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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Tetrahedron. Author manuscript; available in PMC 2010 July 2.
Published in final edited form as:
Tetrahedron. 2007 July 2; 63(27): 6088–6114.
doi:  10.1016/j.tet.2007.03.072
PMCID: PMC2896327
NIHMSID: NIHMS25218

New synthetic technology for the construction of N-hydroxyindoles and synthesis of nocathiacin I model systems

Abstract

A new synthetic method providing expedient access to a wide range of polyfunctionalized N-hydroxyindoles (IV) is reported. These unique constructs are assembled by nucleophilic additions to in situ generated α,β-unsaturated nitrones (III) through carbon–carbon and carbon–heteroatom bond formation. The new synthetic technology was applied to the synthesis of nocathiacin I (1) model systems (2 and 3ac) containing the N-hydroxyindole structural motif.

Keywords: N-hydroxyindole, nitrone, nocathiacin I, nucleophilic addition, synthetic methods

1. Introduction

Nocathiacin I (1, Figure 1), a complex thiopeptide antibiotic isolated from Nocardia sp. (ATCC-202099) and the fungus Amicolaptosis sp., exhibits remarkably potent in vitro and in vivo activity against Gram-positive bacteria.13 One of the most striking structural motifs within the molecular framework of nocathiacin I (1) is the N-hydroxyindole moiety that carries the oxygen ether linkage and bridges the 15-membered depsipeptide ring with the 10-membered macrolide system of the molecule.4 Challenged by the daunting structure of nocathacin I (1) and intrigued by the rarity of its N-hydroxyindole structural motif in nature and the relative scarcity of methods for its assembly,5 we initiated a program directed toward the development of synthetic technologies for the generation of substituted N-hydroxyindoles suitable for potential applications to complex molecule construction.

Figure 1
Structures of nocathiacin I (1) and N-hydroxyindole model systems 2 and 3ac. SEM, 2-(trimethylsilyl)ethoxymethyl; MOM, methoxymethyl.

In this article, we describe a detailed account of our investigations in this area that culminated in a general method for the synthesis of highly substituted N-hydroxyindoles (IV, Scheme 1)6 from readily available aromatic precursors and a variety of nucleophiles through the trapping of in situ generated α,β-unsaturated nitrones and the application of the developed technology to the construction of certain nocathiacin I (1) model systems such as 2 and 3ac (Figure 1).7

Scheme 1
General route for the construction of 3-substituted N-hydroxyindoles (IV).

2. Results and discussion

2.1 Synthetic technology development

Based on certain precedents,5c–g our general strategy for the construction of N-hydroxyindoles, shown in Scheme 1, was devised to take advantage of the ready availability of aromatic nitro compounds as starting materials and the perceived propensity of α,β-unsaturated nitrones to enter into reactions with suitable nucleophiles and give stable adducts. Thus, it was envisioned that reduction of nitro ketoesters I under appropriate conditions should produce hydroxylamines II, which were expected to undergo facile intramolecular condensation to afford the α,β-unsaturated nitrones III, whose existence in the presence of suitable nucleophiles should be transient, leading through 1,5-addition reactions, to N-hydroxyindoles IV.8 Having defined the general cascade for the projected synthesis of N-hydroxyindoles, the synthesis of the starting nitro ketoesters, the exploration of conditions for their reduction, and the range of capable nucleophiles to be employed in this scheme became the first objectives of the investigation.

Scheme 2 summarizes the synthesis of nitro ketoesters 6ag and nitro ketoacid 7a, which were required for the present studies. Thus, reaction of the corresponding nitrotoluene compound with excess dimethyl oxalate in the presence of NaH in DMF at 0 °C furnished ketoesters 5ag in yields ranging from 60–85%.9 Exposure of each of these compounds to Eschenmoser’s salt in the presence of NaH in THF at 0–25 °C then led to the desired α,β-unsaturated ketoesters 6ag in 50–98% yield.10,11 The α,β-unsaturated ketoacid 7a was prepared from methyl ester 6a through the action of Me3SnOH in 1,2-dichloroethane at 70 °C (77% yield), as standard hydrolysis methods resulted in decomposition, as alluded to in a previous communication from our laboratories.12

Scheme 2
Synthesis of nitro ketoesters 6ag and acid 7a. Reagents and conditions: a) NaH (4.0 equiv), (CO2Me)2 (5.0 equiv), DMF, 0 °C, 1 h; then 25 °C, 12 h, 5a (60%), 5b (60%), 5c (85%), 5d (80%), 5e (75%), 5f (75%), 5g (65%); b) NaH (1.1 ...

The desired generation and trapping of the α,β-unsaturated nitrones was achieved under two sets of experimental conditions. Scheme 3 depicts the first procedure (method A) for this cascade sequence involving activated zinc [Zn] (prepared from zinc dust, 1,2-dibromoethane and TMSCl) as the reducing agent as demonstrated with nitro ketoester 6a.13 Thus, refluxing zinc dust with 1,2-dibromoethane in THF, followed by cooling to 25 °C (refluxing/cooling process repeated three additional times) and subsequent addition of TMSCl, followed by a mixture of aqueous 1N NH4Cl and 6a resulted in the formation of N-hydroxyindoline 9 (56% yield) and hydroxylactam 14 (10% yield). The structure of the latter compound was unambiguously proven by X-ray crystallographic analysis (see ORTEP structure, Scheme 3).14 These results can be rationalized by envisioning ring closure within the structure of the initially formed hydroxylamine (8) leading to N-hydroxylamine tertiary alcohol 9 (path A, Scheme 3) on one hand, and 1,4-addition of NH3 to the starting material 6a followed by a lactamization/enolization sequence within the initially formed aminoketoester 13 to generate compound 14 (path B, Scheme 3) on the other. Tertiary alcohol 9 exhibited high reactivity, especially upon exposure to acidic conditions that resulted in the loss of a molecule of water, generating a reactive species presumed to be the α,β-unsaturated nitrone 10, whose isolation proved elusive. The presence of the α,β-unsaturated nitrone 10 was supported by its trapping with a variety of nucleophiles. Thus, reaction of 9 with benzyl alcohol (5.0 equiv) or benzyl mercaptan (5.0 equiv) in DME at 40 °C in the presence of pTsOH led to the formation of N-hydroxyindoles 11 (55% yield) and 12 (90% yield), respectively. These reactions are presumed to proceed either directly from 9 by SN2′-type displacement, or by 1,5-addition to the initially formed nitrone (10), or through both of the potential mechanistic pathways. It is interesting to note that the isolation of N-hydroxyindoles 11 and 12 stands in contrast to the observations of Myers and Herzon in which their initially formed products from 1,5-nucleophilic additions to a sterically congested α,β-unsaturated nitrone proved too labile for isolation, rapidly reverting back to their components instead.5d

Scheme 3
Zn/NH4Cl-induced generation and trapping of isolable tertiary alcohol 9 and in situ generated α,β-unsaturated nitrone 10 to form N-hydroxyindoles (method A). Reagents and conditions: a) Zn dust (4.9 equiv), BrCH2CH2Br (0.33 equiv), THF, ...

In search of a more direct and convenient access to the desired N-hydroxyindoles from the same starting materials, an alternative experimental procedure was explored and optimized as summarized in Scheme 4 and Table 1. According to this method (method B), nitro ketoester 6a was treated with SnCl2·2H2O (2.2 equiv) in the presence of benzyl alcohol (5.0 equiv) or benzyl mercaptan (5.0 equiv) and 4 Å molecular sieves in DME at 40 °C for 1–1.5 h, conditions that led, through path A1, to the formation of adducts 11 (60% yield, see ORTEP drawing, Scheme 4)14 or 12 (55% yield), respectively. The optimum conditions described above were arrived at through a systematic study in which benzyl alcohol (BnOH) was employed as a nucleophile to trap the reactive species reductively generated from nitro ketoester 6a (see Table 1) whereby the effects of stoichiometry, temperature (entries 1–4), water content (entry 9), molecular sieves (entries 9 and 10) and solvent (entries 11 and 12) were varied. It is interesting to note, in contrast to method A, the absence of the N-hydroxy tertiary alcohol 9 as an isolable intermediate in this procedure (method B), presumably due to the fleeting nature of the latter under the prevailing acidic conditions of the reaction medium which apparently promote its rapid conversion, first to nitrone 10 and subsequently to the observed N-hydroxyindole product 11 or 12. The SnCl2·2H2O-induced process, however, also leads to N-hydroxy ketoester 16 (15–17% yield), presumably originating from the initially formed hydroxylamine (8) through pathway A2 (Scheme 4) via an intramolecular aza-Michael addition followed by oxidation/aromatization of the presumed enolic species (15). Another possible mechanism for the formation of N-hydroxy ketoester 16 may involve the corresponding nitroso compound, generated by partial reduction of 6a (or its hydrated counterpart), which could similarly undergo, through its nitrogen atom, intramolecular 1,4-addition to the α,β-unsaturated site; such an event may then be followed by rearrangement (or elimination of H2O) to the observed by-product 16.

Scheme 4
SnCl2·2H2O-induced generation and trapping of in situ generated α,β-unsaturated nitrone 10 to form N-hydroxyindoles (method B). Reagents and conditions: a,b) SnCl2·2H2O (2.2 equiv), 4 Å molecular sieves (20 wt%), ...
Table 1
Optimization of SnCl2·2H2O-induced N-hydroxyindole formation reaction conditions using bromonitroaromatic ketoester 6a.a,b

Having established the SnCl2·2H2O procedure (method B) as the preferred method for the generation and trapping of the reactive α,β-unsaturated nitrones such as 10 (or its hydrated form, N-hydroxy tertiary alcohol 9, Scheme 3), we set out to explore its generality and scope. Tables 2 and and33 summarize our initial findings employing various combinations of nitroaromatic ketoesters with oxygen (Table 2), sulfur (Table 3) and nitrogen (Table 3) nucleophiles. As seen in these tables, both primary and secondary alcohols, thiols and amines participate in these reactions to form the expected N-hydroxyindoles in moderate to excellent yields. Aside from by-product 16 (Scheme 4), another probable contributing factor to the moderate yields in certain cases is the possibility of dimerization/polymerization processes, in which the fleeting nitrone (10, Scheme 4) can be captured by the N-hydroxy group of the desired product.4b Benzyl alcohol and benzyl mercaptan were the hetero-nucleophiles chosen to investigate varying substitutions around the aromatic nuclei of the employed ketoesters. As depicted in Tables 2 and and33 cyano (Table 2, entry 9, Table 3, entry 9), SEM-protected hydroxymethyl (Table 2, entry 5; Table 3, entry 5), and several fluorine-containing (Table 2, entries 6–8; Table 3, entries 6–8) nitro ketoesters successfully enter the reaction.

Table 2
Synthesis of 3-substituted-N-hydroxyindoles through 1,5-addition of oxygen nucleophiles to substituted α,β-unsaturated nitrones.a,b
Table 3
Synthesis of 3-substituted-N-hydroxyindoles through 1,5-addition of sulfur and nitrogen nucleophiles to substituted α,β-unsaturated nitrones.a,b

Finally, phenols (Scheme 5) were employed as nucleophiles with the anticipation that they would yield the oxygen–carbon bonded 1,5-addition products that had been observed with the other oxygen nucleophiles. However, we were somewhat surprised to discover that both phenol and 2,6-dimethoxyphenol led to compounds 35 (40% yield) and 36 (31% yield), respectively, which were formed through carbon–carbon bond forming reactions as the major products. An X-ray crystal structure (see ORTEP drawing, Scheme 5) of the latter compound (36) further confirmed this outcome.14

Scheme 5
Initial observations of C–C bond formation via 1,5-addition of phenolic nucleophiles. Reagents and conditions: a) SnCl2·2H2O (2.2 equiv), 4 Å molecular sieves (20 wt%), phenol (5.0 equiv), DME, 40 °C, 2.0 h, 40%; b) SnCl ...

Intrigued by these initial results we then set out to explore the addition of various carbon nucleophiles to α,β-unsaturated nitrones generated from an array of α,β-unsaturated ketoesters employing the SnCl2·2H2O-based reaction (method B). Our studies began with silyl enol ethers as nucleophiles and 2-bromo-substituted ketoester 6a; the results are shown in Table 4. Thus, in DME at 40 °C and in the presence of SnCl2·2H2O, both cyclic (entries 1–3) and acyclic (entries 4–13) silyl enol ethers, as well as ethyl vinyl ether (entry 14) entered the developed cascade reaction with varying yields, ranging from 30 to 75%. The N-hydroxyindoles formed possess substituents at the 3-position containing α-substituted ketones (or an aldehyde as in entry 14) carrying aliphatic, aromatic and heteroaromatic appendages. Of special interest are the fluoro-substituted indoles (entries 8–10), due to their often superior pharmacological properties,15 and those indoles endowed with synthetically fertile functional groups for further chemical manipulation. The N-hydroxy-3-substituted ketoester 16, whose formation as a by-product has already been discussed above, was also observed in these reactions in small amounts (see Table 4).

Table 4
Synthesis of 3-alkyl-N-hydroxyindoles through 1,5-addition of silyl enol ethers to the α,β-unsaturated nitrone derived from 6a.a

Table 5 demonstrates the successful utilization of silanes and related compounds as well as stannanes as nucleophiles in this reaction. Thus, allyl silanes of varying structures serve well as partners with bromo-substituted nitro ketoester 6a, furnishing novel N-hydroxyindoles (entries 1–4) while the allenyl trimethylsilane (entry 8) led to acetylenic compound 57. Somewhat interestingly, the use of allyl trimethoxysilane in this reaction (entry 5) resulted in the formation of the methoxy N-hydroxyindole 55 (rather than the allyl substituted product). The same methoxy indole was observed when methoxytrimethylsilane was used (entry 6). X-Ray crystallographic analysis of N-hydroxyindole 55 confirmed its structure beyond doubt (see ORTEP drawing, Figure 2). The participation of triethylsilane (entry 7) in this process resulted in the formation of the methyl substituted N-hydroxyindole 56, presumably through 1,5-reduction of the incipient α,β-unsaturated nitrone. The use of allyl stannanes (Table 5, entries 9 and 10) also proved successful, leading to the expected products and demonstrating their potential as partners in this cascade reaction. X-Ray crystallographic analysis of the gem-dimethyl compound 58 confirmed its structure (see ORTEP drawing, Figure 2).14

Figure 2
ORTEP drawings of compounds 55 and 58 drawn at the 50% probability level.
Table 5
Synthesis of 3-alkyl-N-hydroxyindoles through 1,5-addition of silanes and stannanes to the α,β-unsaturated nitrone derived from 6a.a

In order to explore further the generality and scope of the present methodology we proceeded to vary the nitroaromatic partner and combine the new substrates with a number of nucleophiles. Table 6 shows the results with nitroaromatic substrates 6ag (whose preparation has already been discussed above, Scheme 2) and silyl enol ethers 5961. Thus, N-hydroxyindoles 37, 40, 44, and 6279 were formed in moderate to good yields as shown in Table 6. It was of interest to observe that the process tolerates various substituents and substitution patterns, although somewhat higher yields were obtained with the ortho-substituted nitroaromatic substrates. The survival of the nitrile group under the reductive conditions (see Table 6, entry 7) is also of note and underscores the mildness of the process. Furthermore, the fact that fluoro-substituted nitroaromatic substrates enter the reaction (see Table 6, entries 4–6) bodes well for its potential applications in medicinal chemistry due to the special value of fluorinated compounds in pharmaceutical research.

Table 6
Synthesis of 3-alkyl-N-hydroxyindoles through 1,5-addition of silyl enol ethers 59, 60 and 61 to substituted α,β-unsaturated nitrones.a,b

Finally, a study was carried out to determine the optimum stoichiometry of the two partners. Table 7 shows the results using the bromo-substituted nitro ketoester 6a and difluorosilyl enol ether 61 under the standard conditions with SnCl2·2H2O (method B).15 As seen from the table, the yields of product 44 increase from 50 to 75% as the number of equivalents of nucleophile increase from 1 to 5 and appear to plateau (74%) as 10 equivalents of nucleophile is reached. It is, indeed, reassuring that good yields are still possible with a 1:1 stoichiometry of the two partners, making the process viable in cases where the nucleophile is precious.

Table 7
Effect of varying the stoichiometry in the N-hydroxyindole reaction.a

2.2. Application to the synthesis of nocathiacin I model systems

Having developed this synthetic technology to a comfortable level of practicality and scope, we then proceeded to test its applicability to the thiopeptide antibiotic nocathiacin I by targeting suitable model systems. Scheme 6 summarizes the synthesis of the rather simple nocathiacin I model system 2 containing the N-hydroxyindole structural motif bridged to a thiazole moiety through an ether linkage. Thus, the N-Boc acetonide 80, prepared as previously described from Boc-L-Ser-OH,16 was converted to the required N-Boc primary alcohol 81 by exposure to TFA (68% yield), a substrate that reacted smoothly with the N-hydroxy tertiary alcohol 9 under acidic conditions as prescribed above to afford the targeted N-hydroxyindole 2 in 44% yield.

Scheme 6
Construction of N-hydroxyindole nocathiacin I model system 2. Reagents and conditions: a) TFA:CH2Cl2:MeOH (3:2:1), 25 °C, 30 min, 68%; b) pTsOH (3.0 equiv), 4 Å molecular sieves (20 wt%), 81 (4.0 equiv), 9 (1.0 equiv), DME, 25 °C, ...

This initial success led us to attempt the next hurdle of synthesizing the more advanced model systems 3a and 3b (Schemes 1 and and8),8), which contain not only the N-hydroxyindole structural motif of nocathiacin I, but also its 15-membered depsipeptide ether ring. The syntheses of these compounds featured a Yamaguchi macrolactonization as the final step of the macrocycle construction,17 while the ether bridge was formed at an earlier stage through intermolecular nucleophilic addition of a hydroxy component to an in situ generated α,β-unsaturated nitrone. The requisite hydroxy substrate 85 was prepared from N-Boc acetonide 80,16 as shown in Scheme 7. Thus, exposure of 80 to DIBAL-H followed by treatment with NaH and MeI resulted in the formation of methoxy compound 82 in 74% overall yield. Concomitant removal of the Boc and acetonide groups from the latter compound was achieved by exposure to acid (TFA), leading, upon selective silylation (TBSCl, Et3N) of the hydroxy group, to the primary amine 84 (85% yield for the two steps). Finally, coupling of this amine (84) to carboxylic acid 83 (generated by LiOH hydrolysis of ethyl ester 80)16 in the presence of HATU, HOAt and iPr2NEt, furnished, after TBAF-induced desilylation, the targeted hydroxy substrate 85 in 87% overall yield.

Scheme 7
Synthesis of Complex Alcohol 85. Reagents and conditions: a) DIBAL-H (2.0 equiv), toluene, 0 °C, 2 h; b) NaH (2.5 equiv), MeI (7.0 equiv), THF, 0–25 °C, 12 h, 74% (two steps); c) LiOH (1.5 equiv), THF:EtOH:H2O (3:1:1), 25 °C, ...
Scheme 8
Construction of nocathiacin I model systems 3a (N-OSEM) and 3b (N-OMOM) via intermolecular N-hydroxyindole formation. Reagents and conditions: a) Ac2O (5.0 equiv), Et3N (3.0 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 0 °C, 10 min; b) TFA:CH2Cl2:MeOH ...

Scheme 8 depicts the final stages of the synthesis of model systems 3a and 3b beginning with the preparation of hydroxy acetate 86 ready for the anticipated intermolecular N-hydroxyindole formation in partnership with nitro ketoester 6a or N-hydroxy tertiary alcohol 9. Thus, acetylation of 85 (Ac2O, Et3N, 4-DMAP) followed by TFA treatment furnished the desired hydroxy acetate 86 in 82% overall yield. This substrate performed well as a nucleophile in the crucial coupling with the precursor to the indole structural motif employing either of the two methods (A and B) described above. Thus, reaction of 86 with 6a in the presence of SnCl2·2H2O according to method B (40 °C, 6 h) led to N-hydroxyindole 87 in 40% yield. Subsequent protection (SEMCl, iPr2NEt) of the N-hydroxy group of 87, followed by exposure to LiOH, afforded the required hydroxy acid for the anticipated macrolactonization, which was brought about through the action of 2,4,6-trichlorobenzoyl chloride in the presence of Et3N and 4-DMAP, furnishing the N-OSEM protected model system 3a (38% yield for the three steps). The same substrate 86 underwent the key N-hydroxyindole forming reaction with the tertiary alcohol 9, generated from 6a through the [Zn]/NH4Cl protocol (method A), in the presence of pTsOH in DME at 40 °C to yield the same N-hydroxyindole 87 in 56% yield. MOM protection (MOMCl, nBu4NI cat., iPr2NEt) of the latter compound followed by ester hydrolysis (LiOH) and Yamaguchi macrolactonization then led to the MOM-protected nocathiacin I model system 3b in 44% overall yield for the three steps.

Our final investigation in these studies involved the challenging task of forming the relevant N-hydroxyindole ether macrocyclic system through intramolecular, rather than intermolecular, trapping of an incipient α,β-unsaturated nitrone. To this end, and as shown in Scheme 9, the required precursor, hydroxy α,β-unsaturated ketoester 89, was prepared from alcohol 85 and ketoacid 7a, which were coupled through the intermediacy of the acid chloride produced from 7a and oxalyl chloride. Proceeding in the presence of Et3N, this coupling reaction furnished ester 88 (77% yield) which was then reacted with TFA in CH2Cl2:MeOH at 0 °C to afford hydroxy ester 89 in 72% yield. Much to our delight, both methods A and B were found productive in furnishing the desired N-hydroxy indole system 3c. Thus, method A ([Zn]/NH4Cl) allowed first the generation of tertiary alcohol 90, and thence, under the influence of pTsOH, formation of the nocathiacin I model system 3c in 40% overall yield from 89. The same model system 3c was formed, albeit in lower yield (10%), directly from 89 by method B (SnCl2·2H2O), presumably through the fleeting intermediate 91 as shown in Scheme 9.

Scheme 9
Construction of nocathiacin I model system 3c (N-OH) via intramolecular N-hydroxyindole formation. Reagents and conditions: a) 7a (2.0 equiv), oxalyl chloride (2.0 equiv), DMF (cat.), THF, 0 °C, 45 min; then Et3N (4.0 equiv), 85 (1.0 equiv), 0–25 ...

3. Conclusion

The described chemistry provides a versatile entry into substituted N-hydroxyindoles from readily available nitroaromatic systems and suitable partners carrying O–, S–, N– and carbon nucleophilic moieties. Proceeding through a cascade sequence involving trapping of incipient α,β-unsaturated nitrones and/or N-hydroxy tertiary alcohol species, these processes tolerate a variety of functionalities and substituents amenable to further chemical manipulations. Furthermore, the model studies performed in the area of nocathiacin I bode well for a potential application of the method to the construction of this natural product’s most intriguing and challenging structural motif, its N-hydroxyindole moiety. Other applications of the present synthetic technology in chemical synthesis in general, and medicinal chemistry in particular, are also envisioned.

4. Experimental

4.1. General

All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF), toluene, 1,2-dimethoxyethane (DME), and methylene chloride (CH2Cl2) were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Yields refer to chromatographically and spectroscopically (1H NMR) homogenous materials, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Diflurosilyl enol ethers were prepared according to literature procedures.13 Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of phosphomolybdic acid and cerium sulfate, and heat as developing agents. E. Merck silica gel (60, particle size 0.040–0.063 mm) was used for flash column chromatography. Preparative thin-layer chromatography (PTLC) separations were carried out on 0.25 or 0.50 mm E. Merck silica gel plates (60F-254). Optical rotations were recorded on a Perkin-Elmer 343 polarimeter. NMR spectrum were recorded on Bruker DRX-600, DRX-500, AMX-500 or AMX-400 instruments and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, ½ABq = ½AB quartet, m = multiplet, quin = quintuplet, sext = sextet, sep = septet, hept = heptet, br = broad. IR spectra were recorded on a Perkin-Elmer 1600 or Spectrum 100 series FT-IR spectrometer. Electrospray ionization (ESI) mass spectrometry (MS) experiments were performed on an API 100 Perkin-Elmer SCIEX single quadrupole mass spectrometer at 4000V emitter voltage. High-resolution mass spectra (HRMS) were recorded on a VG ZAB-ZSE mass spectrometer using MALDI (matrix-assisted laser-desorption ionization) or ESI (electrospray ionization).

4.1.1. Trimethyl(2-{[(2-methyl-3-nitrobenzyl)oxy]methoxy}ethyl)silane (4c)

To 2-methyl-3-nitrobenzyl alcohol (20 g, 120 mmol) in DMF (600 mL) at 25 °C was added iPr2Net (62.5 mL, 359 mmol), SEMCl (42.2 mL, 239 mmol) and nBu4NI (442 mg, 1.20 mmol). After stirring for 12 h, the reaction mixture was diluted with EtOAc (500 mL), washed with H2O (500 mL), brine (500 mL) and dried (Na2SO4). The resulting solution was concentrated and the residue was subjected to flash column chromatography (silica gel, Et2O:hexanes, 20:80 → 60:40) to afford 4c (35 g, 98%) as a yellow oil; Rf = 0.60 (silica gel, EtOAc:hexanes, 2:8); IR (film) νmax 2953, 2886, 1527, 1465, 1352, 1248, 1189, 1155, 1105, 1057, 1028, 937, 920, 858, 834, 802, 759, 736, 715, 694, 666 cm−1; 1H NMR (500 MHz, CD3CN) δ 7.69 (d, J = 8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 4.73 (s, 2 H), 4.64 (s, 2 H), 3.63 (t, J = 8.5 Hz, 2 H), 2.39 (s, 3 H), 0.91 (t, J = 8.5 Hz, 2 H), 0.01 (s, 9 H); 13C NMR (125 MHz, CD3CN) δ 152.7, 141.2, 134.0, 132.0, 128.0, 124.6, 95.9, 68.5, 66.5, 19.2, 15.1, −0.7 (3 C); HRMS (ESI-TOF) calcd for C14H23NO4SiNa+ [M + Na+] 320.1288, found 320.1284.

4.2. General procedure for the synthesis of ketoesters 5a–g

To a suspension of NaH (60% dispersion in mineral oil, 4.0 equiv) in DMF (1.67 M) at 0 °C was added a solution of nitrotoluene (3.0–15.0 mmol) in DMF (0.74 M) via cannula. After stirring for 10 min, a solution of dimethyl oxalate (5.0 equiv) in DMF (0.96 M) was added via cannula and after stirring for 1 h at 0 °C, the reaction mixture was allowed to warm to 25 °C and stirring was continued for 12 h. The reaction mixture was then cooled to 0 °C, quenched with saturated aqueous NH4Cl (5–25 mL) solution, diluted with EtOAc (20–100 mL), washed with H2O (5–25 mL) and dried (Na2SO4). After concentration, the residue was subjected to flash column chromatography to give the ketoesters.

4.2.1. Methyl 3-(2-bromo-6-nitrophenyl)-2-oxopropanoate (5a)

Rf = 0.78 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 3093, 2956, 1735, 1598, 1527, 1436, 1403, 1349, 1274, 1201, 1059, 803, 736, 718 cm−1; 1H NMR (500 MHz, CD3CN) δ 8.00–7.97 (m, 2 H), 7.46 (t, J = 8.3 Hz, 1 H), 4.67 (s, 2 H), 3.89 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 189.6, 161.4, 151.6, 138.7, 130.9, 129.9, 128.4, 125.3, 53.9, 44.3; HRMS (ESI-TOF) calcd for C10H8BrNO5Na+ [M + Na+] 323.9478, found 323.9475.

4.2.2. Methyl 3-(2-nitrophenyl)-2-oxopropanoate (5b)

Rf = 0.51 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3441 (br), 2959, 2850, 1732, 1605, 1575, 1514, 1437, 1394, 1346, 1261, 1195, 1057, 966, 858, 786, 725, 664 cm−1; 1H NMR (500 MHz, CD3CN) δ 8.10 (d, J = 8.1 Hz, 1 H), 7.71–7.64 (m, 1 H), 7.57–7.51 (m, 1 H), 7.42 (d, J = 7.7 Hz, 1 H), 4.53 (s, 2 H), 3.86 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 190.9, 161.7, 149.6, 135.0, 134.8, 130.2, 129.9, 126.1, 53.8, 44.9; HRMS (ESI-TOF) calcd for C10H9NO5Na+ [M + Na+] 246.0373, found 246.0363.

4.2.3. Methyl 3-[2-nitro-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)phenyl]-2-oxopropanoate (5c)

Rf = 0.38 (silica gel, EtOAc:hexanes, 3:7); IR (film) νmax 2953, 2892, 1735, 1612, 1528, 1438, 1349, 1247, 1188, 1155, 1104, 1056, 1031, 991, 136, 858, 833, 804, 767, 734, 692 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 7.2 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 4.63 (s, 2 H), 4.61 (s, 2 H), 4.59 (s, 2 H), 3.94 (s, 3 H), 3.59 (t, J = 8.4 Hz, 2 H), 0.94 (t, J = 8.4 Hz, 2 H), 0.01 (s, 9 H); 13C NMR (125 MHz, CD3CN) δ 189.1, 161.2, 150.3, 140.1, 135.2, 128.8, 128.7, 125.4, 94.1, 67.4, 66.1, 53.7, 39.6, 18.5, −1.0 (3 C); HRMS (ESI-TOF) calcd for C17H25NO7SiNa+ [M + Na+] 406.1292, found 406.1291.

4.2.4. Methyl 3-(2-fluoro-6-nitrophenyl)-2-oxopropanoate (5d)

Rf = 0.29 (silica gel, EtOAc:hexanes, 2:8); IR (film) νmax 3459 (br), 3107, 2950, 1730, 1531, 1466, 1452, 1429, 1401, 1360, 1332, 1281, 1244, 1226, 1189, 1147, 1064, 971, 837, 800, 763, 735 cm−1; 1H NMR (600 MHz, CD3CN) δ 7.91 (d, J = 7.9 Hz, 1 H), 7.58–7.50 (m, 2 H), 4.53 (s, 2 H), 3.87 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 189.8, 162.0 (d, J = 247.3 Hz), 161.3, 150.4, 130.7 (d, J = 9.2 Hz), 121.8 (d, J = 3.4 Hz), 121.7 (d, J = 20.6 Hz), 118.4 (d, J = 19.5 Hz), 53.8, 36.6; HRMS (ESI-TOF) calcd for C10H8FNO5Na+ [M + Na+] 264.0279, found 264.0269.

4.2.5. Methyl 3-(5-fluoro-2-nitrophenyl)-2-oxopropanoate (5e)

Rf = 0.56 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3413 (br), 3083, 2958, 2919, 2849, 1736, 1590, 1525, 1343, 1249, 1062, 840, 751, 613 cm−1; 1H NMR (600 MHz, CD3CN) δ 8.20 (dd, J = 9.2, 4.1 Hz, 1 H), 7.18–7.13 (m, 1 H), 7.03 (dd, J = 8.7, 4.1 Hz, 1 H), 4.51 (s, 2 H), 3.90 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 188.4, 164.8 (d, J = 256.6 Hz), 160.5, 144.2, 132.5 (d, J = 9.1 Hz), 128.3 (d, J = 10.3 Hz), 120.5 (d, J = 22.8 Hz), 115.8 (d, J = 22.8 Hz), 53.5, 44.4; HRMS (ESI-TOF) calcd for C10H8FNO5Na+ [M + Na+] 264.0279, found 264.0276.

4.2.6. Methyl 3-(4-fluoro-2-nitrophenyl)-2-oxopropanoate (5f)

Rf = 0.45 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3099, 2959, 1734, 1618, 1532, 1499, 1440, 1398, 1349, 1325, 1235, 1133, 1062, 949, 880, 819, 806, 747, 682 cm−1; 1H NMR (500 MHz, CD3CN) δ 7.89 (dd, J = 8.5, 2.5 Hz, 1 H), 7.47–7.45 (m, 2 H), 4.53 (s, 2 H), 3.88 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 190.7, 162.4 (d, J = 247.1 Hz), 161.6, 150.0 (d, J = 8.8 Hz), 136.4 (d, J = 7.9 Hz), 126.3 (d, J = 3.9 Hz), 121.0 (d, J = 21.1 Hz), 113.5 (d, J = 27.3 Hz), 53.8, 44.3; HRMS (ESI-TOF) calcd for C10H8FNO5Na+ [M + Na+] 264.0279, found 264.0269.

4.2.7. Methyl (2Z(E))-3-(4-cyano-2-nitrophenyl)-2-hydroxyacrylate (5g)

Rf = 0.28 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 3372 (br), 3088, 2958, 2926, 2237, 1736, 1619, 1535, 1440, 1396, 1352, 1268, 1062, 912, 834, 795, 747, 677 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 1.6 Hz, 1 H), 7.84 (dd, J = 8.0, 1.6 Hz, 1 H), 6.96 (d, J = 1.4 Hz, 1 H), 6.92 (d, J = 1.4 Hz, 1 H), 3.98 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 161.3, 149.8, 137.8, 136.6, 135.9, 135.3, 129.9, 117.5, 113.7, 102.7, 53.9; HRMS (ESI-TOF) calcd for C11H7N2O5 [M − H] 247.0360, found 247.0369.

4.3. General procedure for the synthesis of α,β-unsaturated ketoesters 6a–g

To a solution of ketoester (0.5–10 mmol) in THF (0.03 M) at 0 °C was added NaH (60% dispersion in mineral oil, 1.1 equiv) and, after stirring for 1 h, dimethylmethylene ammonium chloride (3.0 equiv) was added and the reaction mixture stirred for 12 h at 25 °C. After cooling to 0 °C, the reaction mixture was quenched with saturated aqueous NH4Cl solution (1–20 mL), diluted with EtOAc (5–100 mL), washed with H2O (1–20 mL) and dried (Na2SO4). After concentration, the residue was subjected to flash column chromatography to give the α,β-unsaturated ketoesters.

4.3.1. Methyl 3-(2-bromo-6-nitrophenyl)-2-oxobut-3-enoate (6a)

Rf = 0.53 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3389 (br), 2954, 2913, 2861, 2355, 1719, 1672, 1526, 1472, 1431, 1349, 1237, 1026 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 8.4, 1.3 Hz, 1 H), 7.94 (dd, J = 8.1, 1.3 Hz, 1 H), 7.44 (dd, J = 8.4, 8.1 Hz, 1 H), 6.79 (s, 1 H), 6.17 (s, 1 H), 3.93 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 183.1, 162.5, 149.5, 141.8, 137.9, 134.8, 132.5, 130.5, 126.3, 123.8, 53.3; HRMS (ESI-TOF) calcd for C11H8BrNO5Na+ [M + Na+] 335.9478, found 335.9477.

4.3.2. Methyl 3-(2-nitrophenyl)-2-oxobut-3-enoate (6b)

Rf = 0.29 (silica gel, EtOAc:hexanes, 3:7); IR (film) νmax 3474 (br), 3404 (br), 2953, 2906, 2849, 1740, 1688, 1601, 1567, 1531, 1514, 1433, 1410, 1341, 1271, 1236, 1132, 1028, 958, 859, 790, 761 cm−1; 1H NMR (600 MHz, CD3CN) δ 8.10 (d, J = 8.3 Hz, 1 H), 7.77–7.74 (m, 1 H), 7.65–7.62 (m, 1 H), 7.45 (dd, J = 7.5, 1.3 Hz, 1 H), 6.55 (s, 1 H), 6.51 (s, 1 H), 3.89 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 186.5, 164.3, 148.7, 144.1, 135.2, 134.7, 133.4, 131.4, 131.1, 125.4, 53.7; HRMS (ESI-TOF) calcd for C11H10NO5+ [M + H+] 236.0553, found 236.0550.

4.3.3. Methyl 3-[2-nitro-6-({[2-(trimethylsilyl)ethoxy]methoxy}methyl)phenyl]-2-oxobut-3-enoate (6c)

Rf = 0.55 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 2954, 2884, 1743, 1690, 1525, 1343, 1243, 1131, 1102, 1061, 1032, 938, 861, 832, 761, 732, 691 cm−1; 1H NMR (600 MHz, CD3CN) δ 8.03 (d, J = 8.1 Hz, 1 H), 7.83 (d, J = 7.8 Hz, 1 H), 7.60 (dd, J = 8.1, 7.8 Hz, 1 H), 6.63 (s, 1 H), 6.26 (s, 1 H), 4.62 (s, 2 H), 4.46 (d, J = 3.5 Hz, 2 H), 3.87 (s, 3 H), 3.56 (t, J = 8.3 Hz, 2 H), 0.88 (t, J = 8.3 Hz, 2 H), −0.01 (s, 9 H); 13C NMR (150 MHz, CD3CN) δ 186.2, 164.2, 149.7, 140.8, 140.7, 134.9, 134.6, 130.8, 130.4, 124.7, 95.3, 67.3, 66.0, 53.7, 18.5, −1.4 (3 C); HRMS (ESI-TOF) calcd for C18H25NO7SiNa+ [M + Na+] 418.1292, found 418.1297.

4.3.4. Methyl 3-(2-fluoro-6-nitrophenyl)-2-oxobut-3-enoate (6d)

Rf = 0.54 (silica gel, EtOAc:hexanes, 3:7); IR (film) νmax 3473 (br), 3371 (br), 3096, 3954, 1738, 1687, 1621, 1524, 1447, 1345, 1294, 1248, 1182, 1121, 1065, 1024, 947, 881, 805, 729, 672 cm−1; 1H NMR (500 MHz, CD3CN) δ 8.95 (d, J = 8.3 Hz, 1 H), 7.67–7.63 (m, 1 H), 7.59–7.56 (m, 1 H), 6.76 (s, 1 H), 6.50 (s, 1 H), 3.90 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 186.1, 164.1, 160.7 (d, J = 247.3 Hz), 149.8, 137.4 (d, J = 2.3 Hz), 136.5, 132.1 (d, J = 10.3 Hz), 122.4 (d, J = 22.9 Hz), 121.5 (d, J = 3.4 Hz), 119.9 (d, J = 20.6 Hz), 53.9; HRMS (ESI-TOF) calcd for C11H9FNO5+ [M + H+] 254.0459, found 254.0452.

4.3.5. Methyl 3-(5-fluoro-2-nitrophenyl)-2-oxobut-3-enoate (6e)

Rf = 0.52 (silica gel, EtOAc:hexanes, 3:7); IR (film) νmax 3083, 2959, 1743, 1695, 1585, 1526, 1436, 1347, 1218, 1132, 1036, 948, 843, 727, 611 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.24 (dd, J = 9.2, 5.3 Hz, 1 H), 7.27–7.24 (m, 1 H), 7.08 (dd, J = 8.3, 2.6 Hz, 1 H), 6.64 (s, 1 H), 6.29 (s, 1 H), 3.93 (s, 3 H); 13C NMR (150 MHz, CDCl3) δ 185.3, 165.4 (d, J = 253.2 Hz), 163.5, 144.5, 142.7, 134.6, 134.4 (d, J = 10.3 Hz), 128.1 (d, J = 10.3 Hz), 120.9 (d, J = 25.1 Hz), 117.3 (d, J = 22.8 Hz), 53.4; HRMS (ESI-TOF) calcd for C11H8FNO5Na+ [M + Na+] 276.0279, found 276.0279.

4.3.6. Methyl 3-(4-fluoro-2-nitrophenyl)-2-oxobut-3-enoate (6f)

Rf = 0.33 (silica gel, EtOAc:hexanes, 2:8); IR (film) νmax 3097, 2958, 1741, 1690, 1537, 1338, 1349, 1271, 1213, 1132, 1034, 947, 882, 812, 674 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.87 (dd, J = 8.3, 2.6 Hz, 1 H), 7.43–7.40 (m, 1 H), 7.37 (dd, J = 8.9, 5.7 Hz, 1 H), 6.59 (s, 1 H), 6.31 (s, 1 H), 3.92 (s, 3 H); 13C NMR (150 MHz, CDCl3) δ 183.9, 162.6, 161.7 (d, J = 252.0 Hz), 147.9 (d, J = 8.0 Hz), 142.7, 133.8 (d, J = 8.0 Hz), 132.5, 127.4 (d, J = 3.4 Hz), 121.2 (d, J = 20.5 Hz), 112.5 (d, J = 27.4 Hz), 52.9; HRMS (ESI-TOF) calcd for C11H8FNO5Na+ [M + Na+] 276.0279, found 276.0274.

4.3.7. Methyl 3-(4-cyano-2-nitrophenyl)-2-oxobut-3-enoate (6g)

Rf = 0.55 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 2237, 1742, 1693, 1556, 1537, 1353, 1251, 1140, 1033 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 1.6 Hz, 1 H), 7.98 (dd, J = 7.8, 1.6 Hz, 1 H), 7.54 (d, J = 1.6 Hz, 1 H), 6.75 (s, 1 H), 6.35 (s, 1 H), 3.94 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 185.6, 163.8, 148.8, 142.8, 138.4, 136.3, 135.9, 134.7, 129.4, 117.4, 114.8, 53.9; HRMS (ESI-TOF) calcd for C12H8N2O5Na+ [M + Na+] 283.0325, found 283.0325.

4.5. General procedure for the synthesis of N-hydroxyindoles (method A)

A stirred suspension of Zn dust (4.9 equiv) and dibromoethane (0.33 equiv) in THF (0.20 M) was heated to reflux (70 °C) for approximately 5 min and then allowed to cool to 25 °C. The refluxing/cooling process was repeated three times. TMSCl (0.2 equiv) was then added and the resulting grey suspension was stirred at 25 °C for 10 min. A separate stirred solution containing a mixture of aqueous 1N NH4Cl (2.2 equiv) and nitro ketoester (0.01–0.06 mmol, 1.0 equiv) in THF (0.10 M) was added via cannula to the activated Zn suspension and stirring was continued for 15–30 min in the absence of light at 25 °C. The crude reaction mixture was purified directly by PTLC to afford tertiary alcohol 9 which was added to a stirred solution of pTsOH (3.0 equiv), nucleophile (5.0 equiv) and 4 Å molecular sieves (20 wt%) in DME (0.05–0.10 M) at 25 °C. After 10 min, the reaction mixture was warmed to 40 °C, stirred for 1–3 h, cooled to room temperature and purified directly by PTLC to afford the targeted N-hydroxyindoles.

4.5.1. Methyl 4-bromo-1,2-dihydroxy-3-methyleneindoline-2-carboxylate (9)

Rf = 0.53 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3389, 2954, 2849, 1737, 1596, 1566, 1460, 1431, 1290, 1255, 1231, 1184, 1155, 1096, 1026, 885, 802, 749 cm−1; 1H NMR (600 MHz, CD3CN) δ 7.64 (s, 1 H), 7.14 (t, J = 7.9 Hz, 1 H), 7.11 (dd, J = 7.9, 1.3 Hz, 1 H), 6.85 (dd, J = 7.9, 1.3 Hz, 1 H), 6.32 (s, 1 H), 5.40 (s, 1 H), 5.08 (br s, 1 H), 3.61 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 170.3, 154.8, 144.3, 132.1, 127.3, 123.4, 117.9, 111.8, 111.7, 98.9, 53.6; HRMS (ESI-TOF) calcd for C11H10BrNO4Na+ [M + Na+] 321.9685, found 321.9684.

4.5.2. Methyl 3-[(benzyloxy)methyl]-4-bromo-1-hydroxy-1H-indole-2-carboxylate (11)

Method A and B

Rf = 0.58 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3194, 2952, 2848, 1710, 1525, 1433, 1353, 1312, 1255, 1226, 1185, 1122, 1047, 1024, 909, 874, 771, 730, 690 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.49 (br s, 1 H), 7.45 (d, J = 8.1 Hz, 1 H), 7.39–7.23 (m, 6 H), 7.18 (t, J = 8.1 Hz, 1 H), 5.10 (s, 2 H), 4.61 (s, 2 H), 3.88 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.2, 139.9, 137.2, 129.2 (2 C), 128.9 (2 C), 128.3, 127.1, 126.9, 126.8, 121.0, 116.0, 115.9, 110.2, 72.7, 61.8, 52.9; HRMS (ESI-TOF) calcd for C18H16BrNO4Na+ [M + Na+] 412.0155, found 412.0155.

4.5.3. Methyl 3-[(benzylthio)methyl]-4-bromo-1-hydroxy-1H-indole-2-carboxylate (12)

Method A and B

Rf = 0.57 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3354 (br), 2955, 2908, 2837, 1708, 1672, 1608, 1514, 1484, 1442, 1390, 1255, 1232, 1185, 1120, 738, 692 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.30 (br s, 1 H), 7.45 (dd, J = 8.2, 0.7 Hz, 1 H), 7.33–7.23 (m, 5 H), 7.22–7.16 (m, 2 H), 4.45 (s, 2 H), 3.83 (s, 3 H), 3.79 (s, 2 H); 13C NMR (100 MHz, CD3CN) δ 162.4, 139.9, 137.8, 129.8 (2 C), 129.3 (2 C), 127.7, 127.4, 126.7, 125.6, 120.1, 117.8, 116.1, 110.4, 52.8, 37.2, 26.7; HRMS (ESI-TOF) calcd for C18H16BrNO3SNa+ [M + Na+] 427.9926, found 427.9924.

4.5.4. 4-(2-Bromo-6-nitrophenyl)-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (14)

Rf = 0.20 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3271 (br), 2955, 2919, 1684, 1525, 1455, 1414, 1349, 1220, 1108, 1037, 903, 803, 780 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.3 Hz, 1 H), 7.95 (d, J = 8.3 Hz, 1 H), 7.49 (t, J = 8.3 Hz, 1 H), 6.85 (br s, 1 H), 4.05 (br s, 2 H); 13C NMR (150 MHz, CD3CN) δ 168.5, 154.2, 151.8, 145.1, 138.2, 131.8, 129.1, 126.7, 124.6, 45.1; HRMS (ESI-TOF) calcd for C10H7BrNO3 [M − H] 279.9607, found 279.9615.

4.6. General procedure for the synthesis of N-hydroxyindoles (method B)

To a stirred solution of SnCl2·2H2O (2.2–2.5 equiv) and 4 Å molecular sieves (20 wt%) in DME (0.12–0.16 M) was added nucleophile (5.0 equiv) and nitro ketoester (0.03–0.10 mmol, 1.0 equiv) at 25 °C. The reaction mixture was warmed to 40–45 °C and stirring was continued for 1–72 h in the absence of light. Direct purification of the crude reaction mixture by PTLC afforded the desired N-hydroxyindoles.

4.6.1. Methyl 4-bromo-1-hydroxy-1H-indole-3-carboxylate (16)

Rf = 0.18 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3149, 2914, 2855, 1722, 1634, 1553, 1370, 1311, 1258, 1199, 1164, 1123, 1070, 976, 841, 753, 729 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.54 (br s, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.25 (dd, J = 8.2, 7.9 Hz, 1 H), 3.88 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 178.7, 165.7, 137.4, 137.0, 129.3, 126.1, 122.9, 114.9, 110.1, 109.0, 53.5; HRMS (ESI-TOF) calcd for C11H8BrNO4+ [M + H+] 297.9709, found 297.9709.

4.6.2. Methyl 4-bromo-3-[(hexyloxy)methyl]-1-hydroxy-1H-indole-2-carboxylate (17)

Rf = 0.60 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3178 (br), 2955, 2920, 2849, 1714, 1531, 1437, 1396, 1355, 1314, 1255, 1226, 1185, 1149, 1120, 1073, 879, 773, 732 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.48 (br s, 1 H), 7.41 (dd, J = 8.2, 0.7 Hz, 1 H), 7.32 (dd, J = 7.5, 0.7 Hz, 1 H), 7.15 (dd, J = 8.2, 7.5 Hz, 1 H), 5.00 (s, 2 H), 3.91 (s, 3 H), 3.53 (t, J = 6.4 Hz, 2 H), 1.57–1.50 (m, 2 H), 1.35–1.21 (m, 6 H), 0.86–0.82 (m, 3 H); 13C NMR (100 MHz, CD3CN) δ 162.2, 137.3, 126.9, 126.8, 126.7, 121.0, 116.3, 116.0, 110.2, 70.7, 61.9, 52.9, 32.4, 30.5, 26.7, 23.4, 14.3; HRMS (ESI-TOF) calcd for C17H22BrNO4Na+ [M + Na+] 406.0624, found 406.0618.

4.6.3. Methyl 4-bromo-3-(ethoxymethyl)-1-hydroxy-1H-indole-2-carboxylate (18)

Rf = 0.53 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3166 (br), 2978, 2861, 1713, 1531, 1355, 1249, 1226, 1185, 1126, 1073, 991, 732 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.36 (br s, 1 H), 7.40 (d, J = 8.3 Hz, 1 H), 7.32 (d, J = 7.5 Hz, 1 H), 7.15 (dd, J = 8.3, 7.5 Hz, 1 H), 5.02 (s, 2 H), 3.92 (s, 3 H), 3.60 (q, J = 7.0 Hz, 2 H), 1.17 (t, J = 7.0 Hz, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.8, 137.8, 127.7, 127.4 121.5, 118.9, 116.9, 116.6, 110.7, 66.7, 62.4, 53.5, 16.2; HRMS (ESI-TOF) calcd for C13H14BrNO4Na+ [M + Na+] 349.9998, found 349.9996.

4.6.4. Methyl 4-bromo-3-[(cyclohexyloxy)methyl]-1-hydroxy-1H-indole-2-carboxylate (19)

Rf = 0.58 (silica gel, MeOH:CH2Cl2, 5:95); IR (film) νmax 3173 (br), 2922, 2853, 1713, 1530, 1433, 1348, 1256, 1228, 1188, 1148, 1125, 1057, 948, 771, 736 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.33 (s, 1 H), 7.40 (d, J = 8.3 Hz, 1 H), 7.32 (d, J = 7.5 Hz, 1 H), 7.14 (t, J = 7.9 Hz, 1 H), 5.05 (s, 2 H), 3.91 (s, 3 H), 3.52–3.49 (m, 1 H), 1.97–1.93 (m, 1 H), 1.73–1.69 (m, 2 H), 1.55–1.50 (m, 1 H), 1.34–1.21 (m, 6 H); 13C NMR (150 MHz, CD3CN) δ 162.2, 137.1, 127.1, 127.0, 126.7, 120.8, 116.6, 115.9, 110.1, 78.0, 59.3, 52.8, 33.0 (2 C), 26.6 (2 C), 25.8; HRMS (ESI-TOF) calcd for C17H20BrNO4Na+ [M + Na+] 404.0468, found 404.0469.

4.6.5. Methyl 3-[(benzyloxy)methyl]-1-hydroxy-4-({[2-(trimethylsilyl)ethoxy]methoxy}-methyl)-1H-indole-2-carboxylate (20)

Rf = 0.69 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 2950, 1718, 1439, 1248, 1057, 835 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.24 (s, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.36–7.26 (m, 6 H), 7.46 (d, J = 7.0 Hz, 1 H), 5.05 (s, 2 H), 5.02 (s, 2 H), 4.71 (s, 2 H), 4.56 (s, 2 H), 3.88 (s, 3 H), 3.61 (t, J = 8.5 Hz, 2 H), 0.88 (t, J = 8.5 Hz, 2 H), −0.01 (s, 9 H); 13C NMR (125 MHz, CD3CN) δ 162.7, 139.9, 136.7, 133.6, 130.9, 130.4, 129.2 (2 C), 128.6 (2 C), 128.3, 126.3, 125.7, 122.9, 110.3, 94.9, 72.1, 68.2, 65.8, 63.2, 52.7, 18.6, −1.4 (3 C); HRMS (ESI-TOF) calcd for C25H33NO6SiNa+ [M + Na+] 494.1969, found 494.1969.

4.6.6. Methyl 3-[(benzyloxy)methyl]-4-fluoro-1-hydroxy-1H-indole-2-carboxylate (21)

Rf = 0.76 (silica gel, MeOH:CH2Cl2, 5:95); IR (film) νmax 3194, 2939, 2862, 1711, 1628, 1523, 1434, 1362, 1318, 1263, 1229, 1135, 1097, 1044, 1025, 991, 936, 775, 731, 692 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.30 (br s, 1 H), 7.34–7.24 (m, 7 H), 6.84 (dd, J = 11.4, 7.5 Hz, 1 H), 4.97 (s, 2 H), 4.55 (s, 2 H), 3.88 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.2, 159.2 (d, J = 249.1 Hz), 140.6, 138.2 (d, J = 10.3 Hz), 129.8 (2 C), 129.3 (2 C), 128.9, 127.9 (d, J = 8.4 Hz), 126.2, 115.2 (d, J = 4.0 Hz), 112.3 (d, J = 20.6 Hz), 107.5 (d, J = 4.0 Hz), 107.4 (d, J = 19.3 Hz), 73.7, 64.1, 53.4; HRMS (ESI-TOF) calcd for C18H16FNO4Na+ [M + Na+] 352.0955, found 352.0952.

4.6.7. Methyl 3-[(benzyloxy)methyl]-5-fluoro-1-hydroxy-1H-indole-2-carboxylate (22)

Rf = 0.78 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 3315 (br), 2954, 1708, 1528, 1444, 1259, 1192, 1105 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.22 (s, 1 H), 7.49–7.45 (m, 2 H), 7.36–7.30 (m, 5 H), 7.21–7.15 (m, 1 H), 4.96 (s, 2 H), 4.54 (s, 2 H), 3.88 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.3, 159.0 (d, J = 234.0 Hz), 139.8, 133.1, 129.2 (2 C), 128.7 (2 C), 128.4, 126.0, 123.2 (d, J = 16.4 Hz), 116.8 (d, J = 2.3 Hz), 115.6 (d, J = 27.3 Hz), 112.0 (d, J = 9.8 Hz), 106.4 (d, J = 24.2 Hz), 72.6, 63.6, 52.6; HRMS (ESI-TOF) calcd for C18H15FNO4 [M − H] 328.0991, found 328.0995.

4.6.8. Methyl 3-[(benzyloxy)methyl]-6-fluoro-1-hydroxy-1H-indole-2-carboxylate (23)

Rf = 0.63 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3205 (br), 3032, 2951, 2860, 1714, 1628, 1529, 1438, 1355, 1177, 1054, 917, 832, 755 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.19 (s, 1 H), 7.81 (dd, J = 8.4, 4.8 Hz, 1 H), 7.36–7.23 (m, 5 H), 7.19 (dd, J = 9.0, 1.8 Hz, 1 H), 6.96 (dt, J = 9.3, 2.4 Hz, 1 H), 4.98 (s, 2 H), 4.54 (s, 2 H), 3.88 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.9 (d, J = 240.3 Hz), 162.3, 139.7, 136.5 (d, J = 13.1 Hz), 129.2 (2 C), 129.1, 128.7 (2 C), 128.4, 127.6, 124.2 (d, J = 10.4 Hz), 119.7, 111.1 (d, J = 25.7 Hz), 96.3 (d, J = 27.2 Hz), 72.7, 63.6, 52.5; HRMS (ESI-TOF) calcd for C18H16FNO4Na+ [M + Na+] 352.0955, found 352.0949.

4.6.9. Methyl 3-[(benzyloxy)methyl]-6-cyano-1-hydroxy-1H-indole-2-carboxylate (24)

Rf = 0.71 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 2925, 1854, 2225, 1717, 1660, 1573, 1527, 1438, 1416, 1364, 1258, 1144, 1084, 1018, 867, 735, 698 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.38 (br s, 1 H), 7.94 (d, J = 8.5 Hz, 1 H), 7.93–7.91 (m, 1 H), 7.39 (dd, J = 8.0, 1.5 Hz, 1 H), 7.35–7.30 (m, 5 H), 4.99 (s, 2 H), 4.55 (s, 2 H), 3.91 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 162.4, 139.6, 129.2 (2 C), 128.7 (2 C), 128.5, 127.7, 125.5, 123.9, 123.5, 120.8, 120.4, 117.0, 115.9, 108.8, 72.8, 63.4, 52.9; HRMS (ESI-TOF) calcd for C19H15N2O4 [M − H] 335.1037, found 335.1049.

4.6.10. Methyl 4-bromo-3-[(hexylthio)methyl]-1-hydroxy-1H-indole-2-carboxylate (25)

Rf = 0.63 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3349 (br), 2956, 2912, 2847, 1703, 1681, 1517, 1440, 1397, 1342, 1304, 1255, 1195, 1146, 1118, 982, 872, 774, 741 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.18 (s, 1 H), 7.46 (d, J = 8.5 Hz, 1 H), 7.34 (d, J = 7.5 Hz, 1 H), 7.22 (dd, J = 8.5, 7.5 Hz, 1 H), 4.44 (s, 2 H), 3.93 (s, 3 H), 2.48 (t, J = 7.3 Hz, 2 H), 1.52–1.46 (m, 2 H), 1.33–1.19 (m, 6 H), 0.84 (t, J = 6.6 Hz, 3 H); 13C NMR (125 MHz, CD3CN) δ 162.5, 137.9, 127.4, 126.7, 125.6, 120.0, 118.9, 116.2, 110.4, 52.8, 32.2, 32.1, 30.5, 29.3, 25.9, 23.2, 14.3; HRMS (ESI-TOF) calcd for C17H21BrNO3S [M − H] 398.0431 found 398.0420.

4.6.11. Methyl 4-bromo-1-hydroxy-3-[(phenylthio)methyl]-1H-indole-2-carboxylate (26)

Rf = 0.60 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3342 (br), 2943, 1684, 1514, 1437, 1396, 1343, 1308, 1255, 1191, 1144, 1120, 1020, 979, 873, 773, 738, 691 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.18 (br s, 1 H), 7.46 (d, J = 8.3 Hz, 1 H), 7.35 (d, J = 7.4 Hz, 1 H), 7.28–7.19 (m, 6 H), 4.83 (s, 2 H), 3.69 (s, 3 H); 13C NMR (100 MHz, CD3CN) δ 162.0, 137.6, 136.4, 132.8 (2 C), 129.8 (2 C), 128.1, 127.3, 126.7, 125.8, 119.8, 116.6, 116.1, 110.4, 52.6, 30.1; HRMS (ESI-TOF) calcd for C17H14BrNO3SNa+ [M + Na+] 413.9770 found 413.9761.

4.6.12. Methyl 3-[(cyclohexylthio)methyl]-4-bromo-1-hydroxy-1H-indole-2-carboxylate (27)

Rf = 0.65 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3349 (br), 2956, 2912, 2847, 1703, 1681, 1517, 1440, 1397, 1342, 1304, 1255, 1195, 1146, 1118, 982, 872, 774, 741 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.17 (s, 1 H), 7.45 (d, J = 9.7 Hz, 1 H), 7.33 (d, J = 9.0 Hz, 1 H), 7.20 (dd, J = 9.7, 9.0 Hz, 1 H), 4.47 (s, 2 H), 3.94 (s, 3 H), 2.72–2.64 (m, 1 H), 1.95–1.88 (m, 1 H), 1.75–1.67 (m, 2 H), 1.59–1.54 (m, 1 H), 1.33–1.21 (m, 6 H); 13C NMR (150 MHz, CD3CN) δ 162.5, 137.9, 127.3, 126.6, 125.5, 120.0, 119.2, 116.1, 110.3, 52.8, 44.1, 34.7 (2 C), 26.9 (2 C), 26.5, 24.5; HRMS (ESI-TOF) calcd for C17H21BrNO3S+ [M + H+] 420.0239, found 420.0236.

4.6.13. Methyl 3-[(benzylthio)methyl]-1-hydroxy-4-({[2-(trimethylsilyl)ethoxy]methoxy}-methyl)-1H-indole-2-carboxylate (28)

Rf = 0.65 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 2950, 1709, 1527, 1440, 1248, 1027, 859, 835, 753 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.20 (s, 1 H), 7.44 (dd, J = 8.4, 1.2 Hz, 1 H), 7.34–7.22 (m, 6 H), 7.13 (d, J = 6.8 Hz, 1 H), 4.95 (s, 2 H), 4.64 (s, 2 H), 4.38 (s, 2 H), 3.83 (s, 3 H), 3.80 (s, 2 H), 3.83 (t, J = 7.6 Hz, 2 H), 0.87 (t, J = 7.6 Hz, 2 H), −0.02 (s, 9 H); 13C NMR (125 MHz, CD3CN) δ 162.8, 139.7, 137.1, 133.3, 129.6 (2 C), 129.3 (2 C), 127.7, 126.5, 124.6, 123.3, 120.6, 117.3, 110.7, 94.8, 68.7, 65.9, 52.5, 37.2, 27.6, 18.6, −1.4 (3 C); HRMS (ESI-TOF) calcd for C25H33NO5SSiNa+ [M + Na+] 510.1741, found 510.1731.

4.6.14. Methyl 3-[(benzylthio)methyl]-4-fluoro-1-hydroxy-1H-indole-2-carboxylate (29)

Rf = 0.65 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3356, 2950, 1700, 1630, 1532, 1451, 1355, 1321, 1262, 1236, 1137, 948, 924 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.22 (s, 1 H), 7.33–7.20 (m, 7 H), 6.81 (dd, J = 10.5, 6.5 Hz, 1 H), 4.25 (s, 2 H), 3.85 (s, 3 H), 3.77 (s, 2 H); 13C NMR (125 MHz, CD3CN) δ 162.3, 158.4 (d, J = 248.5 Hz), 139.7, 138.5 (d, J = 10.3 Hz), 129.6 (2 C), 129.2 (2 C), 127.7, 127.5 (d, J = 8.0 Hz), 125.2, 116.5 (d, J = 4.0 Hz), 111.6 (d, J = 20.0 Hz), 106.9 (d, J = 4.3 Hz), 106.5 (d, J = 19.3 Hz), 52.6, 37.0, 27.9; HRMS (ESI-TOF) calcd for C18H15FNO3S [M − H] 344.0762, found 344.0765.

4.6.15. Methyl 3-[(benzylthio)methyl]-5-fluoro-1-hydroxy-1H-indole-2-carboxylate (30)

Rf = 0.52 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 2956, 1718, 1522, 1442, 1262, 1180 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.13 (br s, 1 H), 7.45 (dd, J = 8.5, 4.0 Hz, 1 H), 7.34–7.22 (m, 6 H), 7.17 (dt, J = 9.5, 2.5 Hz 1 H), 4.15 (s, 2 H), 3.84 (s, 3 H), 3.72 (s, 2 H); 13C NMR (125 MHz, CD3CN) δ 162.3, 158.8 (d, J = 233.8 Hz), 139.7, 133.4, 129.6 (2 C), 129.3 (2 C), 127.7, 125.8, 122.9 (d, J = 9.9 Hz), 117.5, 115.7 (d, J = 27.4 Hz), 112.2 (d, J = 9.5 Hz), 106.0 (d, J = 24.0 Hz), 52.5, 37.0, 26.3; HRMS (ESI-TOF) calcd for C18H15FNO3S [M − H] 344.0762, found 344.0769.

4.6.16. Methyl 3-[(benzylthio)methyl]-6-fluoro-1-hydroxy-1H-indole-2-carboxylate (31)

Rf = 0.53 (silica gel, EtOAc:hexanes, 3:7); IR (film) νmax 3315 (br), 2955, 1720, 1530, 1532, 1445, 1399, 1351, 1291, 1266, 1178, 1123 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.19 (br s, 1 H), 7.65 (dd, J = 8.8, 5.2 Hz, 1 H), 7.34–7.23 (m, 5 H), 7.16 (dd, J = 9.2, 2.4 Hz, 1 H), 6.95–6.90 (m, 1 H), 4.17 (s, 2 H), 3.82 (s, 3 H), 3.72 (s, 2 H); 13C NMR (125 MHz, CD3CN) δ 163.0 (d, J = 240.4 Hz), 162.3, 139.7, 136.8 (d, J = 13.3 Hz), 129.7 (2 C), 129.4, 128.3 (2 C), 128.0, 127.7, 123.8 (d, J = 10.4 Hz), 119.5, 110.8 (d, J = 25.6 Hz), 96.4 (d, J = 27.0 Hz), 52.4, 37.0, 26.3; HRMS (ESI-TOF) calcd for C18H15FNO3S [M − H] 344.0762, found 344.0769.

4.6.17. Methyl 3-[(benzylthio)methyl]-6-cyano-1-hydroxy-1H-indole-2-carboxylate (32)

Rf = 0.59 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 2924, 2360, 2224, 1715, 1523, 1444, 1264, 1116 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.31 (s, 1 H), 7.89 (s, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.28–7.22 (m, 5 H), 4.18 (s, 2 H), 3.86 (s, 3 H), 3.72 (s, 2 H); 13C NMR (125 MHz, CD3CN) δ 161.9, 139.5, 134.9, 132.2, 129.6 (2 C), 129.3 (2 C), 127.7, 125.1, 123.6, 123.0, 120.4, 117.7, 115.9, 109.0, 52.8, 37.0, 26.0; HRMS (ESI-TOF) calcd for C19H15N2O3S [M − H] 351.0809, found 351.0813.

4.6.18. Methyl 4-bromo-1-hydroxy-3-(morpholin-4-ylmethyl)-1H-indole-2-carboxylate (33)

Rf = 0.13 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3414 (br), 2923, 2858, 1713, 1642, 1604, 1549, 1517, 1462, 1435, 1353, 1260, 1244, 1221, 1184, 1113, 867, 769, 730 cm−1; 1H NMR (600 MHz, CD3CN) δ 7.47 (d, J = 8.3 Hz, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 7.19 (t, J = 7.9 Hz, 1 H), 4.08 (s, 2 H), 3.93 (s, 3 H) 3.53 (br s, 4 H), 2.48 (br s, 4 H); 13C NMR (150 MHz, CD3CN) δ 162.7, 137.8, 127.7, 126.9, 126.8, 121.3, 116.4, 116.3, 110.2, 67.7 (2 C), 54.0 (2 C), 52.7, 51.1; HRMS (ESI-TOF) calcd for C15H18BrN2O4+ [M + H+] 369.0444, found 369.0446.

4.6.19. Methyl 3-(anilinomethyl)-4-bromo-1-hydroxy-1H-indole-2-carboxylate (34)

Rf = 0.76 (silica gel, MeOH:CH2Cl2, 3:97); IR (film) νmax 3385 (br), 2927, 2843, 1706, 1599, 1496, 1435, 1351, 1309, 1253, 1225, 1183, 1127, 1061, 1024, 767, 739 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.24 (br s, 1 H), 7.48 (d, J = 8.3 Hz, 1 H), 7.37 (d, J = 7.5 Hz, 1 H), 7.22 (dd, J = 8.3, 7.5 Hz, 1 H), 7.12 (dd, J = 8.5, 7.6 Hz, 2 H), 6.69 (d, J = 7.6 Hz, 2 H), 6.65–6.60 (m, 1 H), 4.83 (s, 2 H), 3.91 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 162.4, 149.6, 137.6, 130.0 (2 C), 127.3, 126.7, 120.8, 117.8, 117.5, 115.9, 115.3, 114.0 (2 C), 110.4, 52.9, 38.1; HRMS (ESI-TOF) calcd for C17H16BrN2O3+ [M + H+] 375.0339, found 375.0327.

4.6.20. Methyl 4-bromo-1-hydroxy-3-(4-hydroxybenzyl)-1H-indole-2-carboxylate (35)

Rf = 0.41 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3342 (br), 2943, 1690, 1614, 1508, 1443, 1343, 1249, 1173, 1120, 873, 756, 732 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.16 (br s, 1 H), 7.49 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 7.4 Hz, 1 H), 7.19 (dd, J = 8.3, 7.4 Hz, 1 H), 6.92 (d, J = 8.5 Hz, 2 H), 6.65 (d, J = 8.5 Hz, 2 H), 4.62 (s, 2 H), 3.86 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.5, 155.6, 137.8, 133.5, 129.9 (2 C), 127.2, 126.4, 126.0, 120.6, 120.3, 116.0, 115.6 (2 C), 110.3, 52.5, 29.3; HRMS (ESI-TOF) calcd for C17H14BrNO4Na+ [M + Na+] 397.9998, found 397.9987.

4.6.21. Methyl 4-bromo-1-hydroxy-3-(3-hydroxy-2,4-dimethoxybenzyl)-1H-indole-2-carboxylate (36)

Rf = 0.42 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3414, 2934, 2835, 1708, 1675, 1615, 1489, 1440, 1396, 1347, 1287, 1249, 1085, 1030, 894, 746 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.21 (s, 1 H), 7.51 (d, J = 7.9 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 1 H), 7.21 (t, J = 7.9 Hz, 1 H), 6.46 (d, J = 8.6 Hz, 1 H), 6.38 (s, 1 H), 5.92 (d, J = 8.6 Hz, 1 H), 4.62 (s, 2 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 3.74 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.5, 147.5, 146.0, 139.7, 138.0, 128.6, 127.3, 126.5, 126.4, 121.2, 119.2, 118.6, 116.3, 110.4, 107.5, 60.4, 56.7, 52.6, 24.7; HRMS (ESI-TOF) calcd for C19H18BrNO6Na+ [M + Na+] 458.0210, found 458.0200.

4.6.22. Methyl 4-bromo-1-hydroxy-3-[(2-oxocyclohexyl)methyl]-1H-indole-2-carboxylate (37)

Rf = 0.38 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3319, 2928, 2855, 1705, 1515, 1436, 1399, 1341, 1304, 1251, 1230, 1120, 882, 756, 729 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.14 (br s, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 8.0 Hz, 1 H), 3.90 (s, 3 H), 3.73 (dd, J = 14.2, 4.4 Hz, 1 H), 3.18 (dd, J = 14.2, 9.2 Hz, 1 H), 2.83–2.75 (m, 1 H), 2.37–2.26 (m, 2 H), 2.02–1.96 (m, 1 H), 1.90–1.84 (m, 1 H), 1.78–1.71 (m, 1 H), 1.68–1.58 (m, 1 H), 1.57–1.42 (m, 2 H); 13C NMR (125 MHz, CD3CN) δ 212.7, 162.9, 138.1, 127.1, 126.7, 126.5, 120.8, 120.0, 116.2, 110.4, 53.6, 52.6, 42.7, 33.6, 28.8, 25.8, 24.5; HRMS (ESI-TOF) calcd for C17H18BrNO4Na+ [M + Na+] 402.0311, found 402.0299.

4.6.23. Methyl 4-bromo-1-hydroxy-3-[(2-oxocyclopentyl)methyl]-1H-indole-2-carboxylate (38)

Rf = 0.32 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3318, 2954, 2872, 1713, 1689, 1531, 1437, 1396, 1349, 1307, 1243, 1184, 1143, 1119, 1078, 978, 884, 773, 737 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.29 (br s, 1 H), 7.45 (d, J = 7.9 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.17 (t, J = 7.9 Hz, 1 H), 3.89 (s, 3 H), 3.68 (dd, J = 13.8, 6.2 Hz, 1 H), 3.25 (dd, J = 13.8, 9.2 Hz, 1 H), 2.63–2.54 (m, 1 H), 2.20–2.09 (m, 1 H), 1.97–1.91 (m, 2 H), 1.90–1.83 (m, 1 H), 1.74–1.65 (m, 2 H); 13C NMR (150 MHz, CD3CN) δ 200.0, 162.7, 137.9, 127.1, 126.3, 125.8, 120.4, 120.2, 116.1, 110.3, 52.5, 51.6, 38.5, 29.6, 24.7, 21.0; HRMS (ESI-TOF) calcd for C16H16BrNO4Na+[M + Na+] 388.0155, found 388.0148.

4.6.24. Methyl 4-bromo-1-hydroxy-3-[(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)methyl]-1H-indole-2-carboxylate (39)

Rf = 0.35 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3310, 2944, 2850, 1708, 1676, 1598, 1519, 1451, 1399, 1352, 1300, 1242, 1221, 1116, 1022, 980, 881, 776, 734 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.27 (br s, 1 H), 7.92 (d, J = 7.7 Hz, 1 H), 7.51–7.43 (m, 2 H), 7.31 (t, J = 7.7 Hz, 2 H), 7.26 (d, J = 7.7 Hz, 1 H), 7.18 (t, J = 7.7 Hz, 1 H), 4.06 (br s, 1 H), 3.74 (s, 3 H), 3.39 (br s, 1 H), 3.02–2.92 (m, 2 H), 2.91–2.80 (m, 1 H), 2.07–1.97 (m, 1 H), 1.95 (s, 1 H); 13C NMR (125 MHz, CD3CN) δ 199.7, 162.8, 145.4, 138.0, 134.1, 133.4, 129.9, 127.7, 127.4, 127.2, 126.5, 126.2, 120.8, 119.8, 116.2, 110.4, 52.5, 50.6, 29.0, 28.7, 24.9; HRMS (ESI-TOF) calcd for C21H18BrNO4Na+ [M + Na+] 450.0311, found 450.0297.

4.6.25. Methyl 4-bromo-1-hydroxy-3-(2-methyl-3-oxopentyl)-1H-indole-2-carboxylate (40)

Rf = 0.37 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3300, 2965, 2923, 1708, 1680, 1514, 1441, 1341, 1247, 1184, 1148, 1116, 1090, 1033, 975, 881, 771, 734 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.22 (br s, 1 H), 7.45 (d, J = 7.9 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.19 (t, J = 7.9 Hz, 1 H), 3.91 (s, 3 H), 3.49 (br s, 1 H), 3.35 (br s, 1 H), 3.03–2.97 (m, 1 H), 2.51–2.43 (m, 1 H), 2.34–2.26 (m, 1 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.89 (d, J = 7.2 Hz, 3 H); 13C NMR (150 MHz, CD3CN) δ 215.2, 162.6, 138.0, 127.2, 126.6, 126.3, 120.6, 119.4, 116.1, 110.4, 52.6, 48.9, 35.3, 27.7, 15.9, 7.9; HRMS (ESI-TOF) calcd for C16H18BrNO4Na+ [M + Na+] 390.0311, found 390.0307.

4.6.26. Methyl 4-bromo-1-hydroxy-3-(3-oxo-3-phenylpropyl)-1H-indole-2-carboxylate (41)

Rf = 0.35 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3357, 2914, 1708, 1674, 1594, 1520, 1441, 1395, 1310, 1242, 1146, 1117, 771, 737, 686 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.29 (br s, 1 H), 7.99–7.94 (m, 2 H), 7.60–7.55 (m, 1 H), 7.49–7.43 (m, 3 H), 7.30 (br s, 1 H), 7.18 (t, J = 7.7 Hz, 1 H), 3.85 (s, 3 H), 3.63 (br s, 2 H), 3.35 (t, J = 7.7 Hz, 2 H); 13C NMR (150 MHz, CD3CN) δ 200.1, 162.5, 137.8, 133.9, 129.5, 128.7, 128.6, 127.1, 126.2, 125.5, 121.0, 120.4, 116.0, 110.3, 52.5, 41.7, 20.2 (3 C); HRMS (ESI-TOF) calcd for C19H16BrNO4Na+ [M + Na+] 424.0155, found 424.0154.

4.6.27. Methyl 4-bromo-3-(4,4-dimethyl-3-oxopentyl)-1-hydroxy-1H-indole-2-carboxylate (42)

Rf = 0.46 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3283, 2942, 2872, 1725, 1707, 1519, 1437, 1396, 1349, 1243, 1178, 1149, 1119, 984, 884, 779, 737 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.34 (br s, 1 H), 7.44 (br s, 1 H), 7.29 (br s, 1 H), 7.17 (t, J = 7.4 Hz, 1 H), 3.90 (s, 3 H), 3.40 (br s, 2 H), 2.87 (t, J = 7.9 Hz, 2 H), 1.09 (s, 9 H); 13C NMR (150 MHz, CD3CN) δ 215.7, 162.6, 138.6, 127.2, 126.3, 124.8, 121.5, 120.5, 116.1, 110.3, 52.7, 44.6, 39.7, 26.6, 20.1 (3 C); HRMS (ESI-TOF) calcd for C17H20BrNO4Na+ [M + Na+] 404.0468, found 404.0456.

4.6.28. Methyl 4-bromo-1-hydroxy-3-(2,2,4-trimethyl-3-oxopentyl)-1H-indole-2-carboxylate (43)

Rf = 0.45 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3309, 2972, 2868, 1712, 1689, 1515, 1464, 1440, 1379, 1346, 1271, 1234, 1182, 1140, 1117, 1042, 1000, 878, 798, 775, 742 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.49 (br s, 1 H), 7.49 (br s, 1 H), 7.33 (br s, 1 H), 7.18 (t, J = 7.2 Hz, 1 H), 3.90 (s, 3 H), 3.67 (br s, 2 H), 3.30 (hept, J = 6.6 Hz, 1 H), 1.04 (d, J = 6.6 Hz, 6 H), 0.97 (s, 6 H); 13C NMR (150 MHz, CD3CN) δ 220.1, 162.9, 137.6, 128.1, 127.2, 126.6, 121.8, 116.1, 115.6, 110.4, 52.6, 50.6, 35.0, 29.5, 23.0 (2 C), 20.4 (2 C); HRMS (ESI-TOF) calcd for C18H22BrNO4Na+ [M + Na+] 418.0624, found 418.0620.

4.6.29. Methyl 4-bromo-3-(2,2-difluoro-3-oxo-3-phenylpropyl)-1-hydroxy-1H-indole-2-carboxylate (44)

Rf = 0.47 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3360, 2955, 2919, 1698, 1520, 1449, 1311, 1264, 1184, 1127, 914, 764, 716 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.24 (br s, 1 H), 8.04–8.02 (m, 2 H), 7.68 (t, J = 7.3 Hz, 1 H), 7.53–7.50 (m, 3 H), 7.38–7.36 (m, 1 H), 7.24–7.21 (m, 1 H), 4.46 (t, J = 17.7 Hz, 2 H), 3.80 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 190.5, 162.1, 137.2, 135.4, 133.0, 130.7 (t, J = 3.4 Hz, 2 C), 129.7 (2 C), 127.4, 127.2, 127.1, 121.1, 119.1, 115.9, 110.4, 108.9, 52.7, 29.7 (t, J = 23.8 Hz); HRMS (ESI-TOF) calcd for C19H15BrF2NO4+ [M + H+] 438.0147, found 438.0145.

4.6.30. Methyl 4-bromo-3-[3-(4-chlorophenyl)-2,2-difluoro-3-oxopropyl]-1-hydroxy-1H-indole-2-carboxylate (45)

Rf = 0.31 (silica gel, EtOAc:hexanes, 2:8); IR (film) νmax 1702, 1588, 1448, 1401, 1265, 1091, 762 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.24 (br s, 1 H), 7.96 (d, J = 8.8 Hz, 2 H), 7.53–7.50 (m, 3 H), 7.37 (d, J = 7.5 Hz, 1 H), 7.23 (t, J = 8.8 Hz, 1 H), 4.45 (t, J = 17.5 Hz, 2 H), 3.82 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 189.0, 161.6, 140.8, 136.8, 132.0 (t, J = 3.6 Hz, 2 C), 131.2, 129.5 (2 C), 129.4, 128.5, 126.8, 126.7, 120.6, 115.4, 110.0, 108.3, 52.2, 29.3 (t, J = 23.8 Hz); HRMS (ESI-TOF) calcd for C19H14BrClF2NO4+ [M + H+] 471.9757, found 471.9752.

4.6.31. Methyl 4-bromo-3-(2,2-difluoro-3-oxo-3-thien-2-ylpropyl)-1-hydroxy-1H-indole-2-carboxylate (46)

Rf = 0.25 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3335 (br), 3105, 2954, 1714, 1679, 1614, 1517, 1447, 1411, 1345, 1311, 1266, 1186, 1148, 1127, 1058, 932, 879, 839, 761, 733 cm− 1; 1H NMR (500 MHz, CD3CN) δ 9.36 (br s, 1 H), 7.95 (dd, J = 4.5, 1.3 Hz, 1 H), 7.86–7.84 (m, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.38 (d, J = 7.0 Hz, 1 H), 7.26–7.18 (m, 2 H), 4.44 (t, J = 17.0 Hz, 2 H), 3.84 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 183.8, 162.1, 139.3, 138.3, 137.2, 137.1 (t, J = 5.4 Hz), 130.1, 127.5, 127.3, 127.1, 121.1, 118.9, 115.9, 110.5, 108.8, 52.7, 30.0 (t, J = 23.8 Hz); HRMS (ESI-TOF) calcd for C17H13BrF2NO4S+ [M + H+] 443.9711, found 443.9711.

4.6.32. Methyl 4-bromo-1-hydroxy-3-(3-oxobutyl)-1H-indole-2-carboxylate (47)

Rf = 0.37 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 3342, 2942, 1707, 1519, 1437, 1396, 1354, 1243, 1184, 1119, 879, 773, 737 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.36 (br s, 1 H), 7.45 (d, J = 8.2 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 1 H), 7.18 (t, J = 8.2 Hz, 1 H), 3.91 (s, 3 H), 3.44 (t, J = 8.0 Hz, 2 H), 2.78 (t, J = 8.0 Hz, 2 H), 2.11 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 208.7, 162.5, 137.9, 127.2, 126.3, 125.6, 121.1, 120.4, 116.0, 110.4, 52.7, 46.3, 29.9, 19.8; HRMS (ESI-TOF) calcd for C14H14BrNO4Na+ [M + Na+] 361.9998, found 361.9990.

4.6.33. Methyl 3-(2-acetyl-3-oxobutyl)-4-bromo-1-hydroxy-1H-indole-2-carboxylate (48)

Rf = 0.23 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3392, 2956, 1710, 1697, 1617, 1519, 1433, 1353, 1243, 1180, 1140, 1117, 870, 773, 733 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.11 (br s, 1 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.35 (d, J = 7.0 Hz, 1 H), 7.21 (t, J = 7.0 Hz, 1 H), 4.26 (t, J = 6.0 Hz, 1 H), 3.90 (s, 3 H), 3.71 (d, J = 6.0 Hz, 2 H), 2.04 (s, 6 H); 13C NMR (125 MHz, CD3CN) δ 205.1 (2 C), 162.3, 137.9, 127.3, 126.7, 126.6, 120.4, 117.4, 115.8, 110.5, 69.6, 52.7, 30.7, 23.7 (2 C); HRMS (ESI-TOF) calcd for C16H16BrNO5Na+ [M + Na+] 404.0104, found 404.0100.

4.6.34. Methyl 4-bromo-1-hydroxy-3-(3-methoxy-2,2-dimethyl-3-oxopropyl)-1H-indole-2-carboxylate (49)

Rf = 0.36 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3323, 2944, 1714, 1513, 1433, 1393, 1347, 1249, 1180, 1134, 1025, 985, 865, 773, 733 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.12 (br s, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.33 (d, J = 7.5 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1 H), 3.89 (s, 3 H), 3.72 (s, 2 H), 3.51 (s, 3 H), 1.11 (s, 6 H); 13C NMR (125 MHz, CD3CN) δ 178.3, 162.8, 137.7, 127.8, 127.2, 126.7, 121.8, 116.6, 116.3, 110.5, 52.7, 52.3, 44.7, 32.7, 25.1 (2 C); HRMS (ESI-TOF) calcd for C16H18BrNO5Na+ [M + Na+] 406.0260, found 406.0243.

4.6.35. Methyl 4-bromo-1-hydroxy-3-(3-oxopropyl)-1H-indole-2-carboxylate (50)

Rf = 0.20 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3471, 1701, 1695, 1537, 1437, 1384, 1237, 1190, 1172, 1149, 1119, 920, 873, 773, 737 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.77 (s, 1 H), 9.31 (br s, 1 H), 7.46 (d, J = 7.9 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.20 (t, J = 7.9 Hz, 1 H), 3.91 (s, 3 H), 3.56 (t, J = 7.7 Hz, 2 H), 2.80 (t, J = 7.7 Hz, 2 H); 13C NMR (125 MHz, CD3CN) δ 203.0, 162.4, 137.9, 127.3, 126.3, 125.5, 120.6, 120.4, 115.9, 110.4, 52.7, 46.7, 18.2; HRMS (ESI-TOF) calcd for C13H11BrNO4 [M − H] 323.9877, found 323.9863.

4.6.36. Methyl 4-bromo-3-but-3-enyl-1-hydroxy-1H-indole-2-carboxylate (51)

Rf = 0.67 (silica gel, MeOH:CH2Cl2, 3:97); IR (film) νmax 3360, 2953, 1679, 1638, 1615, 1516, 1440, 1341, 1312, 1254, 1143, 1120, 911, 876, 771, 736 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.23 (br s, 1 H), 7.44 (d, J = 7.9 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 1 H), 7.18 (t, J = 7.9 Hz, 1 H), 6.00–5.89, (m, 1 H), 5.03 (dd, J = 17.2, 1.9 Hz, 1 H), 4.95 (d, J = 10.2 Hz, 1 H), 3.91 (s, 3 H), 3.39–3.33 (m, 2 H), 2.38 (q, J = 7.5 Hz, 2 H); 13C NMR (125 MHz, CD3CN) δ 162.8, 139.2, 137.9, 127.2, 126.4, 125.4, 122.2, 120.5, 116.2, 115.3, 110.3, 52.6, 37.3, 24.7; HRMS (ESI-TOF) calcd for C14H15BrNO3+ [M + H+] 324.0230, found 324.0234.

4.6.37. Methyl 4-bromo-1-hydroxy-3-(3-methylbut-3-enyl)-1H-indole-2-carboxylate (52)

Rf = 0.69 (silica gel, MeOH:CH2Cl2, 1:99); IR (film) νmax 3346, 2960, 2925, 1679, 1511, 1440, 1398, 1342, 1271, 1257, 1239, 1117, 986, 882, 775, 737 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.19 (br s, 1 H), 7.44 (d, J = 7.9 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 1 H), 7.17 (t, J = 7.9 Hz, 1 H), 4.75 (s, 2 H), 3.92 (s, 3 H), 3.41–3.35 (m, 2 H), 2.35–2.30 (m, 2 H), 1.81 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.7, 146.8, 137.7, 127.1, 126.2, 125.0, 122.4, 120.3, 116.1, 110.6, 110.2, 52.5, 41.2, 24.2, 22.5; HRMS (ESI-TOF) calcd for C15H15BrNO3 [M − H] 336.0241, found 336.0238.

4.6.38. Methyl 4-bromo-3-[3-(chloromethyl)but-3-enyl]-1-hydroxy-1H-indole-2-carboxylate (53)

Rf = 0.70 (silica gel, MeOH:CH2Cl2, 1:99); IR (film) νmax 3377, 2954, 2907, 1678, 1513, 1443, 1396, 1343, 1313, 1255, 1119, 908, 879, 787, 732 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.20 (s, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.19 (t, J = 8.0 Hz, 1 H), 5.20 (s, 1 H), 5.05 (s, 1 H), 4.19 (s, 2 H), 3.93 (s, 3 H), 3.42 (t, J = 8.4 Hz, 2 H), 2.49 (t, J = 8.4 Hz, 2 H); 13C NMR (150 MHz, CD3CN) δ 162.7, 146.5, 137.8, 127.2, 126.3, 125.2, 121.7, 120.3, 116.1, 115.4, 110.3, 52.7, 49.0, 36.0, 24.2; HRMS (ESI-TOF) calcd for C15H14BrClNO3 [M − H] 369.9851, found 369.9852.

4.6.39. Methyl 4-bromo-3-(cyclopenta-2,4-dien-1-ylmethyl)-1-hydroxy-1H-indole-2-carboxylate (54)

Rf = 0.75 (silica gel, MeOH:CH2Cl2, 1:99); IR (film) νmax 3356, 2943, 1675, 1614, 1515, 1445, 1398, 1342, 1304, 1257, 1121, 986, 878, 775, 737 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.38 (br s, 1 H), 7.47 (d, J = 7.9 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 1 H), 7.18 (t, J = 7.9 Hz, 1 H), 6.34–6.29 (m, 1 H), 6.24–6.19 (m, 1 H), 5.83 (br s, 1 H), 4.43 (br s, 2 H), 3.89 (s, 3 H), 2.93 (s, 2 H); 13C NMR (150 MHz, CD3CN) δ 162.6, 150.3, 138.0, 133.2, 131.7, 127.7, 127.2, 126.4, 125.7, 120.5, 120.4, 116.3, 110.4, 52.6, 44.1, 26.4; HRMS (ESI-TOF) calcd for C16H13BrNO3 [M − H] 346.0084, found 346.0072.

4.6.40. Methyl 4-bromo-1-hydroxy-3-(methoxymethyl)-1H-indole-2-carboxylate (55)

Rf = 0.32 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3175, 2937, 2887, 1709, 1525, 1436, 1404, 1346, 1311, 1257, 1227, 1187, 1123, 1073, 934, 879, 775, 736, 666 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.38 (br s, 1 H), 7.44 (dd, J = 8.3, 0.7 Hz, 1 H), 7.34 (dd, J = 7.6, 0.7 Hz, 1 H), 7.18 (dd, J = 8.3, 7.6 Hz, 1 H), 4.97 (s, 2 H), 3.93 (s, 3 H), 3.35 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 162.3, 137.3, 127.1, 127.0, 126.8, 121.0, 116.0, 115.9, 110.2, 63.4, 57.7, 52.9; HRMS (ESI-TOF) calcd for C12H12BrNO4Na+ [M + Na+] 335.9842, found 335.9834.

4.6.41. Methyl 4-bromo-1-hydroxy-3-methyl-1H-indole-2-carboxylate (56)

Rf = 0.58 (silica gel, MeOH:CH2Cl2, 1:99); IR (film) νmax 3436, 2919, 1672, 1613, 1519, 1443, 1272, 1184, 1119, 978, 873, 761, 726, 679, 608, 561 cm−1; 1H NMR (400 MHz, CD3CN) δ 9.09 (s, 1 H), 7.43 (d, J = 7.9 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.17 (t, J = 7.9 Hz, 1 H), 3.92 (s, 3 H), 2.78 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 162.9, 138.2, 127.3, 126.1, 125.7, 121.4, 118.5, 116.7, 110.3, 52.6, 12.0; HRMS (ESI-TOF) calcd for C11H9BrNO3 [M − H] 281.9771, found 281.9770.

4.6.42. Methyl 4-bromo-1-hydroxy-3-pent-3-ynyl-1H-indole-2-carboxylate (57)

Rf = 0.68 (silica gel, MeOH:CH2Cl2, 1:99); IR (film) νmax 3360, 2942, 2907, 2848, 1689, 1513, 1443, 1396, 1255, 1119, 1025, 879, 802, 767, 732, 667 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.13 (br s, 1 H), 7.46 (d, J = 7.9 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 1 H), 7.19 (t, J = 7.9 Hz, 1 H), 3.93 (s, 3 H), 3.48 (t, J = 7.4 Hz, 2 H), 2.46–2.41 (m, 2 H), 1.69 (t, J = 2.4 Hz, 3 H); 13C NMR (150 MHz, CD3CN) δ 162.6, 137.8, 127.1, 126.4, 126.2, 120.3, 120.2, 116.0, 110.2, 79.1, 77.3, 52.6, 24.6, 22.2, 3.4; HRMS (ESI-TOF) calcd for C15H13BrNO3 [M − H] 334.0084, found 334.0083.

4.6.43. Methyl 4-bromo-3-(2,2-dimethylbut-3-enyl)-1-hydroxy-1H-indole-2-carboxylate (58)

Rf = 0.53 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3366, 2951, 2917, 1686, 1519, 1439, 1387, 1306, 1254, 1122, 1018, 903, 868, 793, 770, 742, 684 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.08 (s, 1 H), 7.46 (s, 1 H), 7.31 (s, 1 H), 7.16 (t, J = 7.2 Hz, 1 H), 5.87 (dd, J = 17.4, 10.8 Hz, 1 H), 4.77 (d, J = 10.8 Hz, 1 H), 4.69 (d, J = 17.4 Hz, 1 H), 3.88 (s, 3 H), 3.49 (br s, 2 H), 0.97 (s, 6 H); 13C NMR (150 MHz, CD3CN) δ 163.2, 149.0, 137.7, 128.0, 127.2, 126.6, 121.8, 117.2, 116.4, 110.9, 110.3, 52.5, 40.1, 34.8, 26.5 (2 C); HRMS (ESI-TOF) calcd for C16H17BrNO3 [M − H] 350.0397, found 350.0396.

4.6.44. Methyl 1-hydroxy-3-[(2-oxocyclohexyl)methyl]-1H-indole-2-carboxylate (62)

Rf = 0.26 (silica gel, EtOAc:hexanes, 2:8); IR (film) νmax 3020, 1742, 1702, 1528, 1447, 1214 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.03 (br s, 1 H), 7.68 (d, J = 9.6 Hz, 1 H), 7.44 (d, J = 9.6 Hz, 1 H), 7.36 (t, J = 9.0 Hz, 1 H), 7.12 (t, J = 9.0 Hz, 1 H), 3.91 (s, 3 H), 3.45 (dd, J = 16.5, 5.7 Hz, 1 H), 2.89 (dd, J = 11.1, 5.7 Hz, 1 H), 2.75–2.70 (m, 1 H), 2.37–2.33 (m, 2 H), 2.03–1.97 (m, 1 H), 1.86–1.83 (m, 1 H), 1.77–1.73 (m, 1 H), 1.67–1.63 (m, 1 H), 1.54 (ddt, J = 30.0, 14.4, 4.2 Hz, 1 H), 1.47–1.39 (ddd, J = 30.0, 14.4, 4.2 Hz, 1 H); 13C NMR (125 MHz, CD3CN) δ 212.7, 163.1, 136.8, 126.8, 124.5, 123.7, 121.9, 121.4, 121.3, 110.5, 52.4, 52.3, 42.5, 34.3, 28.7, 25.5, 25.1; HRMS (ESI-TOF) calcd for C17H20NO4+ [M + H+] 302.1387, found 302.1387.

4.6.45. Methyl 1-hydroxy-3-(2-methyl-3-oxopentyl)-1H-indole-2-carboxylate (63)

Rf = 0.63 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 2929, 1700, 1540, 1507, 1457, 1259, 119 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.06 (br s, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 1 H), 7.38–7.35 (m, 1 H), 7.15–7.12 (m, 1 H), 3.93 (s, 3 H), 3.30–3.26 (m, 1 H), 3.01–2.94 (m, 2 H), 2.50–2.42 (m, 1 H), 2.34–2.26 (m, 1 H), 1.01 (d, J = 7.0 Hz, 3 H), 0.86 (t, J = 7.5 Hz, 3 H); 13C NMR (125 MHz, CD3CN) δ 215.2, 162.3, 126.9, 124.2, 123.4, 122.3, 121.8, 121.5, 120.6, 110.5, 52.3, 47.8, 35.4, 28.8, 16.7, 7.9; HRMS (ESI-TOF) calcd for C16H19NO4Na+ [M + Na+] 312.1206, found 312.1199.

4.6.46. Methyl 3-(2,2-difluoro-3-oxo-3-phenylpropyl)-1-hydroxy-1H-indole-2-carboxylate (64)

Rf = 0.52 (silica gel, EtOAc:hexanes, 2:8); IR (film) νmax 3375, 1697, 1598, 1535, 1448, 1264, 1122 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.12 (br s, 1 H), 8.04–7.99 (m, 2 H), 7.72–7.68 (m, 2 H), 7.55–7.51 (m, 3 H), 7.4 (t, J = 3.0 Hz, 1 H), 7.2 (t, J = 3.0 Hz, 1 H), 4.1 (t, J = 21.3 Hz, 2 H), 3.8 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 190.5 (t, J = 28.5 Hz), 162.4, 136.2, 135.4, 135.1, 130.7 (t, J = 3.2 Hz), 130.6 (t, J = 3.2 Hz), 129.8, 129.7, 126.9, 125.8, 123.8, 122.1, 121.9, 110.5, 52.4, 31.1 (t, J = 24.4 Hz); HRMS (ESI-TOF) calcd for C19H16F2NO4+ [M + H+] 360.1042, found 360.1039.

4.6.47. Methyl 1-hydroxy-3-[(2-oxocyclohexyl)methyl]-4-({[2-(trimethylsilyl)ethoxy]-methoxy}methyl)-1H-indole-2-carboxylate (65)

Rf = 0.25 (silica gel, EtOAc:hexanes, 2:8); IR (film) νmax 3240 (br), 2936, 2860, 1709, 1438, 1396, 1235, 1125, 1037 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.11 (br s, 1 H), 7.43 (d, J = 7.0 Hz, 1 H), 7.31–7.30 (m, 1 H), 7.11 (d, J = 6.5 Hz, 1 H), 4.85 (br s, 2 H), 4.67 (s, 2 H), 3.90 (s, 3 H), 3.65–3.56 (m, 3 H), 3.12–3.05 (m, 1 H), 2.65–2.63 (m, 1 H), 2.35–2.30 (m, 2 H), 2.05–1.97 (m, 1 H), 1.88–1.84 (m, 1 H), 1.80–1.73 (m, 1 H), 1.65–1.61 (m, 1 H), 1.53–1.42 (m, 2 H), 0.88 (dd, J = 9.0, 8.0 Hz, 2 H), −0.01 (s, 9 H); 13C NMR (125 MHz, CD3CN) δ 212.7, 163.3, 137.5, 133.5, 129.6, 126.2, 125.5, 123.2, 120.7, 110.7, 94.7, 68.3, 65.8, 53.3, 52.3, 42.5, 33.7, 28.6, 25.7, 18.6, −1.4 (3 C); HRMS (ESI-TOF) calcd for C23H36NO6Si+ [M + H+] 462.2306, found 462.2304.

4.6.48. Methyl 1-hydroxy-3-(2-methyl-3-oxopentyl)-4-({[2-(trimethylsilyl)ethoxy]methoxy}-methyl)-1H-indole-2-carboxylate (66)

Rf = 0.50 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3240 (br), 2950, 1714, 1520, 1456, 1398, 1248, 1128, 1102, 1028, 859, 836 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.14 (br s, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.32–7.29 (m, 1 H), 7.13 (d, J = 6.5 Hz, 1 H), 4.94 (d, J = 12.0 Hz, 1 H), 4.90 (d, J = 12.0 Hz, 1 H), 4.70 (s, 2 H), 3.92 (s, 3 H), 3.59 (dd, J = 9.0, 8.0 Hz, 2 H), 3.42 (dd, J = 14.0, 6.0 Hz, 1 H), 3.19 (dd, J = 14.0, 7.0 Hz, 1 H), 2.93 (dd, J = 14.0, 7.0 Hz, 1 H), 2.47–2.37 (m, 1 H), 2.25–2.18 (m, 1 H), 1.01 (d, J = 7.0 Hz, 3 H), 0.90–0.83 (m, 5 H), −0.01 (s, 9 H); 13C NMR (125 MHz, CD3CN) δ 215.2, 163.1, 133.4, 126.2, 125.0, 124.5, 123.3, 120.9, 120.0, 110.7, 94.7, 68.4, 65.9, 52.4, 48.6, 35.6, 29.3, 18.6, 16.3, 7.8, −1.4 (3 C); HRMS (ESI- TOF) calcd for C23H35NO6SiNa+ [M + Na+] 472.2126, found 472.2126.

4.6.49. Methyl 3-(2,2-difluoro-3-oxo-3-phenylpropyl)-1-hydroxy-4-({[2-(trimethylsilyl)-ethoxy]methoxy}methyl)-1H-indole-2-carboxylate (67)

Rf = 0.36 (silica gel, EtOAc:hexanes, 1:5); IR (film) νmax 2951, 1700, 1449, 1251, 1096, 1028 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.21 (br s, 1 H), 8.07–8.03 (m, 2 H), 7.71–7.68 (m, 1 H), 7.55–7.49 (m, 3 H), 7.36–7.33 (m, 1 H), 7.16 (d, J = 6.5 Hz, 1 H), 4.95 (d, J = 16.0 Hz, 2 H), 4.66 (s, 2 H), 4.32 (t, J = 18.0 Hz, 2 H), 3.79 (s, 3 H), 3.54 (t, J = 8.0 Hz, 2 H), 0.81 (t, J = 8.0 Hz, 2 H), −0.04 (s, 9 H); 13C NMR (125 MHz, CD3CN) δ 196.2, 159.9, 136.2, 136.1, 133.6, 131.5 (t, J = 3.0 Hz, 2 C), 130.6, 130.5 (2 C), 130.4, 126.9, 126.5, 124.5, 120.7, 114.4, 100.6, 95.3, 69.2, 66.6, 53.2, 32.1, 19.2, −0.8 (3 C); HRMS (ESI-TOF) calcd for C26H31F2NO6SiNa+ [M + Na+] 542.1781, found 542.1767.

4.6.50. Methyl 4-fluoro-1-hydroxy-3-[(2-oxocyclohexyl)methyl]-1H-indole-2-carboxylate (68)

Rf = 0.47 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3295 (br), 2931, 2849, 1702, 1631, 1566, 1531, 1443, 1401, 1361, 1314, 1255, 1231, 1131, 937, 785, 732 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.19 (br s, 1 H), 7.29–7.23 (m, 2 H), 6.77 (dd, J = 11.4, 7.4 Hz, 1 H), 3.92 (s, 3 H), 3.50 (dd, J = 14.0, 4.8 Hz, 1 H), 2.99 (dd, J = 14.0, 5.7 Hz, 1 H), 2.72–2.66 (m, 1 H), 2.35–2.27 (m, 2 H), 2.00–1.93 (m, 1 H), 1.87–1.85 (m, 1 H), 1.75–1.72 (m, 1 H), 1.67–1.59 (m, 1 H), 1.56–1.49 (m, 1 H), 1.46–1.39 (m, 1 H); 13C NMR (150 MHz, CD3CN) δ 212.8, 162.7, 158.8 (d, J = 248.4 Hz), 138.8 (d, J = 10.3 Hz), 127.3 (d, J = 8.0 Hz), 125.0, 118.8 (d, J = 3.4 Hz), 112.4 (d, J = 19.5 Hz), 106.9 (d, J = 3.4 Hz), 106.2 (d, J = 20.6 Hz), 52.7, 52.5, 42.5, 33.7, 28.6, 26.3, 25.5; HRMS (ESI-TOF) calcd for C17H18FNO4Na+ [M + Na+] 342.1112, found 342.1102.

4.6.51. Methyl 4-fluoro-1-hydroxy-3-(2-methyl-3-oxopentyl)-1H-indole-2-carboxylate (69)

Rf = 0.46 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3299 (br), 2970, 1714, 1633, 1538, 1455, 1404, 1361, 1318, 1235, 1137 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.18 (br s, 1 H), 7.31–7.26 (m, 2 H), 6.80 (dd, J = 12.0, 7.5 Hz, 1 H), 3.97 (s, 3 H), 3.35 (dd, J = 13.5, 5.5 Hz, 1 H), 3.09 (dd, J = 13.5, 9.0 Hz, 1 H), 2.97–2.91 (m, 1 H), 2.53–2.43 (m, 1 H), 2.41–2.35 (m, 1 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.92 (t, J = 7.0 Hz, 3 H); 13C NMR (125 MHz, CD3CN) δ 214.9, 162.6, 158.6 (d, J = 248.0 Hz), 138.6, 132.1, 127.3 (d, J = 8.3 Hz), 124.8, 112.6, 106.9 (d, J = 3.9 Hz), 106.2 (d, J = 19.8 Hz), 52.5, 48.1, 34.9, 29.6, 15.8, 7.9; HRMS (ESI-TOF) calcd for C16H18FNO4Na+ [M + Na+] 330.1112, found 330.1109.

4.6.52. Methyl 3-(2,2-difluoro-3-oxo-3-phenylpropyl)-4-fluoro-1-hydroxy-1H-indole-2-carboxylate (70)

Rf = 0.52 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3364 (br), 2956, 2926, 2848, 1700, 1636, 1540, 1450, 1323, 1269, 1240, 1142, 1091, 946, 764, 716 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.21 (br s, 1 H), 8.02 (d, J = 7.8 Hz, 2 H), 7.69–7.66 (m, 1 H), 7.52 (dd, J = 8.0, 7.3 Hz, 2 H), 7.33–7.28 (m, 2 H), 6.85–6.81 (m, 1 H), 4.12 (t, J = 17.3 Hz, 2 H), 3.97 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 190.4, 161.8, 137.3, 136.4, 135.4, 132.9, 130.6 (t, J = 3.8 Hz, 2 C), 129.6 (2 C), 127.2 (d, J = 8.6 Hz), 126.1, 117.3, 113.0, 107.1, 106.8 (d, J = 3.8 Hz), 106.6 (d, J = 20.0 Hz), 52.4, 32.8 (t, J = 26.7 Hz); HRMS (ESI-TOF) calcd for C19H15F3NO4+ [M + H+] 378.0948, found 378.0943.

4.6.53. Methyl 5-fluoro-1-hydroxy-3-[(2-oxocyclohexyl)methyl]-1H-indole-2-carboxylate (71)

Rf = 0.65 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 3311 (br), 2937, 2855, 1707, 1577, 1532, 1447, 1403, 1342, 1251, 1192, 1169, 849, 799, 757 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.04 (s, 1 H), 7.43 (dd, J = 9.0, 4.5 Hz, 1 H), 7.40 (dd, J = 9.5, 2.5 Hz, 1 H), 7.15 (dt, J = 9.5, 2.5 Hz, 1 H), 3.89 (s, 3 H), 3.39 (dd, J = 14.0, 5.0 Hz, 1 H), 2.85 (dd, J = 14.0, 8.5 Hz, 1 H), 2.73–2.68 (m, 1 H), 2.39–2.27 (m, 2 H), 2.04–1.98 (m, 1 H), 1.89–1.83 (m, 1 H), 1.77–1.73 (m, 1 H), 1.68–1.50 (m, 2 H), 1.44–1.40 (m, 1 H); 13C NMR (125 MHz, CD3CN) δ 212.8, 162.7, 158.8 (d, J = 233.1 Hz), 133.6, 126.1, 123.8 (d, J = 9.5 Hz), 120.8 (d, J = 5.4 Hz), 115.6 (d, J = 26.9 Hz), 112.0 (d, J = 9.4 Hz), 106.3 (d, J = 24.0 Hz), 52.4, 52.3, 42.5, 34.4, 28.7, 25.6, 25.2; HRMS (ESI-TOF) calcd for C17H19FNO4+ [M + H+] 320.1293, found 320.1289.

4.6.54. Methyl 5-fluoro-1-hydroxy-3-(2-methyl-3-oxopentyl)-1H-indole-2-carboxylate (72)

Rf = 0.58 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 3300 (br), 2934, 1699, 1540, 1522, 1456, 1250, 1178, 1110 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.08 (br s, 1 H), 7.44 (dd, J = 9.0, 4.5 Hz, 1 H), 7.36 (dd, J = 9.5, 2.5 Hz, 1 H), 7.18–7.14 (m, 1 H), 3.93 (s, 3 H), 3.26–3.21 (m, 1 H), 2.97–2.92 (m, 2 H), 2.54–2.43 (m, 1 H), 2.32–2.26 (m, 1 H), 1.02 (d, J = 7.5 Hz, 3 H), 0.86 (t, J = 7.5 Hz, 3 H); 13C NMR (125 MHz, CD3CN) δ 215.2, 162.6, 158.9 (d, J = 233.3 Hz), 133.4, 125.8, 123.5 (d, J = 9.6 Hz), 120.1 (d, J = 5.1 Hz), 115.6 (d, J = 27.5 Hz), 112.1 (d, J = 9.5 Hz), 106.2 (d, J = 23.8 Hz), 52.4, 47.7, 35.3, 28.7, 16.7, 7.8; HRMS (ESI-TOF) calcd for C16H19FNO4+ [M + H+] 330.1112, found 330.1104.

4.6.55. Methyl 3-(2,2-difluoro-3-oxo-3-phenylpropyl)-5-fluoro-1-hydroxy-1H-indole-2-carboxylate (73)

Rf = 0.50 (silica gel, EtOAc:hexanes, 4:6); IR (film) νmax 3383 (br), 2922, 2851, 1700, 1598, 1580, 1528, 1438, 1402, 1379, 1337, 1304, 1251, 1190, 1169, 1108, 1079, 1015, 970, 952, 936, 913, 850, 794, 785, 762, 732, 707, 682 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.11 (s, 1 H), 8.00 (d, J = 7.8 Hz, 2 H), 7.70 (t, J = 7.2 Hz, 1 H), 7.53 (t, J = 7.82 Hz, 2 H), 7.48 (dd, J = 9.0, 4.2 Hz, 1 H), 7.40 (d, J = 9.6 Hz, 1 H), 7.20 (dt, J = 9.6, 2.4 Hz, 1 H), 4.04 (t, J = 17.4 Hz, 2 H), 3.76 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 191.1, 162.7, 158.9 (d, J = 233.9 Hz), 136.2, 133.7, 131.4 (t, J = 3.3 Hz, 2 C), 131.2, 130.5 (2 C), 127.9, 124.7 (d, J = 10.4 Hz), 120.4, 120.2, 116.5 (d, J = 27.3 Hz), 112.8 (d, J = 9.6 Hz), 106.8 (d, J = 24.3 Hz) 53.2, 31.8 (t, J = 24.5 Hz); HRMS (ESI-TOF) calcd for C19H15F3NO4+ [M + H+] 378.0948, found 378.0943.

4.6.56. Methyl 6-fluoro-1-hydroxy-3-[(2-oxocyclohexyl)methyl]-1H-indole-2-carboxylate (74)

Rf = 0.44 (silica gel, EtOAc:hexanes, 3:7, eluted 2 ×); IR (film) νmax 3286 (br), 2924, 2854, 1706, 1629, 1537, 1446, 1402, 1352, 1264, 1219, 1177, 1110, 1034, 924, 834, 809 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.06 (s, 1 H), 7.68 (dd, J = 8.8, 4.8 Hz, 1 H), 7.13 (dd, J = 9.6, 2.2 Hz, 1 H), 7.91 (dt, J = 9.6, 2.5 Hz, 1 H), 3.87 (s, 3 H), 3.42 (dd, J = 14.0, 4.8 Hz, 1 H), 2.86 (dd, J = 14.0, 9.2 Hz, 1 H), 2.72–2.67 (m, 1 H), 2.37–2.23 (m, 2 H), 2.01–1.98 (m, 1 H), 1.86–1.84 (m, 1 H), 1.76–1.72 (m, 1 H), 1.65–1.58 (m, 1 H), 1.56–1.49 (m, 1 H), 1.44–1.37 (m, 1 H); 13C NMR (150 MHz, CD3CN) δ 213.0, 163.2 (d, J = 239.5 Hz), 163.0 135.6, 125.3, 124.2 (d, J = 11.4 Hz), 122.0, 120.7, 110.8 (d, J = 25.1 Hz), 96.5 (d, J = 27.4 Hz), 52.7, 52.6, 42.8, 34.7, 29.0, 25.9, 25.4; HRMS (ESI-TOF) calcd for C17H19FNO4+ [M + H+] 320.1293, found 320.1282.

4.6.57. Methyl 6-fluoro-1-hydroxy-3-(2-methyl-3-oxopentyl)-1H-indole-2-carboxylate (75)

Rf = 0.56 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 3313, 2924, 2877, 1698, 1539, 1456, 1396, 1260, 1223, 1175, 1110 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.10 (br s, 1 H), 7.68–7.65 (m, 1 H), 7.15 (dd, J = 9.5, 2.5 Hz, 1 H), 6.95–6.91 (m, 1 H), 3.92 (s, 3 H), 3.30–3.24 (m, 1 H), 3.00–2.93 (m, 2 H), 2.51–2.43 (m, 1 H), 2.33–2.25 (m, 1 H), 1.02 (d, J = 6.5 Hz, 3 H), 0.86 (t, J = 7.5 Hz, 3 H); 13C NMR (125 MHz, CD3CN) δ 215.2, 163.0 (d, J = 239.8 Hz), 162.6, 132.9, 124.9, 123.8 (d, J = 10.5 Hz), 121.0, 120.2, 110.7 (d, J = 25.6 Hz), 96.3 (d, J = 27.1 Hz), 52.4, 47.8, 35.4, 28.7, 16.7, 7.9; HRMS (ESI-TOF) calcd for C16H18FNO4Na+ [M + Na+] 330.1112, found 330.1110.

4.6.58. Methyl 3-(2,2-difluoro-3-oxo-3-phenylpropyl)-6-fluoro-1-hydroxy-1H-indole-2-carboxylate (76)

Rf = 0.52 (silica gel, EtOAc:hexanes, 3:7, eluted 2 ×); IR (film) νmax 3362, 2962, 2923, 2853, 1699, 1632, 1598, 1537, 1449, 1401, 1355, 1264, 1223, 1177, 1112, 1063, 924, 907, 880, 834, 812 cm−1; 1H NMR (600 MHz, CD3CN) δ 9.12 (br s, 1 H), 7.99 (d, J = 7.9 Hz, 2 H), 7.71–7.67 (m, 2 H), 7.51 (t, J = 7.9 Hz, 2 H), 7.18 (dd, J = 9.1, 1.7 Hz, 1 H), 6.98 (dt, J = 9.1, 1.7 Hz, 1 H), 4.06 (t, J = 17.5 Hz, 2 H), 3.74 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 191.0, 163.3 (d, J = 240.6 Hz), 162.5, 136.8 (d, J = 14.7 Hz), 135.9, 133.5, 131.1 (t, J = 3.4 Hz, 2 C), 130.3, 130.2 (2 C), 126.9 (d, J = 3.4 Hz), 124.4 (d, J = 10.3 Hz), 121.0, 120.1, 111.9 (d, J = 26.2 Hz), 96.7 (d, J = 27.4 Hz), 52.8, 31.5 (t, J = 23.9 Hz); HRMS (ESI-TOF) calcd for C19H15F3NO4+ [M + H+] 378.0948, found 378.0941.

4.6.59. Methyl 6-cyano-1-hydroxy-3-[(2-oxocyclohexyl)methyl]-1H-indole-2-carboxylate (77)

Rf = 0.42 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3300 (br), 2930, 2856, 2359, 2221, 1711, 1519, 1446, 1263, 1117 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.22 (br s, 1 H), 7.88 (s, 1 H), 7.85 (d, J = 8.5 Hz, 1 H), 7.36 (dd, J = 8.5, 1.0 Hz, 1 H), 3.92 (s, 3 H), 3.45 (dd, J = 14.0, 5.0 Hz, 1 H), 2.88 (dd, J = 14.0, 9.0 Hz, 1 H), 2.72–2.68 (m, 1 H), 2.38–2.26 (m, 2 H), 2.03–1.99 (m, 1 H), 1.89–1.84 (m, 1 H), 1.77–1.73 (m, 1 H), 1.67–1.50 (m, 2 H), 1.46–1.38 (m, 1 H); 13C NMR (125 MHz, CD3CN) δ 212.6, 162.3, 135.0, 127.5, 126.0, 123.3, 123.2, 120.7, 120.5, 115.8, 108.8, 52.7, 52.4, 42.5, 34.5, 28.7, 25.6, 25.0; HRMS (ESI-TOF) calcd for C18H18N2O4Na+ [M + Na+] 349.1159, found 349.1149.

4.6.60. Methyl 6-cyano-1-hydroxy-3-(2-methyl-3-oxopentyl)-1H-indole-2-carboxylate (78)

Rf = 0.55 (silica gel, EtOAc:hexanes, 6:4); IR (film) νmax 3242 (br), 2969, 2357, 2224, 1712, 1537, 1445, 1259, 1233, 1117 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.31 (br s, 1 H), 7.87 (s, 1 H), 7.81 (d, J = 8.5 Hz, 1 H), 7.36 (dd, J = 8.5, 1.5 Hz, 1 H), 3.95 (s, 3 H), 3.28 (m, 1 H), 3.00–2.93 (m, 2 H), 2.51–2.43 (m, 1 H), 2.32–2.24 (m, 1 H), 0.86 (d, J = 7.0 Hz, 3 H), 1.01 (t, J = 7.0 Hz, 3 H); 13C NMR (125 MHz, CD3CN) δ 215.1, 162.2, 134.8, 127.3, 125.7, 123.4, 123.1, 120.4, 120.0, 115.8, 108.8, 52.7, 47.7, 35.4, 28.4, 16.8, 7.9; HRMS (ESI-TOF) calcd for C17H19N2O4+ [M + H+] 315.1339, found 315.1331.

4.6.61. Methyl 6-cyano-3-(2,2-difluoro-3-oxo-3-phenylpropyl)-1-hydroxy-1H-indole-2-carboxylate (79)

Rf = 0.47 (silica gel, EtOAc:hexanes, 1:1); IR (film) νmax 2930, 2846, 2358, 2222, 1711, 1560, 1437, 1260, 1117 cm−1; 1H NMR (500 MHz, CD3CN) δ 9.38 (br s, 1 H), 8.00 (d, J = 8.0 Hz, 2 H), 7.92 (s, 1 H), 7.85 (d, J = 8.5 Hz, 1 H), 7.71–7.68 (m, 1 H), 7.54–7.51 (m, 2 H), 7.41 (dd, J = 8.5, 1.0 Hz, 1 H), 4.08 (t, J = 17.5 Hz, 2 H), 3.79 (s, 3 H); 13C NMR (125 MHz, CD3CN) δ 203.1, 170.7, 135.6, 135.3, 133.7, 133.6, 130.8 (t, J = 3.1 Hz, 2 C), 129.8, 129.7 (2 C), 126.0, 123.8, 123.4, 120.8, 114.6, 105.9, 105.6, 54.3, 31.4; HRMS (ESI-TOF) calcd for C20H13F2N2O4 [M − H] 383.0849, found 383.0850.

4.7. Synthesis of nocathiacin I model systems 2 and 3a–c

4.7.1. Ethyl 2-{(1S)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}-1,3-thiazole-4-carboxylate (81)

Thiazole ethyl ester 80 (150 mg, 0.42 mmol) was dissolved in CH2Cl2 (2.8 mL) and MeOH (1.4 mL) and cooled to 0 °C. Trifluroacetic acid (4.2 mL) was added dropwise over 5 min to the reaction mixture, and after stirring at 0 °C for 2.5 h, toluene (5 mL) was added and the reaction mixture was concentrated. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution (5 mL), brine (5 mL) and dried over Na2SO4. The solution was then concentrated and the residue was subjected to flash column chromatography (silica gel, EtOAc:hexanes, 1:1 → 80:20) to afford primary alcohol 81 (91 mg, 68%) as a yellow foam; Rf = 0.40 (silica gel, MeOH:CH2Cl2, 5:95); IR (film) νmax 3354 (br), 2978, 2919, 1707, 1502, 1484, 1390, 1361, 1337, 1231, 1167, 1091, 1055, 1020, 856, 756 cm−1; 1H NMR (600 MHz, CD3CN) δ 8.17 (s, 1 H), 6.04 (s, 1 H), 4.93 (s, 1 H), 4.31 (ddd, J = 7.8, 3.1, 0.9 Hz, 2 H), 3.88 (t, J = 6.1 Hz, 2 H), 3.22 (t, J = 5.7 Hz, 1 H), 1.42 (br s, 9 H), 1.33 (t, J = 6.1 Hz, 3 H); 13C NMR (150 MHz, CD3CN) δ 173.9, 162.0, 156.4, 147.8, 129.0, 80.4, 64.5, 62.0, 56.0, 28.5, 14.5 (3 C); HRMS (ESI-TOF) calcd for C13H20N2O5SNa+ [M + Na+] 339.0985, found 339.0985.

4.7.2. Methyl 4-bromo-3-[({(2S)-2-[(tert-butoxycarbonyl)amino]-2-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]ethyl}oxy)methyl]-1-hydroxy-1H-indole-2-carboxylate (2)

Primary alcohol 81 (16.9 mg, 0.05 mmol) was dissolved in DME (350 μL) and to this solution was added 4 Å molecular sieves (20 wt%), pTsOH (7.6 mg, 0.04 mmol) and tertiary alcohol 9 (4.0 mg, 0.013 mmol) at 25 °C. After stirring for 10 min, the reaction mixture was heated to 40 °C for 2 h after which the crude reaction mixture was allowed to cool to room temperature and purified directly by PTLC (silica gel, EtOAc:hexanes, 7:3) to afford model system 2 (3.5 mg, 44%) as a yellow oil; Rf = 0.43 (silica gel, EtOAc:hexanes, 7:3); [α]D32 = −3.0 (CHCl3, c = 0.50); IR (film) νmax 3354, 2978, 2919, 1707, 1490, 1460, 1437, 1390, 1360, 1255, 1231, 1161, 1119, 1090, 1025, 879, 773, 743 cm1; 1H NMR (600 MHz, CD3CN, 66 °C) δ 9.22 (s, 1 H), 8.06 (s, 1 H), 7.50 (d, J = 7.7 Hz, 1 H), 7.36 (d, J = 7.7 Hz, 1 H), 7.22 (t, J = 7.7 Hz, 1 H), 5.81 (br s, 1 H), 5.17 (½ABq, J = 11.4 Hz, 1 H), 5.14 (½ABq, J = 11.4 Hz, 1 H), 5.04 (dt, J = 7.4, 4.8 Hz, 1 H), 4.33 (q, J = 7.0 Hz, 2 H), 3.97 (s, 3 H), 3.96 (dd, J = 10.0, 4.8 Hz, 1 H), 3.93 (dd, J = 10.0, 4.8 Hz, 1 H), 1.39 (s, 9 H), 1.35 (t, J = 7.0 Hz, 3 H); 13C NMR (150 MHz, CD3CN) δ 174.0, 162.2, 162.0, 156.2, 147.7, 137.2, 128.9, 127.2, 127.0, 126.9, 120.9, 115.9, 115.2, 110.2, 80.4, 71.2, 62.1, 61.9, 54.2, 53.1, 28.4 (3 C), 14.5; HRMS (ESI-TOF) calcd for C24H28BrN3O8SNa+ [M + Na+] 620.0673, found 620.0674.

4.7.3. tert-Butyl (4S)-4-[4-(methoxymethyl)-1,3-thiazol-2-yl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (82)

Thiazole ethyl ester 80 (530 mg, 1.49 mmol) was dissolved in toluene (6.0 mL) and cooled to 0 °C. DIBAL-H (2.0 mL, 3.0 mmol, 1.5 M in toluene) was then added dropwise and the reaction mixture stirred for 2.5 h after which the reaction was slowly quenched at 0 °C with MeOH (2 mL) and the resulting mixture was warmed to 25 °C and stirred for 12 h with saturated aqueous sodium potassium tartrate solution (5 mL). The mixture was extracted with EtOAc (3 × 20 mL) and the combined organic layers were dried over Na2SO4 and the resulting solution was concentrated. The residue was taken up in THF (6.0 mL) and cooled to 0 °C and to this solution was added NaH (150 mg, 3.7 mmol, 60% dispersion in mineral oil) and MeI (649 μL, 10.43 mmol). The reaction mixture was allowed to warm to room temperature over 12 h at which time the reaction mixture was poured over ice water (10 mL), extracted with EtOAc (20 mL), washed with brine (10 mL) and dried (Na2SO4). The solution was then concentrated and the residue was subjected to flash column chromatography (silica gel, EtOAc:hexanes, 60:40 → 80:20) to afford methyl ether 82 (360 mg, 74% over two steps) as a yellow oil; Rf = 0.52 (silica gel, EtOAc:hexanes, 7:3); [α]D33 = −24.1 (CHCl3, c = 0.60); IR (film) νmax 3383 (br), 2971, 1874, 1698, 1455, 1371, 1255, 11164, 1092, 1049 cm−1; 1H NMR (500 MHz, CD3CN, 66 °C) δ 7.22 (s, 1 H), 5.19 (dd, J = 6.2, 1.9 Hz, 1 H), 4.47 (d, J = 0.7 Hz, 2 H), 4.29 (dd, J = 9.2, 6.2 Hz, 1 H), 4.07 (dd, J = 9.2, 1.9 Hz, 1 H), 3.37 (s, 3 H), 1.69 (s, 3 H), 1.52 (s, 3 H), 1.38 (br s, 9 H); 13C NMR (150 MHz, CD3CN, 66 °C) δ 174.6, 155.2, 147.8, 117.2, 95.3, 81.2, 71.2 (2 C), 70.1, 60.7, 58.8 (2 C), 28.9 (3 C); HRMS (ESI-TOF) calcd for C15H25N2O4S+ [M + H+] 329.1529, found 329.1518.

4.7.4. (1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-[4-(methoxymethyl)-1,3-thiazol-2-yl]ethanamine (84)

Methyl ether 82 (50 mg, 0.152 mmol) was dissolved in CH2Cl2 (761 μL) and cooled to 0 °C. TFA (761 μL) was then added dropwise and the reaction mixture stirred for 10 min at 0 °C and then 1 h at 25 °C at which time the reaction was diluted with toluene (2 mL) and concentrated (3×). After drying under high vacuum for 30 min, the crude amino alcohol was dissolved in CH2Cl2 (317 μL) and cooled to 0 °C. Et3N (70 μL, 0.50 mmol), and TBSCl (50 mg, 0.33 mmol) were then added and the reaction mixture was warmed to 25 °C. After 3 h, the mixture was washed with saturated aqueous NaHCO3 solution (1 mL), brine (1 mL) and then dried over Na2SO4. The resulting solution was concentrated and the residue was subjected to flash column chromatography (silica gel, EtOAc:hexanes, 80:20 → 100:0) to afford primary amine 84 (39.0 mg, 85% over two steps) as a yellow oil; Rf = 0.57 (silica gel, MeOH:CH2Cl2, 5:95); [α]D31 = − 7.6 (CH2Cl2, c = 1.23); IR (film) νmax 3378 (br), 2931, 2848, 1461, 1255, 1091, 838, 764, 602 cm−1; 1H NMR (600 MHz, CD3CN) δ 7.19 (s, 1 H), 4.44 (s, 2 H), 4.19 (dd, J = 6.1, 4.3 Hz, 1 H), 3.88 (dd, J = 9.9, 4.3 Hz, 1 H), 3.78 (dd, J = 9.9, 6.1 Hz, 1 H), 3.33 (s, 3 H), 0.85 (s, 9 H), 0.03 (s, 3 H), 0.01 (s, 3 H); 13C NMR (150 MHz, CD3CN) δ 177.1, 154.9, 117.5, 71.2, 69.1, 58.8, 56.9, 26.3 (3 C), 19.0, −4.87, −4.94; HRMS (ESI-TOF) calcd for C13H27N2O2SSi+ [M + H+] 303.1484, found 303.1487.

4.7.5. tert-butyl (4S)-4-{4-[({(1S)-2-hydroxy-1-[4-(methoxymethyl)-1,3-thiazol-2-yl]ethyl}amino)carbonyl]-1,3-thiazol-2-yl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (85)

Amine 84 (846 mg, 2.80 mmol) was dissolved in DMF (7 mL), cooled to 0 °C and then iPr2NEt (974 μL, 5.59 mmol) was added followed by cannula addition of thiazole acid 83 (918 mg, 2.80 mmol) dissolved in DMF (7 mL). HATU (1.17 g, 3.08 mmol) and HOAt (419 mg, 3.08 mmol) were then added and the reaction mixture stirred for 1 h at 0 °C and 2 h at 25 °C after which EtOAc (25 mL) was added and the reaction mixture was washed with aqueous 5% HCl solution (10 mL), H2O (10 mL), saturated aqueous NaHCO3 solution (10 mL), brine (10 mL) and dried over Na2SO4. The resulting solution was concentrated and the residue was taken up in THF (75 mL) and cooled to 0 °C. TBAF (3.36 mL, 1.0 M in THF) was added dropwise and after 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl solution (20 mL), extracted with EtOAc (2 × 25 mL), washed with brine (20 mL) and dried over Na2SO4. The resulting solution was concentrated and the residue was subjected to flash column chromatography (silica gel, EtOAc:hexanes, 20:80 → 90:10) affording complex alcohol 85 (1.21 g, 87% over two steps) as a light yellow foam; Rf = 0.42 (silica gel, MeOH:CH2Cl2, 5:95); [α]D32 = −10.9 (CH2Cl2, c = 0.80); IR (film) νmax 3389 (br), 2966, 2731, 2872, 1696, 1467, 1531, 1472, 1373, 1249, 1167, 1091, 1049, 761 cm−1; 1H NMR (500 MHz, CD3CN, 66 °C) δ 8.13 (d, J = 5.5 Hz, 1 H), 8.07 (d, J = 1.0 Hz, 1 H), 7.26 (d, J = 1.0 Hz, 1 H), 5.41–5.37 (m, 1 H), 5.24 (d, J = 6.6 Hz, 1 H), 4.51 (s, 2 H), 4.34–4.31 (m, 1 H), 4.16–4.13 (m, 1 H), 4.10–4.04 (m, 2 H), 3.97 (dd, J = 11.4, 4.8 Hz, 1 H), 3.39 (s, 3 H), 1.72 (s, 3 H), 1.57 (s, 3 H), 1.39 (br s, 9 H); 13C NMR (150 MHz, CD3CN, 66 °C) δ 175.9, 171.9, 162.3, 155.9, 155.8, 151.0, 125.6, 118.3, 71.6, 70.3, 65.8, 65.7, 61.1, 61.0, 59.4, 55.0 (2 C), 29.3 (3 C); HRMS (ESI-TOF) calcd for C21H31N4O6S2+ [M + H+] 499.1679, found 499.1670.

4.7.6. (2S)-2-{[(2-{(1S)-1-[(tert-Butoxycarbonyl)amino]-2-hydroxyethyl}-1,3-thiazol-4-yl)carbonyl]amino}-2-[4-(methoxymethyl)-1,3-thiazol-2-yl]EtOAc (86)

A solution of complex alcohol 85 (95 mg, 0.19 mmol) in CH2Cl2 (1.0 mL) was cooled to 0 °C and Et3N (80 μL, 0.57 mmol) and 4-DMAP (2.3 mg, 0.02 mmol) were added followed by Ac2O (90 μL, 0.95 mmol). After 10 min at 0 °C, the reaction mixture was diluted with CH2Cl2 (3 mL) and washed with aqueous 5% HCl solution (3 mL), saturated aqueous NaHCO3 solution (3 mL), brine (3 mL) and dried over Na2SO4. The resulting solution was concentrated and the residue was taken up in CH2Cl2 (1.26 mL) and MeOH (630 μL) and cooled to 0 °C. TFA (1.88 mL) was then added dropwise and after 30 min the reaction mixture was diluted with toluene (5 mL) and concentrated (3×). The residue was subjected to flash column chromatography (silica gel, EtOAc:hexanes, 1:1 → 100:0) affording hydroxy acetate 86 (78 mg, 82% over two steps) as a yellow oil; Rf = 0.17 (silica gel, EtOAc:hexanes, 8:2); [α]D31 = −6.8 (CHCl3, c = 0.50); IR (film) νmax 3309 (br), 2930, 1712, 1661, 1533, 1460, 1382, 1248, 1165, 1059, 797, 679, 590 cm−1; 1H NMR (600 MHz, CD3CN, 66 °C) δ 8.16 (d, J = 4.8 Hz, 1 H), 8.10 (s, 1 H), 7.30 (s, 1 H), 5.41–5.37 (m, 1 H), 5.92 (br s, 1 H), 5.62–5.64 (m, 1 H), 4.99–4.96 (m, 1 H), 4.62 (ddd, J = 11.8, 4.8, 1.3 Hz, 1 H), 4.57 (ddd, J = 11.8, 6.5, 0.8 Hz, 1 H), 4.51 (s, 2 H), 3.97–3.95 (m, 2 H), 3.39 (s, 3 H), 2.00 (s, 3 H), 1.45 (s, 9 H); 13C NMR (150 MHz, CD3CN) δ 173.7, 171.4, 169.4, 161.6, 156.4, 154.8, 149.8, 125.4, 118.1, 80.3, 70.5, 65.5, 64.4, 58.4, 55.9, 51.3, 28.4 (3 C), 20.8; HRMS (ESI-TOF) calcd for C20H29N4O7S2+ [M + H+] 501.1472, found 501.1459.

4.7.7. Methyl 3-[({(2S)-2-{4-[({(1S)-2-(acetyloxy)-1-[4-(methoxymethyl)-1,3-thiazol-2-yl]ethyl}amino)carbonyl]-1,3-thiazol-2-yl}-2-[(tert-butoxycarbonyl)amino]ethyl}oxy)-methyl]-4-bromo-1-hydroxy-1H-indole-2-carboxylate (87)

Method A: To a stirred solution of pTsOH (13.3 mg, 0.07 mmol), and 4 Å molecular sieves (20 wt%) in DME (470 μL) was added hydroxy acetate 86 (23 mg, 0.046 mmol) and tertiary alcohol 9 (7 mg, 0.023 mmol) at 25 °C. After 10 min, the reaction mixture was warmed to 40 °C, stirred for 3 h, allowed to cool to room temperature and purified directly by PTLC (silica gel, EtOAc:hexanes, 80:20) to afford N-hydroxyindole 87 (10 mg, 56%) as a yellow oil; Method B: To a stirred solution of SnCl2·2H2O (10.4 mg, 0.046 mmol) and 4 Å molecular sieves (20 wt%) in DME (110 μL) was added hydroxy acetate 86 (41 mg, 0.082 mmol) in DME (100 μL) and ketoester 6a (6.6 mg, 0.021 mmol) at 25 °C. The reaction mixture was warmed immediately to 40 °C and stirring was continued for 6 h in the absence of light at which time the reaction mixture was allowed to cool to room temperature and purified directly by PTLC (silica gel, MeOH:Et2O, 2:98) to afford N-hydroxyindole 87 (6.6 mg, 40%) as a yellow oil; Rf = 0.26 (silica gel, EtOAc:hexanes, 7:3); [α]D31 = +1.7 (CH2Cl2, c = 0.20); IR (film) νmax 3331 (br), 2919, 2849, 1725, 1708, 1400, 1531, 1449, 1431, 1378, 1249, 1061, 761 cm−1; 1H NMR (600 MHz, CD3CN, 66 °C) δ 9.30 (br s, 1 H), 8.09–8.05 (m, 1 H), 7.97 (d, J = 9.6 Hz, 1 H), 7.48 (d, J = 8.3 Hz, 1 H), 7.34 (d, J = 7.8 Hz, 1 H), 7.31 (d, J = 6.1 Hz, 1 H), 7.20 (t, J = 7.7 Hz, 1 H), 5.84 (br s, 1 H), 5.66–5.63 (m, 1 H), 5.19–5.14 (m, 2 H), 5.07–5.03 (m, 1 H), 4.61–4.55 (m, 2 H), 4.52 (s, 2 H), 4.01 (dd, J = 10.1, 5.2 Hz, 1 H), 3.97–3.94 (m, 4 H), 3.39 (s, 3 H), 1.99 (s, 3 H), 1.40 (s, 9 H); 13C NMR (150 MHz, CD3CN) δ 173.8, 171.4, 169.3, 162.0 (2 C), 161.5, 156.2, 154.8, 149.7, 137.3, 127.0, 126.8, 126.2, 125.2, 120.7, 115.8, 115.1, 110.1, 80.4, 71.3, 70.4, 65.5, 64.7, 58.4, 54.1 52.9, 51.3, 28.4 (3 C), 20.8; HRMS (ESI-TOF) calcd for C31H36BrN5O10S2Na+ [M + Na+] 804.0979, found 804.0979.

4.7.8. tert-Butyl (4S,11S)-15-bromo-4-[4-(methoxymethyl)-1,3-thiazol-2-yl]-1,6-dioxo-19-{[2-(trimethylsilyl)ethoxy]methoxy}-3,4,5,6,11,12,14,19-octahydro-1H-7,10-epiazeno[1,12,8,4]dioxathiazacyclohexadecino[15,14-b]indol-11-ylcarbamate (3a)

N-hydroxyindole 87 (34 mg, 0.043 mmol) was dissolved in DMF (1.5 mL) and cooled to 0 °C at which time iPr2NEt (23 μL, 0.130 mmol), SEMCl (15 μL, 0.087 mmol) and nBu4NI (1.6 mg, 0.004 mmol) were added and the reaction mixture was warmed to 25 °C. After 10 min, the reaction mixture was diluted with EtOAc (5 mL), washed with aqueous 5% HCl solution (3 mL) and dried over Na2SO4. The resulting solution was concentrated and the residue was taken up in THF (2.58 mL), MeOH (860 μL) and H2O (860 μL) and then cooled to 0 °C. LiOH (3 mg, 0.129 mmol) was added and, after warming to 25 °C over 4 h, the reaction mixture was diluted with EtOAc (5 mL), cooled to 0 °C, quenched with aqueous 5% HCl solution, separated, and the organic layer dried with Na2SO4. After azeotroping with toluene (3 × 5 mL), the residue was dissolved in toluene (4.3 mL) and Et3N (240 μL, 1.72 mmol) and 2,4,6-trichlorobenzoyl chloride (202 μL, 1.29 mmol) were added. After stirring for 12 h at 25 °C, the reaction mixture was added dropwise over the course of 12 h (syringe pump) to a solution of 4-DMAP (158 mg, 1.29 mmol) in toluene (80 mL). After addition was complete, the resulting mixture was stirred at 25 °C for a further 12 h, then cooled to 0 °C and acidified to pH ~ 3 with an aqueous 10 mg/mL solution of KHSO4. The layers were separated and the aqueous layer was re-extracted with EtOAc (2 × 40 mL). The combined organic layers were then washed with a 1:1 solution of saturated aqueous NaHCO3:brine (40 mL) and the aqueous layer was re-extracted with EtOAc (2 × 40 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by PTLC (silica gel, EtOAc:hexanes, 60:40) to give macrocycle 3a (14 mg, 38% over three steps) as a yellow oil; Rf = 0.37 (silica gel, EtOAc:hexanes, 8:2); [α]D33 = −12.3 (CH2Cl2, c = 0.72); IR (film) νmax 3353 (br), 2924, 2854, 2086, 1712, 1536, 1494, 1366, 1214, 1170, 1105, 859, 836, 777 cm−1; 1H NMR (600 MHz, CD3CN) δ 8.44 (d, J = 7.5 Hz, 1 H), 8.04 (s, 1 H), 7.51 (dd, J = 8.3, 0.9 Hz, 1 H), 7.41 (dd, J = 7.4, 0.9 Hz, 1 H), 7.30 (s, 1 H), 7.24 (t, J = 7.9 Hz, 1 H), 6.00 (d, J = 7.9 Hz, 1 H), 5.66–5.62 (m, 1 H), 5.34 (d, J = 3.9 Hz, 1 H), 5.21 (d, J = 10.1 Hz, 1 H), 5.18 (dd, J = 11.4, 3.9 Hz, 1 H), 5.14–5.12 (m, 2 H), 5.08 (d, J = 7.5 Hz, 1 H), 5.04 (dd, J = 11.4, 5.7 Hz, 1 H), 4.48 (s, 2 H), 4.17–4.14 (m, 1 H), 3.94 (dd, J = 9.6, 2.6 Hz, 1 H), 3.80–3.70 (m, 2 H), 3.36 (s, 3 H), 1.40 (br s, 9 H), 0.86 (t, J = 7.0 Hz, 2 H), −0.02 (s, 9 H); 13C NMR (150 MHz, CD3CN) δ 170.9, 170.1, 163.0, 162.0, 161.7, 155.3, 149.4, 138.1, 128.0, 127.8, 127.5, 126.7, 122.1, 119.2, 116.3, 113.2, 111.5, 103.3, 72.2, 70.8, 69.6, 65.6, 65.2, 62.7, 58.8, 52.7, 52.6, 28.6 (3 C), 18.9, −1.3 (3 C); HRMS (ESI-TOF) calcd for C34H45BrN5O9S2Si+ [M + H+] 838.1606, found 838.1604.

4.7.9. tert-butyl (4S,11S)-15-bromo-19-(methoxymethoxy)-4-[4-(methoxymethyl)-1,3-thiazol-2-yl]-1,6-dioxo-3,4,5,6,11,12,14,19-octahydro-1H-7,10-epiazeno[1,12,8,4]dioxathiazacyclohexadecino[15,14-b]indol-11-ylcarbamate (3b)

N-hydroxyindole 87 (30 mg, 0.038 mmol) was dissolved in DMF (1.9 mL) and cooled to 0 °C at which time iPr2NEt (20 μL, 0.114 mmol), MOMCl (6 μL, 0.076 mmol) and nBu4NI (1.4 mg, 0.004 mmol) were added and the reaction mixture was warmed to 25 °C. After 10 min, the reaction mixture was diluted with EtOAc (5 mL), washed with aqueous 5% HCl solution (3 mL) and dried over Na2SO4. The resulting solution was concentrated and the residue was taken up in THF (2.28 mL), MeOH (760 μL) and H2O (760 μL) and then cooled to 0 °C. LiOH (2.7 mg, 0.114 mmol) was added and after warming to 25 °C over 4 h, the reaction mixture was diluted with EtOAc (5 mL), cooled to 0 °C, quenched with aqueous 5% HCl solution, separated, and the organic layer dried with Na2SO4. After azeotroping with toluene (3 × 5 mL), the residue was dissolved in toluene (4.0 mL) and Et3N (212 μL, 1.52 mmol) and 2,4,6-trichlorobenzoyl chloride (178 μL, 1.14 mmol) were added. After stirring for 12 h at 25 °C, the reaction mixture was added dropwise over the course of 12 h (syringe pump) to a solution of 4-DMAP (139 mg, 1.14 mmol) in toluene (71 mL). After addition was complete, the resulting mixture was stirred at 25 °C for a further 12 h, then cooled to 0 °C and acidified to pH ~ 3 with an aqueous 10 mg/mL solution of KHSO4. The layers were separated and the aqueous layer was re-extracted with EtOAc (2 × 40 mL). The combined organic layers were then washed with a 1:1 solution of saturated aqueous NaHCO3:brine (40 mL) and the aqueous layer was re-extracted with EtOAc (2 × 40 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by PTLC (silica gel, EtOAc:hexanes, 80:20) to give macrocycle 3b (12.7 mg, 44% over three steps) as a yellow oil; Rf = 0.36 (silica gel, EtOAc:hexanes, 8:2); [α]D32 = −10.5 (CH2Cl2, c = 0.68); IR (film) νmax 3330 (br), 2919, 2849, 1725, 1713, 1608, 1531, 1449, 1384, 1260, 1067, 803 cm−1; 1H NMR (600 MHz, CD3CN) δ 8.45 (d, J = 7.9 Hz, 1 H), 8.04 (s, 1 H), 7.52 (dd, J = 8.3, 0.9 Hz, 1 H), 7.42 (dd, J = 7.5, 0.9 Hz, 1 H), 7.30 (s, 1 H), 7.26 (dd, J = 8.3, 7.5 Hz, 1 H), 6.00 (d, J = 8.3 Hz, 1 H), 5.66–5.62 (m, 1 H), 5.36–5.33 (m, 1 H), 5.22–5.18 (m, 2 H), 5.13 (d, J = 10.1 Hz, 1 H), 5.09 (d, J = 7.5 Hz, 1 H), 5.05 (d, J = 7.5 Hz, 1 H), 5.02 (dd, J = 11.4, 5.2 Hz, 1 H), 4.48 (s, 2 H), 4.18–4.14 (m, 1 H), 3.95 (dd, J = 10.1, 3.1 Hz, 1 H), 3.52 (s, 3 H), 3.36 (s, 3 H), 1.40 (br s, 9 H); 13C NMR (150 MHz, CD3CN, 66 °C) δ 171.0, 170.1, 163.0, 162.0, 161.7, 155.3, 149.4, 138.2, 128.2, 127.9, 127.7, 126.8, 122.2, 119.3, 116.3, 113.2, 111.5, 105.3, 80.7, 72.2, 70.8, 65.2, 62.8, 59.0, 58.8, 52.7, 52.6, 28.7 (3 C); HRMS (ESI-TOF) calcd for C30H34BrN5O9S2Na+ [M + Na+] 774.0873, found 774.0869.

4.7.10. tert-Butyl (4S)-4-{4-[({(1S)-2-{[3-(2-bromo-6-nitrophenyl)-2-oxobut-3-enoyl]oxy}-1-[4-(methoxymethyl)-1,3-thiazol-2-yl]ethyl}amino)carbonyl]-1,3-thiazol-2-yl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (88)

Complex alcohol 85 (10 mg, 0.02 mmol) was dissolved in THF (80 μL), cooled to 0 °C, and oxalyl chloride (3.5 μL, 0.04 mmol) was added followed by DMF (1 drop). After 45 min at 0 °C, Et3N (11 μL, 0.08 mmol) and acid 7a (18 mg, 0.06 mmol) in THF (80 μL) were added and the reaction mixture was allowed to warm to 25 °C over 2 h. THF was concentrated in vacuo and the residue was dissolved in CH2Cl2 (5 mL), washed with ice H2O (5 mL) and dried (Na2SO4). The resulting solution was concentrated and the residue was purified by PTLC (silica gel, EtOAc:hexanes, 80:20) to afford α-ketoester 88 (12 mg, 77%) as a yellow oil; Rf = 0.71 (silica gel, EtOAc:hexanes, 8:2); [α]D32 = −3.5 (CHCl3, c = 0.34); IR (film) νmax 3377 (br), 3119, 2978, 2919, 1754, 1689, 1666, 1531, 1443, 1372, 1255, 1149, 1091, 1049, 961, 908, 808, 755 cm−1; 1H NMR (600 MHz, CD3CN, 70 °C) δ 8.17 (d, J = 8.8 Hz, 1 H), 8.10 (d, J = 1.7 Hz, 1 H), 8.00 (dd, J = 8.3, 1.3 Hz, 1 H), 7.97 (dd, J = 7.8, 0.8 Hz, 1 H), 7.50 (t, J = 8.3 Hz, 1 H), 7.32 (d, J = 0.9 Hz, 1 H), 6.61 (s, 1 H), 6.25 (dd, J = 10.1, 0.9 Hz, 1 H), 5.84–5.80 (m, 1 H), 5.24–5.21 (m, 1 H), 4.95–4.87 (m, 2 H), 4.50 (s, 2 H), 4.32–4.29 (m, 1 H), 4.16 (dd, J = 9.1, 1.7 Hz, 1 H), 3.38 (s, 3 H), 1.69 (s, 3 H), 1.56 (s, 3 H), 1.28 (br s, 9 H); 13C NMR (150 MHz, CD3CN, 66 °C) δ 175.9, 169.2, 163.7, 162.2, 156.1, 150.3, 143.1, 139.1, 137.1, 133.0, 132.5, 126.9, 125.9, 125.2 (2 C), 119.0, 96.4, 81.5, 71.3 (2 C), 68.1, 60.60, 60.59, 59.2, 51.8 (2 C), 29.1 (3 C); HRMS (ESI-TOF) calcd for C31H35BrN5O10S2+ [M + H+] 780.1003, found 780.1001.

4.7.11. (2S)-2-{[(2-{(1S)-1-[(tert-Butoxycarbonyl)amino]-2-hydroxyethyl}-1,3-thiazol-4-yl)carbonyl]amino}-2-[4-(methoxymethyl)-1,3-thiazol-2-yl]ethyl 3-(2-bromo-6-nitrophenyl)-2-oxobut-3-enoate (89)

α-ketoester 88 (10 mg, 0.013 mmol) was dissolved in CH2Cl2 (330 μL) and MeOH (170 μL) and cooled to 0 °C. TFA (500 μL) was added dropwise and, after stirring for 1 h at 0 °C, the reaction mixture was diluted with toluene (3 mL) and concentrated (2×). The residue was purified by PTLC (silica gel, EtOAc:hexanes, 80:20) to afford N-Boc amino alcohol 89 (6.8 mg, 72%) as a yellow oil; Rf = 0.29 (silica gel, EtOAc:hexanes, 8:2); [α]D33 = −0.4 (CH2Cl2, c = 0.78); IR (film) νmax 3383 (br), 3109, 2971, 2923, 2850, 1746, 1698, 1686, 1649, 1528, 1346, 1243, 1158, 1031, 740, 595 cm−1; 1H NMR (600 MHz, CD3CN) δ 8.19 (d, J = 7.0 Hz, 1 H), 8.09 (s, 1 H), 8.01–7.98 (m, 1 H), 7.98–7.96 (m, 1 H), 7.52–7.48 (m, 1 H), 7.32 (s, 1 H), 6.62 (dd, J = 2.2, 0.9 Hz, 1 H), 6.25 (dd, J = 6.1, 1.3 Hz, 1 H), 5.87–5.80 (m, 2 H), 4.98–4.90 (m, 3 H), 4.51 (s, 2 H), 4.95–4.85 (m, 2 H), 3.39 (s, 3 H), 1.43 (br s, 9 H); 13C NMR (150 MHz, CD3CN) δ 185.3, 174.0, 171.8, 168.9, 163.4, 161.9, 155.5, 151.2, 150.1, 142.6, 138.8, 136.9, 132.5, 132.1, 126.5, 125.8, 124.9, 120.5, 118.6, 80.8, 70.9, 67.6, 64.8, 58.8, 51.3, 28.8 (3 C); HRMS (ESI-TOF) calcd for C28H31BrN5O10S2+ [M + H+] 740.0690, found 740.0687.

4.7.12. tert-butyl (4S,11S)-15-bromo-19-hydroxy-4-[4-(methoxymethyl)-1,3-thiazol-2-yl]-1,6-dioxo-3,4,5,6,11,12,14,19-octahydro-1H-7,10-epiazeno[1,12,8,4]dioxathiaza-cyclohexadecino[15,14-b]indol-11-ylcarbamate (3c)

Method A: A stirred suspension of Zn dust (5.0 mg, 0.078 mmol) and dibromoethane (0.46 μL, 0.005 mmol) in THF (79 μL) was heated to reflux (70 °C) for approximately 5 min and then allowed to cool to 25 °C. The refluxing/cooling process was repeated three times. TMSCl (0.41 μL, 0.003 mmol) was then added and the resulting grey suspension was stirred at 25 °C for 10 min. A separate stirred solution containing a mixture of aqueous 1 N NH4Cl (36 μL, 0.036 mmol) and N-Boc amino alcohol 89 (12 mg, 0.016 mmol) in THF (153 μL) was added via cannula to the activated Zn suspension and stirring was continued for 15 min at 25 °C. The crude reaction mixture was diluted with EtOAc (5 mL) and washed with saturated aqueous NaHCO3 solution (1 mL) filtered through celite and dried (Na2SO4). The resulting solution was concentrated and the residue was dissolved in DME (16 mL). 4 Å Molecular sieves (20 wt%), and pTsOH (9 mg, 0.048 mmol) were added and, after 10 min at 25 °C and 12 h at 40 °C, the reaction mixture was cooled to room temperature and purified by PTLC (silica gel, MeOH:Et2O, 5:95) to give N-hydroxyindole macrocycle 3c (4.6 mg, 40%) as a yellow oil; Method B: To a stirred solution of SnCl2·2H2O (5.2 mg, 0.022 mmol) and 4 Å molecular sieves (20 wt%) in DME (50 μL) was added N-Boc amino alcohol 89 (5.3 mg, 0.007 mmol) in DME (50 μL) at 25 °C. The reaction mixture was warmed immediately to 45 °C and stirring was continued for 3 h in the absence of light at which time the reaction mixture was allowed to cool to room temperature and purified directly by PTLC (silica gel, MeOH:Et2O, 7:93) to afford N-hydroxyindole macrocycle 3c (0.51 mg, 10%) as a yellow oil; 3c (+ 3c′) [ca 1:1 mixture of N-Boc rotamers (1H NMR)] Rf = 0.63 (silica gel, MeOH:Et2O, 5:95); [α]D33 = +1.0 (CH2Cl2, c = 0.23); IR (film) νmax 3346, 2924, 2850, 1709, 1668, 1534, 1494, 1458, 1365, 1251, 1223, 1185, 1163, 1122, 1100, 778, 743 cm−1; 1H NMR (600 MHz, CD3CN, 67 °C) δ 9.05 (s, 1 H), 8.97 (s, 1 H), 8.47 (d, J = 8.3 Hz, 1 H), 8.47 (d, J = 6.1 Hz, 1 H), 8.01 (s, 1 H), 7.97 (s, 1 H), 7.48 (dd, J = 8.3, 2.6 Hz, 1+1 H), 7.39 (dd, J = 7.8, 2.1 Hz, 1+1 H), 7.34 (s, 1 H), 7.32 (s, 1 H), 7.23 (dd, J = 8.3, 7.8 Hz, 1+1 H), 5.85 (br s, 1+1 H), 5.68–5.63 (m, 1+1 H), 5.43 (d, J = 10.5 Hz, 1 H), 5.37–5.35 (m, 1+1 H), 5.33–5.31 (m, 1+1 H), 5.26 (d, J = 10.1 Hz, 1 H), 5.23 (d, J = 10.1 Hz, 1 H), 5.18–5.14 (m, 1 H), 5.08–5.04 (m, 1 H), 5.01 (dd, J = 11.8, 4.3 Hz, 1 H), 5.01 (dd, J = 11.8, 4.9 Hz, 1 H), 4.54 (d, J = 0.8 Hz, 2 H), 4.53 (d, J = 0.8 Hz, 2 H), 4.37 (dd, J = 10.1, 3.5 Hz, 1 H), 4.37 (dd, J = 10.1, 3.5 Hz, 1 H), 4.02 (dd, J = 9.6, 3.0 Hz, 1 H), 3.41 (s, 3 H), 3.40 (s, 3 H), 1.46 (s, 9 H), 1.44 (s, 9 H); 13C NMR (150 MHz, CD3CN) δ = 169.6, 167.6, 162.4, 162.3, 156.3, 149.1, 137.7, 130.9, 127.8, 127.7, 127.2, 125.9, 121.4, 121.3, 116.2, 111.7, 110.6, 70.7, 64.4, 62.6, 62.0, 48.7, 53.1, 52.8, 52.6, 28.6 (3 C); HRMS (ESI-TOF) calcd for C28H31BrN5O8S2+ [M + H+] 708.0792, found 708.0786.

Acknowledgments

We thank Drs. D. H. Huang, G. Siuzdak, and R. Chadha for NMR spectroscopic, mass spectrometric, and X-ray crystallographic assistance, respectively. Financial support for this work was provided by grants from the National Institutes of Health (U.S.A.), the National Science Foundation, and the Skaggs Institute for Chemical Biology, and predoctoral fellowship support from the American Chemical Society (2006–2007, to A.A.E., sponsored by Boehringer-Ingelheim).

Footnotes

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References and notes

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