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DOI: 10.1002/ejoc.201100242

Synthetic Studies on Dragmacidin D: Synthesis and Assembly of ThreeFragments Towards an Advanced Intermediate

Masato Oikawa,*[a,b] Minoru Ikoma,[b] and Makoto Sasaki[b]

Keywords: Cross-coupling / Natural products / Nitrogen heterocycles / Synthesis design

We report herein the approach to the key advanced interme-diate in the synthesis of the bioactive marine natural productdragmacidin D. By employing a modular synthesis strategyof three fragments (5, 7, and 8), the advanced intermediate3 has been successfully synthesized in 2.5% yield over 15

Introduction

Dragmacidins are a family of marine bis(indole) alka-loids isolated from deep-water sponges including Dragmaci-don, Halicortex, Spongosorites, and Hexadela and the tuni-cate Didemnum candidum (Figure 1). Structurally, dragmac-idins are composed of pyrazines at different levels of oxi-dation, namely piperazine,[1–3] dihydropyrazinone, or pyraz-inone,[4–7] connected to disubstituted indoles at the 2- and5-positions. The indoles are also structurally diverse, beingpresent at various levels of oxidation.

The natural products of the dragmacidin family exhibita broad range of biological activities. Dragmacidin,[1] drag-macidins A,[2] B,[2] and C[3] show biological activities suchas modest antifungal, antiviral, and cytotoxic activities. Inparticular, dragmacidins D,[4] E,[5] and F[6,7] exhibit the fol-lowing interesting biological activities: Dragmacidins D andE are potent inhibitors of protein phosphatases and, in par-ticular, dragmacidin D shows selectivity against proteinphosphatase 1 (PP1).[5] Dragmacidin D also shows selectiveinhibition activity against neural oxide synthase (nNOS),[8]

which is related to neurodegenerative disorders such asAlzheimer’s, Parkinson’s, and Huntington’s diseases.[9]

Moreover, dragmacidin F shows antiviral activity againstthe herpes simplex virus (HSV-I) with an EC50 value of95.8 μm and the human immunodeficiency virus (HIV-I)with an EC50 value of 0.91 μm.[7]

Several synthetic studies of dragmacidins have been re-ported. In 1994, Jiang et al. accomplished a total synthesis

[a] Graduate School of Nanobioscience and University-IndustryCooperative Research Center, Yokohama City University,Seto 22-2, Kanazawa-ku, Yokohama 236-0027, JapanFax: +81-45-787-2403E-mail: [email protected]

[b] Graduate School of Life Sciences, Tohoku University,Aoba-ku, Sendai 980-8577, JapanSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201100242.

© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2011, 4654–46664654

steps by starting from nitrotoluene 20. The synthesis also in-volves sequential cross-coupling reactions, namely Sonoga-shira and Suzuki–Miyaura reactions, so that various ana-logues can be efficiently synthesized, which will allow thestudy of structure–activity relationships of dragmacidin D.

Figure 1. Natural bis(indole) alkaloid dragmacidin and its conge-ners.

of dragmacidin.[10] In 2002, Stoltz and co-workers achieveda total synthesis of dragmacidin D (Scheme 1).[11] For thekey construction of the central pyrazine ring they employedthe Suzuki–Miyaura cross-coupling reaction[12] between anindole and an oxypyrazine, and the total synthesis was ef-ficiently achieved in high yield. The Suzuki–Miyaura reac-tion on a pyrazine framework was successfully controlledchemoselectively (Br vs. I) by the reaction temperature.However, the preparation of the aminoimidazole fragmentrequired a large number of steps (nine steps; the longestlinear sequence: 17 steps) and was inefficient, because imid-azole is inherently poorly reactive (structure not shown). Inaddition, they employed an α-nitro ketone (structure notshown) as the synthetic intermediate, which easily suffers

Synthetic Studies on Dragmacidin D

Scheme 1. Stoltz and co-workers’ total synthesis of dragmacidin D.[11]

from isomerization at the α-position, and hence racemiza-tion at the C-6�� asymmetric carbon center was observedin their synthesis of dragmacidin D.

Stoltz and co-workers also accomplished the total syn-thesis of dragmacidin F,[13] for which the Suzuki–Miyauracross-coupling reaction between an indole and an oxypyraz-ine was again performed (Scheme 2). Thus, their syntheticstudies have shown the usefulness of the Suzuki–Miyauracross-coupling reaction in the synthesis of complex naturalproducts in the presence of various functional groups.

Its intriguing biological activities as well as its attractivestructural complexity as a challenging synthetic targetprompted us to explore a new synthetic pathway to dragma-cidin D (1) that is amenable to the synthesis of variousstructural analogues, which would allow their structure–ac-tivity relationships to be studied.[14]

Our plan for the synthesis of dragmacidin D (1) is shownin Scheme 3. It was proposed to construct the C-6�� asym-metric carbon atom of dragmacidin D by an asymmetrichydrogenation of intermediate 2 by using the nitrogen atomof the 2-aminoimidazole group as a directing function-ality.[15] The central pyrazinone ring would be constructedby Staudinger/aza-Wittig reaction of the advanced interme-diate 3 followed by oxidation. The intermediate 3 would beobtained by an azidoamine/acyl chloride coupling reactionbetween two indoles, the left- and right-hand fragments 4and 5. Synthesis of the left-hand fragment 4 was envisionedto be realized by the Suzuki–Miyaura cross-coupling reac-tion between imidazolylboronic acid 7 and indolylvinyl bro-

Eur. J. Org. Chem. 2011, 4654–4666 © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 4655

Scheme 2. Stoltz and co-workers’ total synthesis of dragmaci-din F.[13]

mide 8. Note that in Stoltz and co-workers’ synthesis,[11] theN1��–C5�� bond was tediously formed over nine reactionsteps. Our coupling strategy would not only improve thesynthetic efficiency but also allow rapid access to analoguesbearing diverse aryl groups at the 6��-position in place of

M. Oikawa, M. Ikoma, M. SasakiFULL PAPER

Scheme 3. Our synthetic strategies for dragmacidin D (1).

the imidazolyl moiety by employing a variety of commer-cially available arylboronic acids. In this paper we reportour efforts to synthesize the key advanced intermediate 3 inthe synthesis of dragmacidin D (1).[14]

Results and Discussion

The synthesis of the imidazole fragment 7 is shown inScheme 4. First, imidazole (10) was protected with theMOM group (MOMCl, NaH). To protect the 2��-position(dragmacidin D numbering) the phenylthio group was em-ployed, because more straightforward nitrogen functionali-ties such as a nitro group have been found to be unstableunder the conditions required for the subsequent boronateformation (data not shown). In general, the phenylthio

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group can be readily removed by several methods (e.g., so-dium amalgam[16] or direct nucleophilic substitution[17])and can be substituted directly by nitrogen functional

Scheme 4. Synthesis of the imidazole fragment 7.


groups. Thus, selective deprotonation at the 2��-position byBuLi at –78 � –35 °C followed by treatment with diphenyldisulfide gave sulfide 12 in 62% yield.[18] The next step wasto boronate the 5��-position. Deprotonation was again ef-fected with BuLi at –78 � –40 °C for 1 h, and subsequentaddition of trimethyl borate gave the desired boronic acid7 in 77 % crude yield after treatment with acid. As reportedpreviously,[19] the boronation was highly regioselective asjudged from subsequent cross-coupling reactions (see be-low).

The protecting group at the 1��-position was found toplay a key role in the preparation and reaction of the cross-coupling substrate as follows. First, we envisioned using anMOM group (Scheme 5). The synthesis started with theknown indole 13,[20] which was treated with MOMCl andNaH to give 14 in 97 % yield. The cyano group in 14 wasconverted into the methyl ketone by using excess Grignardreagent (MeMgBr) at 60 °C to provide 15 in 76% yield.

Scheme 5. Attempts to construct the C5��–C6�� bond by the Su-zuki–Miyaura cross-coupling reaction.

Methyl ketone 15 was then transformed into enol phos-phate 16. The reaction proceeded smoothly by usingKHMDS and (EtO)2P(=O)Cl in the presence of HMPA togive 16 in 65 % yield along with recovered 15 (26%), whichwould be generated by the hydrolysis of 16. Because enolphosphate 16 was first found to be unreactive in the cross-coupling reaction with boronic acid 7 under various condi-tions (data not shown), we attempted to transform 16 intovinyl iodide 17 by using TMSI,[21] in situ generated fromTMSCl and NaI in CH2Cl2. Under these conditions, how-ever, enol phosphate 16 decomposed, and the desired vinyliodide 17 was not obtained at all. Changing the solvent toCH3CN did not improve the result even at a lower tempera-ture (–20 °C). The main decomposition process was sup-posed to be the polymerization of the indole under acidicconditions. Therefore, the use of less acidic conditions forthe synthesis of the vinyl halide or its equivalent was ex-


plored. Enol triflate is known as a reactive functional groupin Suzuki–Miyaura cross-coupling reactions[12] and is gen-erally prepared under the same basic conditions as thoseused for the preparation of enol phosphate (see 15 � 16).By using KHMDS, methyl ketone 15 was treated withComins’ reagent.[22] The reaction proceeded smoothly tofurnish the crude enol triflate 18, which, in turn, was sub-sequently used for the cross-coupling reaction with boronicacid 7. It was found, however, that no reaction took place,and methyl ketone 15 was regenerated.

The unsuccessful experiments described in Scheme 5indicated two problems to be solved: (1) Indole compoundsbearing the MOM protecting group at the 1��-position donot survive reactions under acidic conditions, and (2) anenol triflate is not suitable for the cross-coupling reactionbecause of its instability. The indole fragment used as thecross-coupling substrate was therefore improved as follows.First, it was decided to protect the N-1�� atom by an elec-tron-withdrawing Ts group. Secondly, a bromide group wasemployed as the leaving group at the 6��-position in thecross-coupling reaction. Thirdly, a two-step reaction wasplanned for the introduction of the 4��-vinyl bromide moi-ety, that is, an aryl bromide is replaced by an ethynyl groupto which hydrogen bromide is then added. The new syn-thetic intermediates were expected to be stable under theacidic conditions and to survive a series of reactions. Ac-cording to the new synthetic plan, bromoindole 9 was firstsynthesized by a modification[23] of the Batcho–Leimgruberindole synthesis[24] (Scheme 6). Thus, compound 20[23] wastransformed into enamine 21 by treatment with N,N-di-methylformamide dimethyl acetal (DMFDMA) and pyr-rolidine, and the nitro group was then reduced with zincmetal in AcOH in place of Raney-Ni and hydrazine[23] to

Scheme 6. Synthesis of N-Ts-protected indolylvinyl bromide 26 asa new cross-coupling substrate.

M. Oikawa, M. Ikoma, M. SasakiFULL PAPERgive the bromoindole 9 in 73% yield after concomitant cy-clization. N-Tosylation of 9 by a conventional method(TsCl, NaH) yielded 22 in high yield (95%).

The ethynyl group was next introduced into 22 by theSonogashira reaction.[25] Our initial attempt to treat 22 withethynyltrimethylsilane using [Pd(PPh3)4] and CuI in Et2NHat reflux (ca. 55 °C), however, did not provide the desiredcross-coupling product, and only unreacted 22 was reco-vered (data not shown). In general, Sonogashira reactionsof aryl bromides proceed well at 50 °C when electron-with-drawing groups are present at the ortho or para position ofthe aryl ring.[26] In 22, the para position of the aryl ringis substituted by an electron-donating methoxy group, andhence the reactivity was expected to be diminished. There-fore, we presumed that a higher temperature would be effec-tive for the Sonogashira coupling reaction of 22. For thispurpose Et3N (b.p. 89 °C) and ethynyltriisopropylsilane (23,b.p. 100 °C at 20 Torr)[27] were used instead of Et2NH (b.p.55 °C) and ethynyltrimethylsilane (b.p. 53 °C). 1,4-Dioxanewas employed as co-solvent to improve the solubility of thecatalyst and coupling substrates. With these improvements,the cross-coupling reaction of 22 proceeded smoothly at100 °C to give the desired 24 in 76 % yield. In this case,unreacted aryl bromide 22 was recovered in 16% yield.

The transformation of 24 into the vinyl bromide was nextexplored. The TIPS group was removed by TBAF to givealkyne 25 in 87% yield. When alkyne 25 was treated withHBr (33 % solution in AcOH) at 0 °C, the desired HBr ad-dition proceeded smoothly in 30 min to provide vinyl bro-mide 26 in 90% yield with complete regioselectivity. Thevinyl bromide 26 is apparently more stable than enol phos-phate 16 and triflate 18. In addition, the bromide 26 wasobtained in pure form after workup and thus could be usedin the next Suzuki–Miyaura cross-coupling reaction with-out purification.

With vinyl bromide 26 in hand, the Suzuki–Miyauracross-coupling reaction of imidazolylboronic acid 7(3 equiv.) was examined at 100 °C in 1,4-dioxane by using[Pd(PPh3)4] and aqueous Cs2CO3 (Scheme 7). As expectedfrom our substrate design as described above, the reactionproceeded smoothly to give the desired product 27 in goodyield (77%).

Scheme 7. Model reaction for the construction of the C5��–C6��bond by the Suzuki–Miyaura cross-coupling reaction.

Having synthesized the left-hand indole fragment withthe imidazole fragment, we next turned our attention to thesynthesis of the indole fragment bearing a substituent at the3��-position (Scheme 8). First, an oxalyl group was intro-duced at the 3��-position of bromoindole 9 by treatment


with oxalyl chloride followed by alkaline methanolysis togive the methyl ester 28 in 91 % yield. After protection ofthe indole nitrogen atom with a Ts group (TsCl, Et3N,DMAP), the oxo ester side-chain was reduced with NaBH4

in MeOH to provide diol 30 in 95% yield. The diol wasprotected as its acetonide (CSA, 2,2-dimethoxypropane) in76% yield, and subsequent Sonogashira cross-coupling withethynyltriisopropylsilane (23) [Pd(PPh3)4, CuI, Et3N,100 °C] gave 32 in 94% yield. The TIPS group was thenremoved by TBAF to furnish ethynylindole 33 in 94 % yield.

Scheme 8. Synthesis of model ethynylindole 33 bearing a side-chainat the 3��-position.

An attempt to obtain vinyl bromide 34 from alkyne 33by treatment with HBr in AcOH failed, giving a complexmixture of products (Scheme 9) due to decomposition ofthe acetonide group. Thus, the diol functionality was pro-tected by the acetyl groups as follows: The acetonide in 33was removed by acidic methanolysis (CSA, MeOH), andthe resulting diol was acetylated (Ac2O, pyridine, DMAP)to give diacetate 35 in 79% yield for two steps. As expected,

Scheme 9. Synthesis of the model indolylvinyl bromide 36 bearinga side-chain at the 3��-position.


addition of hydrogen bromide to 35 provided vinyl bromide36 in 65 % yield.

We also synthesized indolylglycine 8 as the left-hand in-dole fragment by direct Mannich-type Friedel–Crafts alkyl-ation at the 3��-position of the indole ring of 9 with p-anisidine and ethyl glyoxylate, according to the method re-ported by Jiang and Huang (Scheme 10).[16] Although ad-dition of a minimum amount of CH2Cl2 as solvent was nec-essary in our case to dissolve 9, the desired product 37 wasobtained satisfactorily in 83 % yield. After protection of theindole nitrogen atom by Ts, the p-methoxyphenyl group(designated as Ar) was removed by CAN to give amine 39in moderate yield (62%). Note that overoxidation at the 6-position also took place to give an oxo ester as a side-prod-uct in 33% yield (structure not shown). The amino groupwas then protected by a Boc group to give 40 in 60 % yield,which, in turn, was subjected to Sonogashira cross-cou-pling[25] with ethynyltriisopropylsilane (23) to give (silyl-ethynyl)indole 41 in good yield (92%). Alkyne 41 was fur-ther converted into vinyl bromide 8 by TBAF treatment(100%) and subsequent HBr addition (88 %). Note that theBoc protecting group was stable under the conditions ofHBr addition (0 °C, 15 min). Although removal of the Bocgroup was reasonably observed after a longer reaction time(1 h), the molecular skeleton was recovered without suffer-ing serious decomposition.

Scheme 10. Synthesis of indolylglycine 8 as the left-hand indolefragment (Ar = p-methoxyphenyl).

With the two vinyl bromides 8 and 36 bearing side-chainsat the 3��-position in hand, Suzuki–Miyaura cross-couplingreaction with imidazolylboronic acid 7 was next examined(Scheme 11). In both cases, boronic acid 7 (3 equiv.) wasused with [Pd(PPh3)4] (10 mol-%) and Cs2CO3 (3 equiv.) in1,4-dioxane. In the reaction of vinyl bromide 36, water was


also added to the reaction mixture as in the reaction be-tween 7 and 26 shown in Scheme 7. Although the reactionof 36 was sluggish at room temp., the desired cross-couplingproduct 43 was obtained in 84% yield at an elevated tem-perature (95 °C). Mild methanolysis (K2CO3, MeOH) of 43delivered diol 44 in 93% yield.

Scheme 11. Suzuki–Miyaura cross-coupling reaction of imidazolyl-boronic acid 7 with vinyl bromides 8 and 36.

For the reaction of 8, NaOEt (3 equiv.) was used as baseunder non-aqueous conditions to avoid protodeborylationof 7 and undesirable hydrolysis of the ethyl ester in 8 andthe product 45. The cross-coupling reaction of boronic acid7 and vinyl bromide 8 thus proceeded smoothly at 100 °Cto provide 45 in 61 % yield. Towards the left-hand fragment4, ethyl ester 45 was reduced with LiBH4 in THF to furnishalcohol 46 in moderate yield (73%).

Advanced intermediate 3 was synthesized from alcohol46 as shown in Scheme 12. First, the left-hand fragment4 for coupling with right-hand fragment 5 was prepared.Tosylation of 46 (TsCl, Et3N, DMAP) gave 47 in 90 % yield,which was treated with NaN3 in DMF at 80 °C to provideazide 48 in 77 % yield. Removal of the Boc group was theneffected by TFA in CH2Cl2 to give the left-hand fragment4 in good yield (89%), ready for coupling with the right-hand fragment 5.

The coupling of the left-hand fragment 4 with the right-hand fragment 5, readily prepared from commercially avail-able 6-bromoindole in 85% yield by reaction with oxalylchloride in Et2O,[28] was next explored. It was found thatwith acyl chloride 5 (1 equiv.) in the presence of Et3N(3 equiv.) and DMAP (1.5 equiv.), the reaction was quiteslow, and only a trace amount of the product 3 was de-tected. Even with an excess (3 equiv.) of 5, the reaction wasstill sluggish at room temp. The reaction mixture was there-fore heated to 40 °C. Under these reaction conditions, thecoupling was found to proceed smoothly to give the desired

M. Oikawa, M. Ikoma, M. SasakiFULL PAPER

Scheme 12. Synthesis of the advanced intermediate 3 in the synthe-sis of dragmacidin D.

advanced intermediate 3 in acceptable yield (72%). Notethat the fragments were also coupled successfully in 60 %yield by carbodiimide-induced N-acylation (EDCI, HOBt,Et3N, DMF) between 4 and the carboxylic acid derivedfrom 5 (data not shown).

Conclusions

We have established a synthetic route to bis(indole) 3, anadvanced intermediate in the synthesis of marine bis(indole)alkaloid dragmacidin D (1). Starting from 20 and theBatcho–Leimgruber indole synthesis,[24] intermediate 3 wassynthesized in 2.5% total yield over 15 steps. Our synthesisalso features the highly efficient construction of the C5��–C6�� bond by two sequential cross-coupling reactions, theSonogashira[25] and Suzuki–Miyaura reactions,[12] on bro-moindole 9. Efforts are underway to synthesize dragmaci-din D (1) from the advanced intermediate 3. Although cy-clization of the central pyrazinone ring (or the dihydropyr-azinone precursor) is expected to be readily realized on 3based on precedent[28] as well as on our model studies, theother important transformation, the displacement of the2��-phenylthio group with a nitrogen functionality, is pre-dicted to be rather difficult from our independent modelstudies. Our future efforts will therefore be focused on thecrucial transformation at the 2��-position as well as theasymmetric induction at the 6��-position.

The synthesis employs a modular synthesis strategy[29]

that is believed to be amenable to the synthesis of various


structural analogues, which will allow the structure–activityrelationships to be explored in several assay systems includ-ing the inhibition against protein phosphatases and neuraloxide synthase. Further studies are currently underway inour laboratories, and the results will be reported in duecourse.

Experimental Section

General Methods: The experimental techniques and methods ofcharacterization have been summarized in our previous paper.[30]

N-Methoxymethylimidazole (11): NaH (60% in mineral oil, 7.10 g,0.176 mol) was added to a stirred solution of imidazole (10; 3.00 g,0.0441 mol) in THF (40 mL) at 0 °C, and the resulting suspensionwas stirred at the same temperature for 30 min. MOMCl (4.00 mL,0.0529 mol) was added, and the mixture was warmed to roomtemp. After 3 h, the reaction mixture was quenched with saturatedaqueous NH4Cl (50 mL) and extracted with CHCl3 (50 mL �3).The combined organic layers were washed with brine (20 mL),dried with Na2SO4, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (60 g,MeOH/CHCl3 = 1:9) to give N-methoxymethylimidazole (11;4.59 g, 99%) as a colorless oil. IR (film): ν̃ = 2929, 2360, 1698,1507, 1457, 1397, 1287, 1224, 1190, 1101, 917, 828, 739, 662 cm–1.1H NMR (500 MHz, CDCl3): δ = 7.58 (s, 1 H), 7.08 (s, 1 H), 7.02(s, 1 H), 5.21 (s, 2 H), 3.24 (s, 3 H) ppm. 13C NMR (125 MHz,CDCl3): δ = 137.3, 129.9, 118.8, 77.5, 55.9 ppm. HRMS (FAB):calcd. for C5H8N2ONa [M + Na]+ 135.0529; found 135.0524.

Phenylthioimidazole 12: BuLi (1.6 m solution in THF, 13.3 mL,0.0212 mol) was slowly added to a stirred solution of imidazole 11(1.985 g, 0.0177 mol) in THF (20 mL) at –78 °C over 15 min. Afterstirring at –35 °C for 1 h, a solution of diphenyl disulfide (4.30 g,0.0195 mol) in THF (10 mL) was added. The resultant solution waswarmed to room temp. After 30 min, the reaction mixture waspoured into saturated aqueous NH4Cl (100 mL) and extracted withEtOAc (150 mL). The combined organic layers were washed withbrine (50 mL), dried with Na2SO4, and concentrated under reducedpressure. The residue was purified by column chromatography onsilica gel (40 g, hexane/EtOAc = 3:7) to give phenylthioimidazole12 (2.41 g, 62%) as a colorless oil. IR (film): ν̃ = 3107, 2360, 1521,1478, 1395, 1256, 1192, 1094, 1024, 919, 741, 689 cm–1. 1H NMR(500 MHz, CDCl3): δ = 7.28–7.18 (m, 7 H), 5.34 (s, 2 H), 3.18 (s,3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 138.5, 134.4, 130.8,129.1 (�2), 128.4 (�2), 126.7, 122.3, 77.2, 56.1 ppm. HRMS (ESI):calcd. for C11H13N2OS [M + H]+ 221.0743; found 221.0743.

Boronic Acid 7: BuLi (2.6 m solution in hexane, 5.50 mL,14.3 mmol) was added to a stirred solution of imidazole 12 (2.10 g,9.54 mmol) in THF (21 mL) at –78 °C, and the mixture was stirredat –40 °C for 1 h. The mixture was again cooled to –78 °C, tri-methyl borate (5.32 mL, 47.7 mmol) was added, and the mixturewarmed to room temp. After 15 min, the mixture was concentratedunder reduced pressure to remove excess trimethyl borate, and theresidue was dissolved in aqueous NaOH (1 m, 100 mL). The result-ant mixture was washed with Et2O (50 mL) and acidified with coldhydrochloric acid (6 m, 50 mL). The white suspension was extractedwith CHCl3 (50 mL �5), and the combined organic layers weredried with Na2SO4 and concentrated under reduced pressure togive boronic acid 7 (1.93 g, 77%) as a yellow oil, which was usedin the cross-coupling reaction without purification.


N-MOM-indole 14: NaH (60% in mineral oil, 44 mg, 1.1 mmol)was added to a stirred solution of indole 13 (38.0 mg, 0.220 mmol)in THF (2.2 mL) at 0 °C, and the resulting mixture was stirred atthe same temperature for 30 min. MOMCl (0.033 mL, 0.44 mmol)was then added to the mixture, which was warmed to room temp.After 12 h, the resultant mixture was diluted with Et2O (20 mL),washed with saturated aqueous NH4Cl (10 mL) and brine (5 mL),and dried with Na2SO4. The organic layer was concentrated underreduced pressure, and the residue was purified by columnchromatography on silica gel (4 g, hexane/EtOAc = 7:3) to give N-MOM-indole 14 (46.3 mg, 97%) as a colorless oil. IR (film): ν̃ =2936, 2360, 2219, 1606, 1576, 1498, 1385, 1295, 1272, 1170, 1092,947, 913, 731, 637 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.42 (d,J = 8.5 Hz, 1 H), 7.24 (d, J = 3.5 Hz, 1 H), 6.67 (d, J = 3.5 Hz, 2H), 5.67 (s, 2 H), 4.00 (s, 3 H), 3.24 (s, 3 H) ppm. 13C NMR(125 MHz, CDCl3): δ = 151.0, 132.4, 131.3, 127.6, 125.1, 118.9,112.3, 103.4, 102.1, 95.9, 79.3, 55.8 ppm. HRMS (ESI): calcd. forC12H12N2O2Na [M + Na]+ 239.0791; found 239.0790.

Methyl Ketone 15: MeMgBr (3.0 m solution in Et2O, 3.09 mL,9.26 mmol) was added to a stirred solution of cyanide 14(400.3 mg, 1.852 mmol) in THF (18 mL) at room temp., and theresulting mixture was heated at 60 °C. After 20 h, the mixture wascooled to 0 °C, diluted with Et2O (50 mL), and quenched with hy-drochloric acid (0.5 m, 50 mL). The mixture was vigorously stirredat room temp. and extracted with EtOAc (50 mL). The combinedorganic layers were washed with brine (50 mL), dried with Na2SO4,and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (10 g, hexane/EtOAc =7:3) to give methyl ketone 15 (328.1 mg, 76%) as a colorless oil. IR(film): ν̃ = 2935, 2360, 1655, 1561, 1250, 1108, 960, 788, 741,677 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 3.5 Hz, 1 H), 7.25 (d, J = 3.5 Hz, 1 H), 6.68 (d, J

= 8.0 Hz, 1 H), 5.70 (s, 2 H), 4.03 (s, 3 H), 3.23 (s, 3 H), 2.64 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ = 198.1, 151.5, 131.8(�2), 130.1, 126.3, 123.2, 104.9, 102.3, 79.4, 55.7 (�2), 27.4 ppm.HRMS (FAB): calcd. for C13H16NO3 [M + H]+ 234.1125; found234.1124.

Enol Phosphate 16: KHMDS (0.5 m in toluene, 3.80 mL,1.92 mmol) was added to a stirred solution of methyl ketone 15(204.7 mg, 0.915 mmol), HMPA (0.318 mL, 1.83 mmol), and(EtO)2P(O)Cl (0.258 mL, 1.65 mmol) in THF (9.0 mL) at –78 °C.After 40 min, saturated aqueous NH4Cl (30 mL) was added, andthe mixture was extracted with EtOAc (50 mL). The combined or-ganic layers were washed with brine (20 mL), dried with Na2SO4,and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (5 g, hexane/EtOAc = 6:4)to give enol phosphate 16 (219.2 mg, 65%) as a colorless oil. IR(film): ν̃ = 2984, 2359, 1654, 1560, 1382, 1250, 1034, 800, 741,678 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.27 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 3.5 Hz, 1 H), 6.76 (d, J = 3.5 Hz, 1 H), 6.65 (d, J

= 7.5 Hz, 1 H), 5.70 (s, 2 H), 5.28 (dd, J = 2.0, 2.0 Hz, 1 H), 5.17(dd, J = 2.0, 2.0 Hz, 1 H), 4.19–4.09 (m, 4 H), 3.69 (s, 3 H), 3.24(s, 3 H), 1.23–1.27 (m, 6 H) ppm. 13C NMR (125 MHz, CDCl3): δ= 152.5, 148.3, 129.8, 128.4, 125.6, 120.5, 120.4, 120.1, 102.9, 98.3,79.2, 64.3 (�2), 55.6 (�2), 16.0 (�2) ppm. HRMS (FAB): calcd.for C17H24NO6PNa [M + Na]+ 392.1233; found 392.1231.

Enol Triflate 18: KHMDS (0.5 m in toluene, 0.290 mL,0.145 mmol) was added to a stirred solution of methyl ketone 15(16.2 mg, 0.0726 mmol) in THF (1.4 mL) at –78 °C. The mixturewas stirred at –78 °C for 50 min before addition of Comins’ reagent(85.4 mg, 0.218 mmol)[22] in THF (1.0 mL). The reaction was com-pleted after 1.5 h, as judged by TLC. Saturated aqueous NH4Cl


(30 mL) was added to the reaction mixture, which was then ex-tracted with EtOAc (50 mL). The combined organic layers werewashed with brine (20 mL), dried with Na2SO4, and concentratedunder reduced pressure to give the residue, which was used in thesubsequent cross-coupling reaction without purification. Crudeenol triflate 18 was obtained as a yellow oil. 1H NMR (500 MHz,CDCl3): δ = 8.56 (d, J = 3.0 Hz, 1 H), 7.88 (d, J = 8.5 Hz, 1 H),7.39 (d, J = 8.5 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 6.61 (d, J =8.0 Hz, 1 H), 5.71 (s, 1 H), 5.69 (s, 2 H), 5.68 (s, 1 H), 3.69 (s, 3H), 3.23 (s, 3 H) ppm. HRMS (ESI): calcd. for C14H14F3NO5SNa[M + Na]+ 388.0437; found 388.0439.

Bromoindole 9: A solution of nitrotoluene 20[23] (3.68 g,15.1 mmol), (MeO)2CHNMe2 (8.35 mL, 63.9 mmol), and pyrrolid-ine (3.77 mL, 45.2 mmol) in DMF (40 mL) was stirred at reflux for5 h before concentration under reduced pressure. The residue wasdiluted with Et2O (500 mL), washed successively with water(200 mL �3) and brine (50 mL), dried with Na2SO4, and concen-trated under reduced pressure to give crude enamine 21. The crudeenamine 21 thus obtained was dissolved in AcOH (50 mL) andwater (13 mL), and heated at 80 °C. Zinc metal (12.0 g, 0.184 mol)was added portionwise over 20 min, and the mixture was stirred at70–85 °C for 90 min. Insoluble material was removed by filtrationthrough a pad of Celite. The filtrate was diluted with EtOAc(300 mL), washed with saturated aqueous NaHCO3 (300 mL �3),dried with Na2SO4, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (50 g,hexane/EtOAc = 9:1) to give bromoindole 9 (2.48 g, 73 %) as acolorless oil. The spectroscopic data of 9 are identical to those re-ported previously.[23]

N-Ts-indole 22: NaH (60% in mineral oil, 163 mg, 4.07 mmol) wasadded to a solution of indole 9 (306 mg, 1.36 mmol)[23] in THF(5.0 mL) at 0 °C. After 30 min, TsCl (335 mg, 1.76 mmol) wasadded, and the mixture was warmed to room temp. After 12 h,saturated aqueous NH4Cl (100 mL) was added at 0 °C, and themixture was extracted with EtOAc (150 mL). The combined or-ganic layers were washed with brine (50 mL), dried with Na2SO4,and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (5 g, hexane/EtOAc = 8:2)to give N-Ts-indole 22 (498 mg, 95%) as a colorless oil. IR (film):ν̃ = 2936, 2361, 1578, 1478, 1374, 1284, 1245, 1171, 1133, 1079,995, 811, 676, 610, 569, 530 cm–1. 1H NMR (500 MHz, CDCl3): δ= 7.87 (d, J = 3.5 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 2 H), 7.25 (d, J =8.5 Hz, 2 H), 7.23 (d, J = 9.0 Hz, 1 H), 6.69 (d, J = 3.5 Hz, 1 H),6.53 (d, J = 9.0 Hz, 1 H), 3.65 (s, 3 H), 2.38 (s, 3 H) ppm. 13CNMR (125 MHz, CDCl3): δ = 146.7, 144.4, 136.7, 133.4, 129.3(�2), 129.0, 127.1 (�2), 126.3, 113.8, 107.7, 106.7, 105.4, 55.5,21.4 ppm. HRMS (ESI): calcd. for C16H14BrNO3SNa [M + Na]+

401.9770; found 401.9770.

(Silylethynyl)indole 24: A suspension of bromoindole 22 (107 mg,0.282 mmol), ethynyltriisopropylsilane (23; 0.338 mL, 1.41 mmol),[Pd(PPh3)4] (16.3 mg, 0.014 mmol), and CuI (5.4 mg, 0.028 mmol)in Et3N (5.0 mL) and 1,4-dioxane (5.0 mL) was heated at 100 °C.After 21 h, the mixture was cooled to room temp., diluted withEtOAc (20 mL), and washed with saturated aqueous NH4Cl(20 mL) and brine (10 mL). The organic layer was dried withNa2SO4 and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (2 g, hexane/EtOAc = 17:3) to give (silylethynyl)indole 24 (103 mg, 76%) as acolorless oil. IR (film): ν̃ = 2941, 2145, 1597, 1493, 1359, 1288,1173, 1119, 1024, 882, 809, 675, 568, 532 cm–1. 1H NMR(500 MHz, CDCl3): δ = 7.85 (d, J = 3.5 Hz, 1 H), 7.67 (d, J =8.5 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 2 H),

M. Oikawa, M. Ikoma, M. SasakiFULL PAPER6.79 (d, J = 3.5 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 3.67 (s, 3 H),2.37 (s, 3 H), 1.13 (s, 21 H) ppm. 13C NMR (125 MHz, CDCl3): δ= 147.7, 144.3, 137.0, 135.5, 129.3 (�2), 129.1, 128.3, 127.2 (�2),123.9, 108.7, 106.6, 106.5, 104.4, 92.2, 55.4, 21.5, 18.7 (�6), 11.3(�3) ppm. HRMS (ESI): calcd. for C27H36NO3SSi [M + H]+

482.2180; found 482.2175.

Ethynylindole 25: TBAF (1 m solution in THF, 0.415 mL,0.415 mmol) was added to a stirred solution of (silylethynyl)indole24 (103 mg, 0.215 mmol) in THF (5.0 mL) and water (0.010 mL) at0 °C. After 20 min, the mixture was poured into saturated aqueousNH4Cl (10 mL) and extracted with EtOAc (20 mL). The combinedorganic layers were washed with brine (10 mL), dried with Na2SO4,and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (2 g, hexane/EtOAc =17:3) to give ethynylindole 25 (61.0 mg, 87%) as a colorless oil. IR(film): ν̃ = 2940, 2361, 1598, 1492, 1373, 1287, 1172, 1119, 1016,809, 665, 568 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.87 (d, J =4.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 2 H), 7.28 (d, J = 8.5 Hz, 1 H),7.25 (d, J = 8.0 Hz, 2 H), 6.80 (d, J = 4.0 Hz, 1 H), 6.58 (d, J =8.5 Hz, 1 H), 3.68 (s, 3 H), 3.21 (s, 1 H), 2.38 (s, 3 H) ppm. 13CNMR (125 MHz, CDCl3): δ = 147.9, 144.4, 136.9, 135.5, 129.3(�2), 129.2, 128.6, 127.2 (�2), 123.8, 107.0, 106.4, 106.2, 81.2,78.9, 55.3, 21.5 ppm. HRMS (ESI): calcd. for C18H15NO3SNa [M+ Na]+ 348.0665; found 348.0653.

Vinyl Bromide 26: HBr·AcOH (33%, 0.0045 mL, 0.025 mmol) wasadded to a stirred solution of ethynylindole 25 (7.5 mg,0.023 mmol) in THF (0.5 mL) at 0 °C. After 15 min, the mixturewas poured into saturated aqueous NaHCO3 (10 mL) and ex-tracted with EtOAc (15 mL). The combined organic layers werewashed with brine (10 mL), dried with Na2SO4, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (0.5 g, hexane/EtOAc = 9:1) to givevinyl bromide 26 (8.4 mg, 90%) as a colorless oil. IR (film): ν̃ =2938, 2360, 1540, 1492, 1372, 1287, 1172, 1135, 1087, 1010, 811,670, 567, 533 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J =4.0 Hz, 1 H), 7.71 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 7.5 Hz, 1 H),7.24 (d, J = 8.5 Hz, 2 H), 6.90 (d, J = 4.0 Hz, 1 H), 6.61 (d, J =7.5 Hz, 1 H), 5.92 (d, J = 1.5 Hz, 1 H), 5.88 (d, J = 1.5 Hz, 1 H),3.67 (s, 3 H), 2.38 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ= 147.7, 144.3, 137.1, 131.1, 129.3 (�2), 128.9, 127.8, 127.2 (�2),125.7, 124.9, 124.1, 119.9, 113.9, 106.0, 55.3, 21.5 ppm. HRMS(ESI): calcd. for C18H16BrNO3SNa [M + Na]+ 427.9926; found427.9923.

Coupling Product 27: A suspension of imidazolylboronic acid 7(16.4 mg, 0.0622 mmol), vinyl bromide 26 (8.4 mg, 0.021 mmol),[Pd(PPh3)4] (1.2 mg, 1.0 mmol), and Cs2CO3 (20.2 mg,0.0622 mmol) in 1,4-dioxane (1.0 mL) and water (0.1 mL) wasstirred at 100 °C. After 24 h, the mixture was cooled to room temp.,diluted with EtOAc (20 mL), and washed with saturated aqueousNH4Cl (20 mL) and brine (10 mL). The organic layer was driedwith Na2SO4 and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (0.5 g, hex-ane/EtOAc = 3:7) to give coupling product 27 (8.7 mg, 77%) as acolorless oil. IR (film): ν̃ = 3734, 1670, 1540, 1374, 1085, 741,670 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 3.0 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2 H), 7.26–7.17 (m, 8 H), 7.07 (d, J =8.5 Hz, 1 H), 6.62 (d, J = 7.5 Hz, 1 H), 6.24 (d, J = 3.0 Hz, 1 H),5.65 (d, J = 1.5 Hz, 1 H), 5.50 (d, J = 1.5 Hz, 1 H), 4.80 (s, 2 H),3.67 (s, 3 H), 2.99 (s, 3 H), 2.38 (s, 3 H) ppm. 13C NMR (125 MHz,CDCl3): δ = 147.5, 144.3, 141.0, 137.2, 136.6, 135.2, 134.5, 131.6,130.9 (�2), 129.4 (�2), 129.2 (�2), 129.2 (�2), 129.0, 128.6, 127.3,127.0, 125.2, 124.1, 118.3, 109.7, 106.6, 105.7, 75.1, 55.4, 21.6 ppm.


HRMS (ESI): calcd. for C29H28N3O4S2 [M + H]+ 546.1516; found546.1519.

N-Ts-indole 29: Oxalyl chloride (0.0219 mL, 0.258 mmol) wasadded to a stirred solution of bromoindole 9 (19.5 mg, 0.086 mmol)in Et2O (1.0 mL) at 0 °C, and the resulting solution was warmedto room temp. After 12 h, the resultant light-yellow suspension waspoured into a solution of MeOH (1.0 mL) and Et3N (0.5 mL) at0 °C. The mixture was concentrated under reduced pressure, andthe residue was purified by column chromatography on silica gel(0.5 g, hexane/EtOAc = 4:6) to give oxo ester 28 (24.5 mg, 91%) asa yellow oil. Because of its instability, 28 was used in the next reac-tion without full characterization. Data for 28: 1H NMR(500 MHz, CDCl3): δ = 9.07 (br. s, 1 H), 8.19 (s, 1 H), 7.37 (d, J

= 8.5 Hz, 1 H), 6.60 (d, J = 8.5 Hz, 1 H), 3.93 (s, 3 H), 3.92 (s, 3H) ppm. HRMS (ESI): calcd. for C12H11BrNO4 [M + H]+

311.9866; found 311.9866. Et3N (0.0163 mL, 0.117 mmol), DMAP(1.9 mg, 0.016 mmol), and TsCl (16.4 mg, 0.0861 mmol) wereadded to a solution of indole 28 (24.5 mg, 0.0783 mmol) in CH2Cl2(1.0 mL) at 0 °C. After 2 h, saturated aqueous NH4Cl (10 mL) wasadded, and the resultant mixture was extracted with EtOAc(20 mL). The combined organic layers were washed with brine(10 mL), dried with Na2SO4, and concentrated under reduced pres-sure. The residue was purified by column chromatography on silicagel (0.5 g, hexane/EtOAc = 8:2) to give N-Ts-indole 29 (36.2 mg,100%) as a colorless solid. IR (film): ν̃ = 2951, 2360, 1733, 1685,1488, 1375, 1247, 1174, 1007, 812, 660, 567 cm–1. 1H NMR(500 MHz, CDCl3): δ = 8.62 (s, 1 H), 7.73 (d, J = 8.0 Hz, 2 H),7.36 (d, J = 9.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 6.61 (d, J =9.0 Hz, 1 H), 3.95 (s, 3 H), 3.67 (s, 3 H), 2.41 (s, 3 H) ppm. 13CNMR: δ = 179.7, 162.4, 146.6, 145.4, 136.7, 135.6, 129.8, 129.6(�2), 129.3, 127.5 (�2), 126.0, 117.7, 108.9, 105.1, 55.6, 53.2,21.6 ppm. HRMS (FAB): calcd. for C19H17BrNO6S [M + H]+

465.9954; found 465.9949.

Diol 30: NaBH4 (26.6 mg, 0.702 mmol) was added to a stirred solu-tion of oxo ester 29 (65.3 mg, 0.141 mmol) in MeOH (2.0 mL) at0 °C, and the suspension was warmed to room temp. After 12 h,the mixture was poured into saturated aqueous NH4Cl (20 mL)and extracted with EtOAc (30 mL). The combined organic layerswere washed with brine (20 mL), dried with Na2SO4, and concen-trated under reduced pressure. The residue was purified by columnchromatography on silica gel (1 g, hexane/EtOAc = 5:5) to give diol30 (58.4 mg, 95%) as a colorless oil. IR (film): ν̃ = 3033, 1683,1575, 1487, 1363, 1247, 1172, 1091, 991, 811, 568 cm–1. 1H NMR(500 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.70–7.68 (m, 2 H), 7.27–7.24 (m, 3 H), 6.52 (d, J = 9.0 Hz, 1 H), 5.71 (br. d, J = 7.0 Hz, 1H), 4.14 (dd, J = 8.0, 8.0 Hz, 1 H), 3.78 (dd, J = 8.0, 8.0 Hz, 1 H),3.61 (s, 3 H), 2.80 (s, 1 H), 2.38 (s, 3 H), 2.23 (br. s, 1 H) ppm. 13CNMR (125 MHz, CDCl3): δ = 146.9, 144.4, 137.0, 129.4 (�2),128.3 (�2), 128.1, 127.7, 127.1, 126.3, 120.3, 107.8, 104.3, 67.4,67.2, 55.5, 21.5 ppm. HRMS (FAB): calcd. for C18H19BrNO5S [M+ H]+ 440.0162; found 440.0167.

Acetonide 31: 2,2-Dimethoxypropane (0.729 mL, 5.93 mmol) andCSA (27.6 mg, 0.119 mmol) were added to a stirred solution of diol30 (521 mg, 1.19 mmol) in CH2Cl2 (12 mL) at 0 °C, and the re-sulting solution was warmed to room temp. After 1 h, Et3N(0.0165 mL, 0.238 mmol) was added, and the mixture was concen-trated under reduced pressure. The residue was purified by columnchromatography on silica gel (1 g, hexane/EtOAc = 8:2) to giveacetonide 31 (431 mg, 76%) as a colorless oil. IR (film): ν̃ = 3734,2936, 1575, 1363, 1288, 1248, 1173, 1092, 812, 702, 680, 661,569 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.69 (d,J = 8.0 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 1


H), 6.51 (d, J = 8.0 Hz, 1 H), 5.89 (ddd, J = 6.5, 1.0, 1.0 Hz, 1 H),4.58 (dd, J = 8.3, 6.5 Hz, 1 H), 3.83 (dd, J = 8.3, 6.5 Hz, 1 H), 3.62(s, 3 H), 2.38 (s, 3 H), 1.61 (s, 3 H), 1.50 (s, 3 H) ppm. 13C NMR(125 MHz, CDCl3): δ = 146.8, 144.3, 137.0, 129.6, 129.3 (�2),128.1, 127.7, 127.0 (�2), 126.8, 120.2, 109.3, 107.7, 103.8, 71.6(�2), 55.4, 26.5, 25.3, 21.4 ppm. HRMS (FAB): calcd. forC21H22BrNO5SNa [M + Na]+ 502.0294; found 502.0292.

(Silylethynyl)indole 32: According to the same procedure as for thesynthesis of 24, indole 32 (120 mg, 94 %) was obtained as a color-less oil by starting from 31 (105 mg, 0.219 mmol), ethynyltriiso-propylsilane (23; 0.262 mL, 1.11 mmol), CuI (4.2 mg, 0.022 mmol),and [Pd(PPh3)4] (12.7 mg, 0.011 mmol). IR (film): ν̃ = 3420, 2940,1652, 1506, 1456, 1371, 1293, 1174, 1057, 671, 575 cm–1. 1H NMR(500 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.67 (d, J = 8.5 Hz, 2 H),7.28 (d, J = 8.5 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 6.57 (d, J =8.5 Hz, 1 H), 5.93 (dd, J = 6.5, 6.5 Hz, 1 H), 4.62 (dd, J = 8.5,6.5 Hz, 1 H), 3.73 (dd, J = 8.5, 8.5 Hz, 1 H), 3.64 (s, 3 H), 2.37 (s,3 H), 1.60 (s, 3 H), 1.47 (s, 3 H), 1.13 (m, 21 H) ppm. 13C NMR(125 MHz, CDCl3): δ = 147.8, 144.3, 137.2, 131.1, 131.0, 129.3(�2), 127.1 (�2), 126.2, 125.0, 120.9, 109.4, 107.5, 106.7, 105.6,93.3, 72.1, 71.9, 55.4, 26.7, 25.8, 21.6, 18.7 (�6), 11.4 (�3) ppm.HRMS (FAB): calcd. for C32H43NO5SSiNa [M + Na]+ 604.2523;found 604.2522.

Ethynylindole 33: According to the same procedure as for the syn-thesis of 25, indole 33 (82.0 mg, 94%) was obtained as a colorlessoil by starting from 32 (120 mg, 0.207 mmol) and TBAF (1 m solu-tion in THF, 0.227 mL, 0.227 mmol). IR (film): ν̃ = 3277, 2361,1653, 1558, 1506, 1372, 1287, 1173, 1047, 802, 670, 574 cm–1. 1HNMR (500 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.69 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 2 H), 6.59 (d, J

= 8.5 Hz, 1 H), 5.86 (ddd, J = 6.5, 6.5, 1.0 Hz, 1 H), 4.54 (dd, J =8.5, 6.5 Hz, 1 H), 3.83 (dd, J = 8.5, 6.5 Hz, 1 H), 3.65 (s, 3 H), 3.22(s, 1 H), 2.38 (s, 3 H), 1.61 (s, 3 H), 1.49 (s, 3 H) ppm. 13C NMR(125 MHz, CDCl3): δ = 148.1, 144.3, 137.2, 130.3, 129.4 (�2),127.2 (�2), 127.0, 126.5, 121.7, 120.7, 109.5, 106.6, 102.0, 79.4,78.1, 72.3, 71.8, 55.4, 26.7, 25.8, 25.5 ppm. HRMS (FAB): calcd.for C23H24NO5S [M + H]+ 426.1370; found 426.1361.

Diacetate 35: CSA (2.5 mg, 0.011 mmol) was added to a stirredsolution of acetonide 33 (9.1 mg, 0.022 mmol) in MeOH (0.5 mL)at room temp. After 2 h, Et3N (0.5 mL) was added, and the mixturewas concentrated under reduced pressure to give the crude diol.The residue was dissolved in pyridine (0.5 mL), and Ac2O(0.0031 mL, 0.033 mmol) and DMAP (0.26 mg, 0.0022 mmol) wereadded successively at room temp. After 12 h, the mixture waspoured into saturated aqueous NH4Cl (10 mL) and extracted withEtOAc (20 mL). The combined organic layers were washed withbrine (5 mL) and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (1 g, hexane/EtOAc = 7:3) to give diacetate 35 (8.1 mg, 79% for two steps) as acolorless oil. IR (film): ν̃ = 1748, 1558, 1507, 1364, 1220, 1173,1035, 813, 668, 578 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.93(s, 1 H), 7.66 (d, J = 8.5 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.26(d, J = 8.5 Hz, 2 H), 6.93 (dd, J = 6.5, 3.0 Hz, 1 H), 6.56 (d, J =8.0 Hz, 1 H), 4.63 (dd, J = 12.0, 3.0 Hz, 1 H), 4.42 (dd, J = 12.0,6.5 Hz, 1 H), 3.63 (s, 3 H), 3.25 (s, 1 H), 2.34 (s, 3 H), 2.15 (s, 3H), 2.07 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 170.6,169.8, 147.9, 144.5, 136.9, 131.1, 130.6, 129.4 (�2), 127.7, 127.1(�2), 124.7, 116.8, 106.8, 106.2, 81.7, 80.3, 66.9, 65.4, 55.3, 21.6,21.2, 20.8 ppm. HRMS (ESI): calcd. for C48H46N2O14S2Na [2 M+ H]+ 961.2283; found 961.2298.

Vinyl Bromide 36: HBr·AcOH (33%, 0.022 mL, 0.081 mmol) wasadded to a stirred solution of ethynylindole 35 (8.1 mg,


0.017 mmol) in THF (0.5 mL) at 0 °C. After 30 min, the mixturewas poured into saturated aqueous NaHCO3 (10 mL) and ex-tracted with EtOAc (15 mL). The combined organic layers werewashed with brine (10 mL), dried with Na2SO4, and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel (0.5 g, hexane/EtOAc = 8:2) to givevinyl bromide 36 (6.2 mg, 65%) as a colorless oil. IR (film): ν̃ =1748, 1507, 1362, 1218, 1037, 814, 669, 578 cm–1. 1H NMR(500 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.69 (d, J = 7.5 Hz, 2 H),7.28 (d, J = 7.5 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 1 H), 6.70 (d, J =4.5 Hz, 1 H), 6.62 (d, J = 8.0 Hz, 1 H), 5.99 (s, 1 H), 5.89 (s, 1 H),4.50 (dd, J = 12.0, 2.5 Hz, 1 H), 4.35 (dd, J = 12.0, 4.5 Hz, 1 H),3.63 (s, 3 H), 2.40 (s, 3 H), 2.14 (s, 3 H), 2.09 (s, 3 H) ppm. 13CNMR (125 MHz, CDCl3): δ = 170.6, 169.9, 147.6, 144.5, 137.0,129.4 (�2), 128.4, 127.5, 127.2 (�2), 126.6, 126.1, 124.7, 122.9,116.2, 109.7, 106.3, 67.2, 65.7, 55.4, 21.6, 21.1, 20.8 ppm. HRMS(ESI): calcd. for C24H24BrNO7SNa [M + Na]+ 572.0349; found572.0350.

Indolylglycine 37: MgSO4 (1.31 g, 10.9 mmol), p-anisidine (1.34 g,10.9 mmol), and ethyl glyoxylate (1.02 mL, 10.9 mmol) were addedto a stirred solution of bromoindole 9 (1.23 g, 5.44 mmol) inCH2Cl2 (1.5 mL) at 0 °C. After stirring at room temp. for 12 h, themixture was filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (25 g,hexane/EtOAc = 7:3) to give indolylglycine 37 (1.94 g, 83%) as acolorless oil. IR (film): ν̃ = 1733, 1508, 1457, 1235, 1034, 792,669 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.44 (br. s, 1 H), 7.25(s, 1 H), 7.20 (d, J = 8.5 Hz, 1 H), 6.73 (d, J = 9.0 Hz, 2 H), 6.65(d, J = 9.0 Hz, 2 H), 6.50 (d, J = 8.5 Hz, 1 H), 6.06 (s, 1 H), 4.24(m, 1 H), 4.35 (br. s, 1 H), 4.13 (m, 1 H), 3.91 (s, 3 H), 3.70 (s, 3H), 1.24 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3):δ = 173.5, 152.4, 145.6, 140.7, 128.0, 124.4, 123.8, 122.7, 114.9(�2), 114.7 (�2), 114.0, 104.6, 103.1, 61.4, 55.6, 55.4, 53.3,14.0 ppm. HRMS (FAB): calcd. for C20H22BrN2O4 [M + H]+

433.0757; found 433.0760.

N-Ts-indole 38: TsCl (1.00 g, 5.28 mmol), DMAP (107 mg,0.879 mmol), and Et3N (1.83 mL, 13.2 mmol) were added to a solu-tion of indole 37 (1.90 g, 4.40 mmol) in toluene (10 mL) at roomtemp. After stirring at 70 °C for 18 h, the mixture was poured intowater (100 mL) and EtOAc (100 mL). The organic layer was sepa-rated, washed successively with saturated aqueous NaHCO3

(150 mL), saturated aqueous NH4Cl (150 mL), and brine (50 mL),dried with Na2SO4, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (40 g,hexane/EtOAc = 8:2) to give N-Ts-indole 38 (1.79 g, 69%) alongwith unreacted 37 (427 mg, 23%). N-Ts-indole 38 was obtained asa colorless solid. IR (film): ν̃ = 1732, 1652, 1508, 1457, 1374, 1245,1173, 991, 813, 669, 555 cm–1. 1H NMR (500 MHz, CDCl3): δ =7.92 (s, 1 H), 7.58 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 9.0 Hz, 1 H),7.22 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 9.0 Hz, 2 H), 6.66 (d, J =9.0 Hz, 2 H), 6.53 (d, J = 8.5 Hz, 1 H), 6.05 (br. s, 1 H), 4.28 (m,1 H), 4.21 (m, 1 H), 3.72 (s, 3 H), 3.63 (s, 3 H), 2.38 (s, 3 H), 1.23(t, J = 7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.2,152.7, 146.9, 144.5, 140.3, 136.7, 129.6, 129.4 (�2), 128.6, 128.3,127.6, 127.1 (�2), 117.5, 115.2 (�2), 114.7 (�2), 108.0, 104.8, 61.8,55.6, 55.6, 53.4, 21.6, 14.1 ppm. HRMS (FAB): calcd. forC27H28BrN2O6S [M + H]+ 587.0846; found 587.0848.

Amine 39: A solution of CAN (216 mg, 0.394 mmol) in water(1.2 mL) was added to a stirred solution of (p-methoxyphenyl)-amine 38 (115 mg, 0.197 mmol) in CH3CN (2.0 mL) and water(0.5 mL) at –15 °C. After 15 min, aqueous Na2S2O3 (5%, 5 mL)was added, and the mixture was poured into a vigorously stirred

M. Oikawa, M. Ikoma, M. SasakiFULL PAPERmixture of CHCl3 (5 mL) and water (5 mL). The organic layer wasseparated, washed with brine (5 mL), dried with Na2SO4, and con-centrated under reduced pressure. The residue was purified by col-umn chromatography on silica gel (6 g, hexane/Et2O = 1:1) to giveamine 39 (58.5 mg, 62%) along with an oxo ester side-product(30.9 mg, 33%). Amine 39 was obtained as a colorless solid. IR(film): ν̃ = 2979, 1748, 1684, 1488, 1374, 1252, 1175, 986, 799, 659,569 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.86 (s, 1 H), 7.67 (d,J = 8.5 Hz, 2 H), 7.26 (d, J = 8.5 Hz, 1 H), 7.26 (d, J = 8.5 Hz, 2H), 6.52 (d, J = 8.5 Hz, 1 H), 5.42 (br. s, 1 H), 4.26 (q, J = 7.5 Hz,2 H), 3.61 (s, 3 H), 2.39 (s, 3 H), 1.27 (t, J = 7.5 Hz, 3 H) ppm.13C NMR (125 MHz, CDCl3): δ = 168.1, 146.9, 144.8, 136.2, 129.5(�2), 129.4, 128.6, 127.4 (�2), 126.0, 124.7, 111.0, 108.3, 103.6,63.5, 60.4, 55.5, 21.5, 13.6 ppm. HRMS (FAB): calcd. forC20H21BrN2O5SNa [M + Na]+ 503.0247; found 503.0253.

N-Boc-amine 40: Boc2O (0.571 mL, 0.244 mmol) was added to astirred solution of amine 39 (58.5 mg, 0.122 mmol) in CH2Cl2(2.0 mL) at room temp. After 4 h, the mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography on silica gel (1 g, hexane/EtOAc = 2:8) to give N-Boc-amine 40 (42.3 mg, 60%) as a colorless oil. IR (film): ν̃ = 2979,1732, 1507, 1374, 1250, 1175, 992, 812, 737, 668, 569 cm–1. 1HNMR (500 MHz, CDCl3): δ = 7.86 (s, 1 H), 7.66 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 9.0 Hz, 1 H), 7.26 (d, J = 8.5 Hz, 2 H), 6.53 (d, J

= 9.0 Hz, 1 H), 6.09 (br. s, 1 H), 5.36 (br. s, 1 H), 4.26 (q, J =7.5 Hz, 2 H), 3.62 (s, 3 H), 2.39 (s, 3 H), 1.44 (s, 9 H), 1.26 (t, J =7.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.0, 154.7,146.7, 144.5, 136.6, 129.4, 129.3 (�2), 128.3, 127.2, 127.0 (�2),126.2, 116.0, 108.0, 104.3, 79.9, 61.7, 55.4, 49.8, 28.1 (�3), 21.4,13.9 ppm. HRMS (ESI): calcd. for C25H29BrN2O7SNa [M + Na]+

603.0771; found 603.0767.

(Silylethynyl)indole 41: A mixture of bromoindole 40 (109 mg,0.188 mmol), ethynyltriisopropylsilane (23; 0.225 mL, 0.939 mmol),[Pd(PPh3)4] (21.7 mg, 0.0190 mmol), and CuI (1.8 mg,0.0094 mmol) in Et3N (3.0 mL) and 1,4-dioxane (3.0 mL) wasstirred at 100 °C for 21 h. The mixture was then cooled to roomtemp., diluted with EtOAc (20 mL), and washed with saturatedaqueous NH4Cl (20 mL) and brine (10 mL). The organic layer wasdried with Na2SO4 and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (2 g,hexane/EtOAc = 8:2) to give (silylethynyl)indole 41 (118 mg, 92%)as a pale-yellow oil. IR (film): ν̃ = 3399, 2144, 1748, 1716, 1506,1364, 1293, 1257, 1174, 1058, 810, 667, 574 cm–1. 1H NMR(500 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.63 (d, J = 8.0 Hz, 2 H),7.31 (d, J = 8.5 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 6.58 (d, J =8.5 Hz, 1 H), 6.41 (br. s, 1 H), 5.53 (br. s, 1 H), 4.17 (q, J = 7.5 Hz,2 H), 3.64 (s, 3 H), 2.37 (s, 3 H), 1.42 (s, 9 H), 1.16 (t, J = 7.5 Hz,3 H), 1.12 (s, 21 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.1,154.8, 148.0, 144.7, 137.2, 131.9, 131.3, 129.7 (�2), 128.0, 127.4(�2), 125.2, 122.0, 118.0, 108.2, 107.1, 95.0, 80.0, 62.0, 55.7, 50.0,28.5 (�3), 21.9, 19.0 (�6), 14.2, 11.6 (�3) ppm. HRMS (FAB):calcd. for C36H51N2O7SSi [M + H]+ 683.3181; found 683.3176.

Ethynylindole 42: TBAF (1 m solution in THF, 0.250 mL,0.250 mmol) was added to a stirred solution of (silylethynyl)indole41 (151 mg, 0.215 mmol) in THF (2.5 mL) and water (0.004 mL) at0 °C. After 20 min, the mixture was poured into saturated aqueousNH4Cl (10 mL) and extracted with EtOAc (20 mL). The combinedorganic layers were washed with brine (10 mL), dried with Na2SO4,and concentrated under reduced pressure. The residue was purifiedby column chromatography on silica gel (2 g, hexane/EtOAc = 7:3)to give ethynylindole 42 (116 mg, 100 %) as a colorless oil. IR(film): ν̃ = 3649, 2978, 1748, 1716, 1507, 1362, 1253, 1173, 1054,


813, 669, 574 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.84 (s, 1 H),7.66 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 1 H), 7.25 (d, J =8.5 Hz, 2 H), 6.61 (d, J = 8.5 Hz, 1 H), 6.05 (d, J = 8.0 Hz, 1 H),5.41 (d, J = 8.0 Hz, 1 H), 4.26–4.24 (m, 2 H), 3.66 (s, 3 H), 3.24(s, 1 H), 2.38 (s, 3 H), 1.44 (s, 9 H), 1.25 (t, J = 7.5 Hz, 3 H) ppm.13C NMR (125 MHz, CDCl3): δ = 171.0, 154.5, 147.7, 144.3, 136.5,131.4, 130.3, 129.1 (�2), 128.4, 128.0 (�2), 126.9, 124.7, 116.1,106.5, 81.1, 80.2, 79.6, 61.5, 55.1, 48.7, 28.0 (�3), 21.3, 13.8 ppm.HRMS (FAB): calcd. for C27H30N2O7SNa [M + Na]+ 549.1666;found 549.1669.

Vinyl Bromide 8: HBr·AcOH (33%, 0.0618 mL, 0.229 mmol) wasadded to a stirred solution of alkyne 42 (24.1 mg, 0.0460 mmol) inTHF (0.5 mL) at 0 °C. After 30 min, the mixture was poured intosaturated aqueous NaHCO3 (10 mL) and extracted with EtOAc(15 mL). The combined organic layers were washed with brine(10 mL), dried with Na2SO4, and concentrated under reduced pres-sure. The residue was purified by column chromatography on silicagel (0.5 g, hexane/EtOAc = 7:3) to give vinyl bromide 8 (24.5 mg,88%) as a colorless oil. IR (film): ν̃ = 3392, 2978, 1734, 1716, 1506,1366, 1252, 1173, 1021, 891, 813, 680, 573 cm–1. 1H NMR(500 MHz, CDCl3): δ = 7.83 (s, 1 H), 7.68 (d, J = 7.5 Hz, 2 H),7.27 (d, J = 7.5 Hz, 2 H), 7.15 (d, J = 8.5 Hz, 1 H), 6.64 (d, J =8.5 Hz, 1 H), 5.97 (br. s, 1 H), 5.90 (br. s, 1 H), 5.84 (s, 1 H), 5.12(br. s, 1 H), 4.28–4.25 (m, 2 H), 3.64 (s, 3 H), 2.40 (s, 3 H), 1.44 (s,9 H), 1.26 (br. t, J = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz,CDCl3): δ = 171.4, 154.6, 147.5, 144.5, 136.9, 129.4 (�2), 128.3,127.7, 127.2 (�2), 127.2, 126.8, 126.2, 126.0, 125.0, 122.6, 106.6,79.9, 61.8, 55.4, 50.3, 28.3 (�3), 21.6, 14.1 ppm. HRMS (ESI):calcd. for C27H31BrN2O7SNa [M + Na]+ 629.0928; found 629.0927.

Coupling Product 43: A suspension of imidazolylboronic acid 7(23.6 mg, 0.0894 mmol), vinyl bromide 36 (18.1 mg, 0.0298 mmol),[Pd(PPh3)4] (3.4 mg, 0.0030 mmol), and Cs2CO3 (29.1 mg,0.0894 mmol) in 1,4-dioxane (1.5 mL) and water (1.5 mL) wasstirred at 100 °C for 20 h. The mixture was cooled to room temp.,diluted with EtOAc (20 mL), and washed with saturated aqueousNH4Cl (20 mL) and brine (10 mL). The organic layer was driedwith Na2SO4 and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (0.5 g, hex-ane/EtOAc = 6:4) to give coupling product 43 (17.3 mg, 84%) as acolorless oil. IR (film): ν̃ = 3734, 2934, 1747, 1577, 1507, 1363,1237, 1173, 1092, 1037, 814, 679, 579 cm–1. 1H NMR (500 MHz,CDCl3): δ = 7.92 (s, 1 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.32–7.17 (m,8 H), 7.02 (d, J = 8.5 Hz, 1 H), 6.66 (d, J = 8.5 Hz, 1 H), 6.55 (s,1 H), 6.10 (br. s, 1 H), 5.99 (s, 1 H), 5.55 (d, J = 11.0 Hz, 1 H),5.48 (d, J = 11.0 Hz, 1 H), 5.33 (m, 1 H), 4.11 (m, 1 H), 3.66 (s, 3H), 3.29 (s, 3 H), 2.40 (s, 3 H), 1.99 (s, 6 H) ppm. 13C NMR(125 MHz, CDCl3): δ = 170.3, 169.8, 147.1, 144.4, 137.1, 135.5,133.8, 132.8, 132.1, 132.0, 131.9, 129.4 (�2), 129.2 (�2), 129.1(�2), 128.6, 127.2 (�2), 127.1, 126.8, 126.5, 124.7, 117.3, 115.9,106.5, 77.2, 75.4, 66.6, 55.9, 55.3, 21.6, 20.9, 20.7 ppm. HRMS(ESI): calcd. for C35H36N3O8S2 [M + H]+ 690.1938; found690.1938.

Diol 44: K2CO3 (0.30 mg, 0.0025 mmol) was added to a solutionof diacetate 43 (17.3 mg, 0.025 mmol) in MeOH (0.5 mL) at roomtemp. EtOAc (20 mL) was added after stirring for 10 h, and themixture was washed with saturated aqueous NH4Cl (10 mL), driedwith Na2SO4, and concentrated under reduced pressure. The resi-due was purified by column chromatography on silica gel (0.5 g,hexane/EtOAc = 3:7) to give diol 44 (14.0 mg, 93%) as a colorlessoil. IR (film): ν̃ = 3734, 2932, 1652, 1507, 1363, 1235, 1173, 1092,1024, 669, 579 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.90 (s, 1H), 7.70 (d, J = 8.5 Hz, 2 H), 7.28–7.17 (m, 7 H), 6.93 (d, J =


8.5 Hz, 1 H), 6.61 (d, J = 8.5 Hz, 1 H), 6.58 (s, 1 H), 5.92 (s, 1 H),5.35 (dd, J = 13.8, 10.5 Hz, 2 H), 5.30 (s, 1 H), 4.60 (br. s, 1 H),3.66 (s, 3 H), 3.66 (d, J = 6.0 Hz, 1 H), 3.49 (m, 1 H), 3.27 (s, 3H), 2.39 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 147.2,144.2, 137.4, 136.6, 136.1, 134.1, 132.2, 132.1, 129.4 (�2), 129.3(�2), 129.1, 128.8, 128.6, 127.3 (�2), 127.2 (�2), 127.1, 126.4,126.4, 125.1, 120.6, 117.8, 106.3, 75.2, 67.7, 56.1, 55.4, 21.6 ppm.HRMS (FAB): calcd. for C31H32N3O6S2 [M + H]+ 606.1727; found606.1726.

Coupling Product 45: A suspension of imidazolylboronic acid 7(117 mg, 0.444 mmol), vinyl bromide 8 (89.6 mg, 0.148 mmol),[Pd(PPh3)4] (17.1 mg, 0.0148 mmol), NaOEt (30.2 mg,0.444 mmol), and Cs2CO3 (144 mg, 0.444 mmol) in 1,4-dioxane(3.0 mL) was stirred at 100 °C for 4 h. The mixture was then cooledto room temp., diluted with EtOAc (20 mL), and washed with satu-rated aqueous NH4Cl (20 mL) and brine (10 mL). The organiclayer was dried with Na2SO4 and concentrated under reduced pres-sure. The residue was carefully purified by column chromatographyon silica gel (5 g, hexane/EtOAc = 5:5) to give coupling product 45(67.1 mg, 61%) as a colorless oil. IR (film): ν̃ = 3784, 1732, 1716,1698, 1540, 1507, 1362, 1250, 1173, 1024, 719, 669, 575 cm–1. 1HNMR (500 MHz, CDCl3): δ = 7.78 (s, 1 H), 7.70 (d, J = 8.5 Hz, 2H), 7.29–7.15 (m, 7 H), 7.00 (d, J = 7.5 Hz, 1 H), 6.66 (d, J =7.5 Hz, 1 H), 6.64 (br. s, 1 H), 5.95 (s, 1 H), 5.55–5.32 (m, 4 H),4.92 (br. s, 1 H), 4.12–4.05 (m, 2 H), 3.66 (s, 3 H), 3.23 (br. s, 3 H),2.40 (s, 3 H), 1.38 (s, 9 H), 1.14 (br. s, 3 H) ppm. 13C NMR(125 MHz, CDCl3): δ = 171.2, 154.8, 147.0, 144.5, 141.9, 137.0,135.7, 134.9, 134.3, 132.9, 129.4 (�2), 129.2 (�2), 129.0, 128.6(�2), 128.0, 127.3 (�2), 127.1, 126.8, 126.8, 125.2, 117.2, 115.7,106.7, 80.0, 75.4, 67.0, 61.6, 55.9, 55.4, 28.2 (�3), 21.6, 14.0 ppm.HRMS (ESI): calcd. for C38H43N4O8S2 [M + H]+ 747.2517; found747.2519.

Alcohol 46: LiBH4 (4.8 mg, 0.22 mmol) was added to a stirred solu-tion of ester 45 (66.2 mg, 0.0887 mmol) in THF (1.0 mL) at 0 °C.The mixture was stirred at room temp. for 3 h before being pouredinto a stirred mixture of EtOAc (20 mL) and saturated aqueousNH4Cl (30 mL). The organic layer was separated, washed withbrine (10 mL), dried with Na2SO4, and concentrated under reducedpressure. The residue was purified by column chromatography onsilica gel (5 g, hexane/EtOAc = 5:5) to give alcohol 46 (45.6 mg,73%) as a colorless oil. IR (film): ν̃ = 3784, 1698, 1507, 1362, 1241,1172, 1092, 1041, 669, 579 cm–1. 1H NMR (500 MHz, CDCl3): δ =7.82 (s, 1 H), 7.69 (d, J = 8.5 Hz, 2 H), 7.28–7.17 (m, 8 H), 6.96(d, J = 8.0 Hz, 1 H), 6.64 (d, J = 8.0 Hz, 1 H), 6.59 (br. s, 1 H),5.95 (s, 1 H), 5.53–5.42 (m, 2 H), 5.32 (s, 1 H), 4.97 (br. s, 1 H),4.82 (br. s, 1 H), 3.64 (s, 3 H), 3.56 (m, 2 H), 3.27 (s, 3 H), 2.39 (s,3 H), 1.39 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 156.1,147.5, 145.7, 144.5, 141.4, 137.0, 135.1, 131.9, 130.9, 129.6 (�2),129.5 (�2), 129.4, 129.2 (�2), 128.9, 127.8, 127.3, 127.2 (�2),127.0, 126.8, 125.2, 125.1, 120.5, 106.6, 80.2, 76.5, 56.4, 55.4, 49.4,28.3 (�3), 21.6 ppm. HRMS (FAB): calcd. for C36H41N4O7S2 [M+ H]+ 705.2411; found 705.2417.

Tosylate 47: Et3N (0.0090 mL, 0.065 mmol), TsCl (6.2 mg,0.032 mmol), and DMAP (0.3 mg, 0.0022 mmol) were added to astirred solution of alcohol 46 (15.2 mg, 0.212 mmol) in CH2Cl2(1.0 mL) at room temp. After 10 h, the mixture was diluted withEtOAc (20 mL), washed successively with saturated aqueousNH4Cl (10 mL) and brine (10 mL), dried with Na2SO4, and con-centrated under reduced pressure. The residue was purified by col-umn chromatography on silica gel (0.5 g, hexane/EtOAc = 6:4) togive tosylate 47 (16.7 mg, 90%) as a colorless oil. IR (film): ν̃ =3389, 2928, 1709, 1598, 1505, 1362, 1240, 1174, 1093, 1038, 812,


680, 666, 579 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.80 (s, 1 H),7.70 (d, J = 8.5 Hz, 2 H), 7.61 (d, J = 8.5 Hz, 2 H), 7.28–7.18 (m,9 H), 6.91 (d, J = 8.5 Hz, 1 H), 6.61 (d, J = 8.5 Hz, 1 H), 6.54 (br.s, 1 H), 5.90 (s, 1 H), 5.46–4.95 (m, 4 H), 4.95 (m, 2 H), 4.10 (br.s, 1 H), 3.65 (s, 3 H), 3.22 (s, 3 H), 2.39 (s, 3 H), 2.34 (s, 3 H), 1.38(br. s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 154.4, 147.0,144.8, 144.4, 142.6, 137.1, 135.5, 133.9, 132.7, 132.2, 129.9 (�2),129.5, 129.4 (�4), 129.3 (�2), 129.0, 128.6, 127.8 (�2), 127.2 (�2),127.1, 126.6, 126.3, 126.0, 125.1, 117.2, 106.4, 79.9, 75.4, 70.5, 56.0,55.3, 46.4, 28.3 (�3), 21.6, 21.6 ppm. HRMS (FAB): calcd. forC43H47N4O9S3 [M + H]+ 859.2500; found 859.2512.

Azide 48: A solution of tosylate 47 (3.6 mg, 0.0042 mmol) andNaN3 (0.80 mg, 0.013 mmol) in DMF (1.0 mL) was stirred at 80 °Cfor 4 h. The mixture was then diluted with EtOAc (20 mL), washedsuccessively with saturated aqueous NH4Cl (10 mL) and brine(10 mL), dried with Na2SO4, and concentrated under reduced pres-sure. The residue was purified by column chromatography on silicagel (0.5 g, hexane/EtOAc = 7:3) to give azide 48 (2.0 mg, 77%) asa colorless oil. IR (film): ν̃ = 3375, 2930, 2100, 1707, 1602, 1505,1364, 1243, 1171, 1093, 813, 680, 579 cm–1. 1H NMR (500 MHz,CDCl3): δ = 7.89 (s, 1 H), 7.71 (d, J = 8.5 Hz, 2 H), 7.30–7.18 (m,8 H), 6.98 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 8.0 Hz, 1 H), 6.62 (br.s, 1 H), 5.97 (s, 1 H), 5.57–5.40 (m, 2 H), 5.31 (s, 1 H), 4.91 (br. s,1 H), 4.85 (br. s, 1 H), 3.65 (s, 3 H), 3.40 (br. s, 1 H), 3.27 (s, 3 H),2.40 (s, 3 H), 1.40 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ= 154.6, 147.1, 144.4, 142.5, 139.2, 137.1, 135.7, 134.0, 133.8, 132.8,129.6 (�2), 129.4 (�2), 129.2 (�2), 129.0 (�2), 127.3, 127.2, 127.1,126.7, 126.4, 125.2, 117.3, 106.5, 82.9, 75.4, 56.0, 55.3, 54.2, 47.3,28.3 (�3), 21.6 ppm. HRMS (FAB): calcd. for C36H40N7O6S2 [M+ H]+ 730.2476; found 730.2479.

Left-Hand Fragment 4: TFA (0.050 mL) was added to a stirredsolution of N-Boc-amine 48 (2.0 mg, 0.0032 mmol) in CH2Cl2(0.5 mL) at 0 °C. After 2 h, the mixture was poured into a vigor-ously stirred mixture of EtOAc (20 mL) and saturated aqueousNaHCO3 (10 mL). The organic layer was separated, washed withbrine (10 mL), dried with Na2SO4, and concentrated under reducedpressure. The residue was purified by column chromatography onsilica gel (0.5 g, MeOH/CHCl3 = 2:98) to give the left-hand frag-ment 4 (1.5 mg, 89%) as a colorless oil. IR (film): ν̃ = 3379, 2933,2102, 1601, 1438, 1362, 1169, 1094, 813, 577 cm–1. 1H NMR(500 MHz, CDCl3): δ = 7.90 (s, 1 H), 7.71 (d, J = 8.5 Hz, 2 H),7.28–7.20 (m, 7 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.65 (d, J = 8.0 Hz,1 H), 6.65 (br. s, 1 H), 5.95 (s, 1 H), 5.40 (dd, J = 15.8, 10.5 Hz, 2H), 5.31 (s, 1 H), 3.99 (br. s, 1 H), 3.66 (s, 3 H), 3.65 (m, 1 H), 3.28(s, 3 H), 3.15 (m, 1 H), 2.40 (s, 3 H) ppm. 13C NMR (125 MHz,CDCl3): δ = 147.3, 144.3, 143.5, 142.5, 137.3, 135.9, 132.7, 129.7,129.4 (�2), 129.4 (�2), 129.0 (�2), 127.3, 127.2 (�2), 126.8, 126.7,126.4, 126.4, 125.2, 122.3, 117.2, 106.4, 75.2, 58.3, 56.0, 55.3, 48.0,21.6 ppm. HRMS (FAB): calcd. for C31H32N7O4S2 [M + H]+

630.1952; found 630.1950.

Advanced Intermediate 3: Et3N (0.0012 mL, 0.0086 mmol), DMAP(1.2 mg, 0.0043 mmol), and acyl chloride 5[28] (2.4 mg,0.0086 mmol) were added to a stirred solution of amine 4 (1.50 mg,0.00288 mmol) in toluene (1.0 mL) at 0 °C. After stirring at 40 °Cfor 20 h, the mixture was diluted with EtOAc (20 mL), washed suc-cessively with saturated aqueous NaHCO3 (10 mL) and brine(10 mL), dried with Na2SO4, and concentrated under reduced pres-sure. The residue was purified by column chromatography on silicagel (0.5 g, EtOAc/hexane = 3:7) to give advanced intermediate 3(1.81 mg, 72%) as a colorless solid. IR (film): ν̃ = 3301, 3086, 1692,1555, 1513, 1441, 1248, 1176, 1031, 981, 821, 751, 700 cm–1. 1HNMR (500 MHz, CDCl3): δ = 8.62 (br. s, 1 H, NH), 8.12 (br. s, 1

M. Oikawa, M. Ikoma, M. SasakiFULL PAPERH, Ar-H), 7.96 (br. s, 1 H, Ar-H), 7.75–7.72 (m, 3 H, Ar-H), 7.48–7.03 (m, 11 H, Ar-H), 6.73 (s, 1 H, 4��-H), 6.68 (d, J = 8.5 Hz, 1H, Ar-H), 6.00 (br. s, 1 H, Ar-H), 5.60–5.28 (m, 4 H, 6�-H, NH,OCH2O), 3.66 (s, 3 H, Ar-OCH3), 3.66–3.60 (m, 2 H, 5-H), 3.25 (s,3 H, CH2OCH3), 2.39 (s, 3 H, Ar-CH3) ppm. 13C NMR (125 MHz,CDCl3): δ = 198.5 (C-3), 161.6 (C-2), 147.6 (Ar), 144.8 (Ar), 144.8(Ar), 143.2 (Ar), 139.3 (Ar), 137.3 (Ar), 137.1 (Ar), 136.1 (Ar),134.8 (Ar), 132.3 (Ar), 129.7 (�2, Ar), 129.7 (�2, Ar), 129.6 (�2,Ar), 129.3 (Ar), 129.1 (Ar), 127.6 (�2, Ar), 127.6 (Ar), 127.3 (Ar),126.5 (Ar), 125.8 (Ar), 125.5 (Ar), 123.8 (Ar), 123.8 (Ar), 119.7(Ar), 118.0 (Ar), 115.1 (Ar), 113.6 (Ar), 112.9 (Ar), 107.0 (Ar), 75.8(N-CH2-OCH3), 72.9 (C-6), 56.3 (N-CH2-OCH3), 55.6 (Ar-OCH3),46.1 (C-5), 21.9 (Ar-CH3) ppm. HRMS (FAB): calcd. forC41H36BrN8O6S2 [M + H]+ 879.1377; found 879.1379.

Supporting Information (see footnote on the first page of this arti-cle): 1H and 13C NMR spectra of new compounds.

Acknowledgments

A research fellowship to M. I. from the Japan Society for the Pro-motion of Science (JSPS) is gratefully acknowledged.

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Received: February 23, 2011Published Online: June 30, 2011

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