benzyloxy)benzaldehyde (7)

Pyridinium chlorochromate (6.19 g, 28.75 mmol) was sus-pended in dichloromethane (60 mL) and treated with a solution ofalcohol 6 (4.60 g, 14.37 mmol) in dichloromethane (60 mL) at roomtemperature. After 4 h, the reaction mixture was diluted withdiethyl ether (100 mL) and passed through a pad of silica gel byusing diethyl ether as eluant. Evaporation of the solvent afforded 7(4.34 g, 95%) as a light orange color solid; Rf (EtOAc/Hex, 1:9) 0.29;IR (KBr) nmax 2933, 2826, 1687, 1592, 1451, 1349, 1294, 1171,1053 cm�1; 1H NMR (300 MHz, CDCl3): d 9.89 (s, 1H), 7.48e7.30 (m,10H), 7.11 (d, J¼2.2 Hz, 2H), 6.87 (t, J¼2.2 Hz, 1H), 5.09 (s, 4H); 13CNMR (75MHz, CDCl3): d 191.7,160.4,138.4,136.2,128.6,128.2,127.5,108.7, 108.3, 70.4; ESI-MS m/z 319 (MþH)þ; ESI-HRMS found:319.13287 (MþH)þ, for C21H19O3 calcd 319.13287.

4.4. (((5-Vinyl-1,3-phenylene)bis(oxy))bis(methylene))di-benzene (8)

Aldehyde 7 (4.2 g, 13.20 mmol) was dissolved in THF (50 mL)and added dropwise to a cooled (0 �C) solution of methylene-triphenylphosphorane [prepared from Ph3PCH3Br (7.07 g,19.81 mmol) and t-BuOK (2.23 g, 19.81 mmol) at 0 �C in THF(50 mL)]. After 2 h at 0 �C, the reaction was quenched with satu-rated aqueous NH4Cl (60 mL), and the aqueous phase was extractedwith EtOAc (3�100 mL). The organic layer was dried over anhy-drous Na2SO4. The crude product was purified by column chro-matography to yield 8 (3.3 g, 79%) as a white solid; Rf (EtOAc/Hex,1:9) 0.58; IR (KBr) nmax 2870, 1589, 1448, 1338, 1292, 1156,1048 cm�1; 1H NMR (300 MHz, CDCl3): d 7.47e7.29 (m, 10H), 6.67(d, J¼2.2 Hz, 2H), 6.64 (dd, J¼17.3, 10.5 Hz, 1H), 6.54 (t, J¼2.2 Hz,1H), 5.71 (d, J¼17.3 Hz, 1H), 5.25 (d, J¼10.5 Hz, 1H), 5.04 (s, 4H); 13CNMR (75MHz, CDCl3): d 160.0,139.6,136.8,136.7,128.5,127.9,127.5,114.4, 105.5, 101.6, 70.0; ESI-MSm/z 317 (MþH)þ; ESI-HRMS found:317.15329 (MþH)þ, for C22H21O2 calcd 317.15361.

4.5. 2-(3,5-Bis(benzyloxy)phenyl)ethanol (4)

To a solution of 8 (2.8 g, 8.86 mmol) in THF (30 mL) was addedBH3$DMS (2 M in THF, 13.3 mL, 26.57 mmol) dropwise at rt. Thereaction mixture was stirred for overnight. After 12 h, the solutionwas cooled to 0 �C and a cold (0 �C) solution of aqueous NaOH (5 M,17.7 mL, 88.5 mmol) was added dropwise. Then a cold (0 �C) so-lution of H2O2 (33%, 18 mL, 177 mmol) was carefully added drop-wise. After stirring at 0 �C for 10 min, the cold bath was removedand the reaction mixture was vigorously stirred at rt for 1 h. Thereaction mixture was diluted with water (30 mL) and EtOAc(30 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (2�60 mL). The organic layer was dried overanhydrous Na2SO4. The crude product was purified by columnchromatography to afford compound 4 (2.45 g, 83%) as a whitesolid; Rf (EtOAc/Hex, 3:7) 0.22; IR (KBr) nmax 2919, 2876, 1593, 1450,1376,1288,1158,1047 cm�1; 1H NMR (300MHz, CDCl3): d 7.46e7.31(m, 10H), 6.51 (t, J¼2.2 Hz, 1H), 6.48 (d, J¼2.2 Hz, 2H), 5.02 (s, 4H),3.84 (t, J¼6.0 Hz, 2H), 2.80 (t, J¼6.0 Hz, 2H), 1.41 (br s, 1H); 13C NMR(75 MHz, CDCl3): d 160.0, 140.8, 136.8, 128.5, 127.9, 127.5, 108.2,100.1, 70.0, 63.3, 39.4; ESI-MS m/z 335 (MþH)þ; ESI-HRMS found:335.16581 (MþH)þ, for C22H23O3 calcd 335.16417.

4.6. 2-(3,5-Bis(benzyloxy)phenyl)-1-(4-methoxyphenyl)etha-nol ((±)-9)

DesseMartin periodinane (5.83 g, 13.77 mmol) was addedslowly to a stirred solution of alcohol 4 (2.3 g, 6.88 mmol) in CH2Cl2(20 mL) maintained at rt. The reaction mixture was stirred for 18 h.The product was recovered by simple workup procedure that

involves dilution of the mixture with cold aqueous NaOH followedby H2O (40 mL). The organic layer was dried over anhydrousNa2SO4. Evaporation of the solvent afforded the aldehyde (2.03 g,89%), and the crude aldehyde was directly used in the next stepwithout further purification. This aldehyde was dissolved in THF(20 mL) and added dropwise to a cooled (0 �C) solution of (4-methoxyphenyl)magnesium bromide [prepared from 1-bromo-4-methoxybenzene (1.51 mL, 12.22 mmol) and Mg turnings(0.586 g, 24.45 mmol), a crystal of iodine, at 0 �C in THF (20 mL)].After stirring for an additional 2 h, the reaction mixture wasquenched with a saturated aqueous NH4Cl solution and extractedwith EtOAc (3�80 mL). The combined organic extracts were driedwith anhydrous Na2SO4. After filtration and removal of the solvent,the residue was purified by column chromatography to yield (�)-9(1.77 g, 66%) as a pale yellow thick oil; Rf (EtOAc/Hex, 3:7) 0.35; IR(neat) nmax 2925, 1594, 1452, 1247, 1153, 1056 cm�1; 1H NMR(300 MHz, CDCl3): d 7.44e7.29 (m, 10H), 7.27 (d, J¼8.9 Hz, 2H), 6.88(d, J¼8.9 Hz, 2H), 6.50 (t, J¼2.2 Hz, 1H), 6.45 (d, J¼2.2 Hz, 2H), 4.98(s, 4H), 4.83 (dd, J¼8.9, 5.6 Hz, 1H), 3.79 (s, 3H), 2.97e2.88 (m, 2H);13C NMR (75 MHz, CDCl3): d 159.9, 159.0, 140.4, 136.8, 135.9, 128.5,128.0, 127.5, 127.1, 113.7, 108.6, 100.3, 74.7, 70.0, 55.2, 46.3; ESI-MSm/z 441 (MþH)þ; ESI-HRMS found: 463.18686 (MþNa)þ, forC29H28O4Na calcd 463.18798.

4.7. 2-(3,5-Bis(benzyloxy)-2-iodophenyl)-1-(4-methoxyphenyl)ethanol ((±)-2)

N-Iodosuccinimide (0.843 g, 3.75mmol) was added to a solutionof (�)-9 (1.5 g, 3.40 mmol) in CHCl3 (10 mL). The resulting solutionwas stirred at rt for 8 h, quenched with a saturated aqueous NH4Clsolution, and extracted with EtOAc. The combined organic extractswere dried with anhydrous Na2SO4. After removal of the solvent,the residue was purified by column chromatography to yield (�)-2(1.75 g, 91%) as a white solid; Rf (EtOAc/Hex, 3:7) 0.46; IR (KBr) nmax2921, 1583, 1448, 1335, 1250, 1169, 1031 cm�1; 1H NMR (300 MHz,CDCl3): d 7.51 (d, J¼7.5 Hz, 2H), 7.45e7.29 (m, 10H), 6.90 (d,J¼9.0 Hz, 2H), 6.52 (d, J¼2.2 Hz, 1H), 6.46 (d, J¼2.2 Hz, 1H), 5.10 (s,2H), 5.04e4.89 (m, 3H), 3.81 (s, 3H), 3.28e3.05 (m, 2H), 1.90 (d,J¼2.2 Hz,1H); 13C NMR (75MHz, CDCl3): d 159.6,159.0, 158.0, 143.0,136.4, 135.9, 128.6, 128.5, 128.1, 127.8, 127.5, 126.9, 113.7, 109.4, 99.6,83.2, 73.0, 70.9, 70.2, 55.2, 50.9 (some signals are overlapping); ESI-MS m/z 589 (MþNa)þ; ESI-HRMS found: 589.08484 (MþNa)þ, forC29H27O4INa calcd 589.08462.

4.8. 6,8-Bis(benzyloxy)-3-(4-methoxyphenyl)isochroman-1-one ((±)-10)

1,10-Phenanthroline (0.002 g, 0.008 mmol) was added toa mixture of aryl iodide (�)-2 (0.1 g, 0.17 mmol), PdCl2(PPh3)2(0.006 g, 0.008 mmol), and K2CO3 (0.048 g, 0.35 mmol) in 2 mLDMF. The reaction mixture was stirred under a nitrogen atmo-sphere for 5 min at rt. The mixture was flushed with CO, and theflask was fitted with a balloon of CO. The reaction mixture washeated at 100 �C for 24 h. After completion of the reaction, thereaction mixture was diluted with ethyl acetate (15 mL), andwashed with brine (20 mL). The aqueous layer was extracted withethyl acetate (2�60 mL). The organic layer was dried over anhy-drous Na2SO4. The crude product was purified by column chro-matography to afford (�)-10 (0.062 g, 76%) as a yellow solid; Rf(EtOAc/Hex, 3:7) 0.3; IR (neat) nmax 2924, 2855, 1716, 1603, 1514,1377, 1242, 1164, 1075 cm�1; 1H NMR (300 MHz, CDCl3): d 7.55 (d,J¼7.3 Hz, 2H), 7.44e7.28 (m, 10H), 6.92 (d, J¼8.4 Hz, 2H), 6.54 (s,1H), 6.42 (s, 1H), 5.42e5.14 (m, 3H), 5.06 (s, 2H), 3.82 (s, 3H),3.32e3.16 (m, 1H), 3.01e2.87 (m, 1H); 13C NMR (75 MHz, CDCl3):d 163.4, 162.2, 162.1, 159.7, 143.7, 136.4, 135.8, 130.8, 128.8, 128.6,128.4, 128.0, 127.7, 127.65, 127.56, 126.7, 113.9, 105.2, 100.4, 78.3,

B.T.V. Srinivas et al. / Tetrahedron 70 (2014) 8161e81678166

70.5, 70.3, 55.3, 37.1; ESI-MS m/z 467 (MþH)þ; ESI-HRMS found:467.18460 (MþH)þ, for C30H27O5 calcd 467.18530.

4.9. 6,8-Dihydroxy-3-(4-methoxyphenyl)isochroman-1-one((±)-1)

A catalytic amount of 10% Pd/C was added to a stirred solution of(�)-10 (0.030 g, 0.06 mmol) in MeOH (1 mL) under nitrogen at-mosphere. The mixture was flushed with H2 and then left undera static pressure of H2 (balloon) at rt. After 8 h the catalyst wasfiltered and the solution concentrated to give 6,8-dihydroxy-3-(4-methoxyphenyl)isochroman-1-one (�)-1 (0.014 g, 79%) as a yel-low color solid; Rf (EtOAc/Hex, 3:7) 0.2; IR (KBr) nmax 2959, 2853,1655, 1513, 1363, 1251, 1166, 1096, 1052 cm�1; 1H NMR (300 MHz,CDCl3): d 11.08 (s, 1H), 7.41 (d, J¼8.6 Hz, 2H), 6.95 (d, J¼8.6 Hz, 2H),6.27 (d, J¼2.0 Hz,1H), 6.23 (d, J¼2.0 Hz,1H), 5.55 (dd, J¼11.8, 3.0 Hz,1H), 3.78 (s, 3H), 3.25 (dd, J¼16.2, 12.0 Hz, 1H), 3.02 (dd, J¼16.4,3.2 Hz, 1H); 13C NMR (75 MHz, CDCl3þDMSO-d6): d 167.7, 162.9,162.0, 157.7, 140.0, 128.6, 126.1, 112.0, 105.1, 99.4, 98.5, 77.8, 53.3,32.5; ESI-MS m/z 309 (MþNa)þ; ESI-HRMS found: 309.07389(MþNa)þ, for C16H14O5Na calcd 309.07334.

4.10. 2-(3,5-Bis(benzyloxy)-2-iodophenyl)-1-(4-methoxyphenyl)ethanone (3)

Pyridinium chlorochromate (0.685 g, 3.18 mmol) was sus-pended in dichloromethane (10 mL) and treated with a solution ofalcohol (�)-2 (0.9 g, 1.59 mmol) in dichloromethane (10 mL) at rt.After 2 h, the reaction mixture was diluted with diethyl ether(40mL) and passed through a pad of silica gel by using diethyl etheras eluant. Evaporation of the solvent afforded 3 (0.878 g, 98%) asa pale yellow color solid; Rf (EtOAc/Hex, 1:4) 0.42; IR (KBr) nmax2927, 1676, 1578, 1451, 1342, 1253, 1171, 1049 cm�1; 1H NMR(300 MHz, CDCl3): d 8.02 (d, J¼8.8 Hz, 2H), 7.50 (d, J¼7.3 Hz, 2H),7.41e7.31 (m, 8H), 6.95 (d, J¼8.8 Hz, 2H), 6.57 (d, J¼2.5 Hz, 1H), 6.47(d, J¼2.5 Hz, 1H), 5.09 (s, 2H), 4.97 (s, 2H), 4.44 (s, 2H), 3.87 (s, 3H);13C NMR (75 MHz, CDCl3): d 195.1, 163.6, 159.9, 158.2, 140.9, 136.44,136.39, 130.7, 129.8, 128.6, 128.5, 128.0, 127.8, 127.6, 127.0, 113.8,109.1, 99.8, 83.8, 71.0, 70.2, 55.5, 50.7; ESI-MS m/z 587 (MþNa)þ;ESI-HRMS found: 587.06848 (MþNa)þ, for C29H25O4INa calcd587.06897.

4.11. (S)-2-(3,5-Bis(benzyloxy)-2-iodophenyl)-1-(4-methoxyphenyl)ethanol ((S)-2)

To a magnetically stirred solution of (S)-Me-CBS (0.019 g,0.07 mmol) in anhydrous THF (5 mL) was added dropwiseBH3$DMS (2 M in THF, 0.35 mL, 0.70 mmol) at rt and the reactionmixture was stirred for another 30 min. To the generated complexwas then added a solution of ketone 3 (0.20 g, 0.35 mmol) in THF(5 mL) dropwise. The stirring was continued until there wascomplete consumption of starting material (indicated by TLC, ap-proximately 6 h). The reaction mixture was quenched with a sat-urated aqueous solution of NH4Cl and then diluted with water(10 mL). The resulting solution was extracted with EtOAc(3�60 mL). The combined extracts were washed with brine(60 mL), dried with anhydrous Na2SO4, filtered, and concentratedto give the crude product. Purification by column chromatographygave (S)-2 (0.180 g, 90%) as a white solid; Rf (EtOAc/Hex, 3:7) 0.46;[a]D20 þ2.2 (c 0.5, CHCl3); IR (KBr) nmax 2924, 1579, 1514, 1423, 1337,1260, 1173, 1074 cm�1; 1H NMR (300 MHz, CDCl3): d 7.43 (d,J¼7.0 Hz, 2H), 7.37e7.18 (m, 10H), 6.83 (d, J¼8.1 Hz, 2H), 6.43 (s,1H), 6.38 (s, 1H), 5.02 (s, 2H), 4.96e4.81 (m, 3H), 3.73 (s, 3H),3.24e2.92 (m, 2H); 13C NMR (75 MHz, CDCl3): d 159.7, 159.0, 158.0,143.0, 136.4, 135.9, 128.6, 128.5, 128.1, 127.8, 127.5, 127.0, 113.7,109.4, 99.6, 83.2, 73.0, 71.0, 70.2, 55.2, 50.9 (some signals are

overlapping); ESI-MS m/z 589 (MþNa)þ; ESI-HRMS found:589.08398 (MþNa)þ, for C29H27O4INa calcd 589.08462. The en-antiomeric excess was determined to be >99% by HPLC (ChiralpakIA (250�4.6 mm) 5 mm, mobile phase: D¼0.1% TFA in hexane/C¼ethanol, isocratic: 80:20, flow rate¼1.0 mL/min): t1¼8.14 min(major), t2¼8.97 min (minor).

4.12. (S)-6,8-Bis(benzyloxy)-3-(4-methoxyphenyl)isochro-man-1-one ((S)-10)

Prepared as reported above for (�)-10 starting from (S)-2-(3,5-bis(benzyloxy)-2-iodophenyl)-1-(4-methoxyphenyl)ethanol(0.080 g, 0.14 mmol), (S)-10 (0.049 g) was obtained in 76% yieldafter chromatography as a light-yellow solid; Rf (EtOAc/Hex, 3:7)0.3; [a]D20 þ5.0 (c 0.25, CHCl3); IR (neat) nmax 2935, 2850, 1739, 1560,1374, 1249, 1072 cm�1; 1H NMR (300 MHz, CDCl3): d 7.54 (d,J¼7.4 Hz, 2H), 7.46e7.28 (m, 10H), 6.93 (d, J¼8.5 Hz, 2H), 6.54 (s,1H), 6.42 (s, 1H), 5.43e5.15 (m, 3H), 5.06 (s, 2H), 3.82 (s, 3H),3.31e3.17 (m, 1H), 3.02e2.88 (m, 1H); 13C NMR (75 MHz, CDCl3):d 163.3, 162.2, 162.0, 159.6, 143.6, 136.3, 135.7, 130.8, 128.7, 128.5,128.3, 128.0, 127.7, 127.6, 127.5, 126.6, 113.8, 105.2, 100.3, 78.2, 70.5,70.2, 55.2, 37.0; ESI-MS m/z 467 (MþH)þ; ESI-HRMS found:467.18502 (MþH)þ, for C30H27O5 calcd 467.18530. The enantiomericexcess was determined to be >99% by HPLC (Chiralpak IA(250�4.6 mm) 5 mm, hexane/ethanol, isocratic: 20:80, flowrate¼1.0 mL/min): t1¼17.91 min (major).

4.13. Preparation of scorzocreticin ((S)-(D)1)

Prepared as reported above for (�)-1. Starting from (S)-10(0.035 g, 0.075 mmol), the title compound (S)-(þ)1 (0.018 g, 86%)was obtained as a yellow solid after chromatography; Rf (EtOAc/Hex, 3:7) 0.2; [a]D20 þ21.5 (c 0.2, MeO) (lit.8 [a]D20 þ23.3 (c 0.2,MeOH)); IR (neat) nmax 2925, 2853, 1627, 1516, 1361, 1249, 1164,1100, 1057 cm�1; 1H NMR (300 MHz, CDCl3): d 10.52 (s, 1H), 7.42(d, J¼8.7 Hz, 2H), 6.94 (d, J¼8.7 Hz, 2H), 6.27 (d, J¼2.0 Hz, 1H), 6.23(d, J¼2.0 Hz, 1H), 5.56 (dd, J¼11.9, 3.0 Hz, 1H), 3.78 (s, 3H), 3.24(dd, J¼16.2, 12.1 Hz, 1H), 3.03 (dd, J¼16.4, 3.2 Hz, 1H); 13C NMR(75 MHz, CDCl3þDMSO-d6): d 167.7, 162.9, 162.0, 157.7, 140.0,128.6, 126.1, 112.0, 105.1, 99.4, 98.5, 77.8, 53.3, 32.5; ESI-MS m/z309 (MþNa)þ; ESI-HRMS found: 309.07280 (MþNa)þ, forC16H14O5Na calcd 309.07334. The enantiomeric excess was de-termined to be >99% by HPLC (Chiralpak IA (250�4.6 mm) 5 mm,hexane/ethanol, isocratic: 80:20, flow rate¼1.0 mL/min):t1¼9.98 min (major).

4.14. (R)-2-(3,5-Bis(benzyloxy)-2-iodophenyl)-1-(4-methoxyphenyl)ethanol ((R)-2)

Prepared following the procedure used for compound (S)-2 byusing (R)-Me-CBS as the catalyst in 92% yield as a white solid: Rf

(EtOAc/Hex, 3:7) 0.46; [a]D20 �2.5 (c 0.5, CHCl3); IR (KBr) nmax2924, 1579, 1423, 1336, 1260, 1173, 1053 cm�1; 1H NMR(300 MHz, CDCl3): d 7.51 (d, J¼7.6 Hz, 2H), 7.46e7.30 (m, 10H),6.91 (d, J¼9.1 Hz, 2H), 6.52 (d, J¼2.2 Hz, 1H), 6.46 (d, J¼2.2 Hz,1H), 5.10 (s, 2H), 5.06e4.87 (m, 3H), 3.81 (s, 3H), 3.29e3.05 (m,2H); 13C NMR (75 MHz, CDCl3): d 159.7, 159.0, 158.0, 143.0, 136.4,135.9, 128.6, 128.5, 128.1, 127.8, 127.5, 126.9, 113.7, 109.4, 99.6,83.2, 73.0, 70.9, 70.2, 55.2, 50.9 (some signals are overlapping);ESI-MS m/z 589 (MþNa)þ; ESI-HRMS found: 589.08460 (MþNa)þ,for C29H27O4INa calcd 589.08462. The enantiomeric excess wasdetermined to be 98% by HPLC (Chiralpak IA (250�4.6 mm) 5 mm,mobile phase: D¼0.1% TFA in hexane/C¼ethanol, isocratic: 80:20,flow rate¼1.0 mL/min): t1¼8.13 min (minor), t2¼8.95 min(major).

B.T.V. Srinivas et al. / Tetrahedron 70 (2014) 8161e8167 8167

4.15. (R)-6,8-Bis(benzyloxy)-3-(4-methoxyphenyl)isochro-man-1-one ((R)-10)

Prepared following the procedure used for compound (�)-10 in72% yield as a pale yellow solid; Rf (EtOAc/Hex, 3:7) 0.3; [a]D20 �6.1(c 0.25, CHCl3); IR (neat) nmax 2935, 2850, 1714, 1608, 1520, 1377,1243, 1165, 1086 cm�1; 1H NMR (300 MHz, CDCl3): d 7.55 (d,J¼7.4 Hz, 2H), 7.46e7.30 (m, 10H), 6.92 (d, J¼8.5 Hz, 2H), 6.54 (s,1H), 6.42 (s, 1H), 5.43e5.14 (m, 3H), 5.06 (s, 2H), 3.82 (s, 3H),3.34e3.16 (m, 1H), 3.04e2.88 (m, 1H); 13C NMR (75 MHz, CDCl3):d 163.3, 162.2, 162.0, 159.6, 143.6, 136.3, 135.7, 130.8, 128.7, 128.5,128.3, 127.9, 127.7, 127.6, 127.5, 126.6, 113.8, 105.2, 100.3, 78.2, 70.5,70.2, 55.2, 37.0; ESI-MS m/z 467 (MþH)þ; ESI-HRMS found:467.18589 (MþH)þ, for C30H27O5 calcd 467.18530. The enantiomericexcess was determined to be >99% by HPLC (Chiralpak IA(250�4.6 mm) 5 mm, hexane/ethanol, isocratic: 20:80, flowrate¼1.0 mL/min): t1¼34.45 min (major).

4.16. Preparation of scorzocreticin ((R)-(L)1)

Prepared following the procedure used for compound (�)-1 in81% yield as a yellow solid: Rf (EtOAc/Hex, 3:7) 0.2; [a]D20 �20.8 (c0.2, MeOH); IR (KBr) nmax 2952, 2848, 1649, 1580, 1369, 1271, 1096,1046 cm�1; 1H NMR (300 MHz, CDCl3): d 10.52 (s, 1H), 7.41 (d,J¼8.7 Hz, 2H), 6.95 (d, J¼8.7 Hz, 2H), 6.26 (d, J¼2.0 Hz, 1H), 6.22 (d,J¼2.0 Hz, 1H), 5.55 (dd, J¼11.9, 3.0 Hz, 1H), 3.78 (s, 3H), 3.25 (dd,J¼16.2,12.0 Hz,1H), 3.02 (dd, J¼16.4, 3.2 Hz,1H); 13C NMR (75MHz,CDCl3þDMSO-d6): d 167.7, 162.9, 162.0, 157.7, 140.0, 128.6, 126.1,112.0, 105.1, 99.4, 98.5, 77.8, 53.3, 32.5; ESI-MS m/z 309 (MþNa)þ;ESI-HRMS found: 309.07260 (MþNa)þ, for C16H14O5Na calcd309.07334. The enantiomeric excess was determined to be 99% byHPLC (Chiralpak IA (250�4.6 mm) 5 mm, hexane/ethanol, isocratic:80:20, flow rate¼1.0 mL/min): t1¼9.84 min (minor), t2¼12.69 min(major).

Acknowledgements

B.T.V.S. thanks the Council of Scientific and Industrial Research,New Delhi, India for the award of a Senior Research Fellowship(SRF).

Supplementary data

Supplementary data associated with this article can be found inthe online version, at http://dx.doi.org/10.1016/j.tet.2014.07.107.

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