Diversity Oriented Synthesis of Macrocyclic Diaryl

FULL PAPER DOI: 10.1002/ajoc.201300125

Diversity Oriented Synthesis of Macrocyclic Diaryl Ethers by Dçtz Benzannulation Subhabrata Sen,*[a] Rajanikanth Mamidala,[b] Rambabu Gundla,[b] and M. T. Charya[c] Dedicated to Dr. Kent S. Gates Abstract: The intramolecular Dçtz benzannulation with alkyne-tethered aryloxy Fischer carbenes has been applied to synthesize a nine membered diaryl ether linked macrocyclic library. In silico tools, that is, shape space analysis was used to assess the diversity of the library, and polar surface area (PSA) of the compounds were deduced to understand the range of their surface electrostatic potential.

Introduction

Keywords: build/couple/pair · diversity oriented synthesis · Dçtz benzannulation · Fischer carbenes · principal moment of inertia

Diversity oriented synthesis (DOS) is an elegant approach of preparing structurally diverse scaffolds with distinct physicochemical properties.[6] Since its first inception in 1999 by Schreiber, this strategy has been used to generate several structurally diverse libraries in the most efficient manner possible.[7] Ideally, the DOS-generated libraries have a high degree of structural and functional diversity that charters large areas of chemical space. However there are very few examples of DOS-mediated macrocyclic library synthesis.[8, 11] Our efforts are inspired by diaryl ether macrocyclic natural products,[9] and offer facile, diversity oriented synthesis of a library of diaryl ether macrocycles by intramolecular Dçtz Benzannulation of aryloxy Fisher carbenes tethered with long chain alkynes.[11] Diaryl ether linkages are expected to confer rigidity upon the structure.[10] It is also well-illustrated in medicinal chemistry that increasing the rigidity of the compound can increase its binding affinity for a target. Additionally extra rigidity in a molecular architecture generates additional shape diversity by affecting its overall 3D structure.[12]

Macrocyclic systems have evolved in the course of time to address various biochemical functions.[1] They tend to offer appropriate solutions to modulate challenging biological problems that arise from protein–protein interactions.[2] Their constrained conformation along with lower bond count improves their pharmacokinetics, as well as their pharmacological and physicochemical properties over their acyclic counterparts.[3] Hence these attributes make them an ideal candidate to bridge the gap in the chemical space between small molecules and biologics. Despite a number of drugs based on macrocyclic natural products, the number of macrocycles in commercial library databases is extremely low.[4] To a large extent this can be rationalized by paucity of efficient synthetic protocols.[5] Generally high dilution conditions (submillimolar) is the most effective strategy for macrocyclization, but this is not a viable approach in the field of drug discovery with respect to cost and capacity. Our aim has been to devise macrocyclization strategies under normal dilution reaction conditions that will overcome these challenges and, hence, will be accepted into drug discovery.

Results and Discussion We aimed to synthesize novel macrocycles based upon structures type A and B (Scheme 1). Both of them have diaryl ether linkages that provide rigidity to the system. Inspired by polycyclic ethers as natural products, ether linkag-

[a] S. Sen Department of Chemistry, Shiv Nadar University Chithera, Dadri, Greater Noida, Uttar Pradesh (India) E-mail: [email protected] Homepage: http://www.snu.edu.in/naturalsciences/Subhabrata_Sen_profile.aspx [b] R. Mamidala, R. Gundla Chemistry, GVKBio 28 A IDA Nacharam, Hyderabad, AP (India) [c] M. T. Charya Chemistry, Jawaharlal Nehru Technological University Kukatpally, Hyderabad, AP (India) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ajoc.201300125.

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Scheme 1. Macrocyclic frameworks.

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2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

ÝÝ These are not the final page numbers!

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Subhabrata Sen et al.

es have been incorporated into the macrocycle.[13] Additionally, long saturated and unsaturated chains provide flexibility to orient in 3D space depending on the orientation of the biological target. The furan ring provides the opportunity to generate synthetic handles by ozonolysis for further derivatization, which will enable us to optimize any “hits” obtained from biological screening. The proof of concept investigation aimed to generating a library of nine compounds on the basis of these structures. The outline of our strategy, which is based around the build/couple/pair (B/C/P) approach by Schreiber, is shown in Scheme 2.[14] The build step involves the synthesis of

Scheme 3. Build phase: synthesis of phenols 2–6. DIAD = diisopropyl azodicarboxylate

with NaH at 0 8C. The resulting Fisher carbenes 7–11 are bright red in color and were afforded in reasonable yields (56–72 %, Scheme 4). With the Fisher carbenes 7–11 in hand, we attempted the intramolecular Dçtz Benzannulation[17] (pairing step), in THF (20 mm) to generate the diaryl ether moiety in conjunction with the construction of the macrocyclic architecture. A typical procedure involved freeze-thaw-degassing of a solution of appropriate Fischer carbenes 7–11 in THF, and subsequent thermal heating in oil bath at 50 8C to

Scheme 2. “Build/couple/pair” synthetic strategy.

a carbene salt and the corresponding phenols tethered with alkynes. Coupling of the carbene salt with several alkyne tethered sodium phenolates would generate various aryloxy Fisher carbenes. Subsequent pairing would involve intramolecular Dçtz Benzannulation in presence of tetrahydrofuran (THF) at ambient temperature to furnish macrocycles. To begin with, carbene salt 1 was prepared from chromium hexacarbonyl and 2-furyl lithium by following a literature protocol proposed by Pulley et al.[15] Phenols 2–4 were obtained from lactonization of cinnamic acid with butynol, pentynol, or hexynol, triphenylphosphine (PPh3), and diethyl azodicarboxylate in THF as solvent. The remaining necessary phenols 5 and 6 were prepared from monoalkylation of p-quinones with 5-chloropentyne and 6-chlorohexyne (Scheme 3).[16] In the coupling steps, the aryloxy Fisher carbenes were efficiently generated by acylation of 1 with freshly distilled acetyl bromide and subsequent quenching of the resulting acylate complex 1 a with suitable phenoxides of 2 a–6 a, which were generated by treating ethereal solutions of 2–6

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Scheme 4. Coupling to generate alkyne-tethered aryloxy carbenes.

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Scheme 5. Pairing towards the macrocycles.

Once we had a hand on these macrocycles, in silico algorithms were applied to evaluate the diversity generated by this set of molecules. Each molecule was plotted against 1000 Food and Drug Administration (FDA)-approved compounds from our in-house database according to the normalized principal moment of inertia (PMI) formalism of Sauer and Schwartz, to assess the shape-based distribution (Figure 1).[18] The PMI plot is a rapid and visual way to demonstrate diversity corresponding to the area of shapespace covered by a collection of molecules. A wide shapespace distribution is an important property for a collection of molecules to have, as biological activity of small molecules has been attributed to their shape-space. Thus, screening collections that have a high degree of molecular shape diversity augments the chances of a wide range of biological activity. Each molecule was aligned to principal inertial moment axes in SYBYL. 22 and the normalized PMI values were computed by using a program that was developed in house (available upon request to the authors).[19] The plot in Figure 1 illustrates a reasonable coverage of shape-space for macrocycles 12–20 (depicted as red dots) on the axis between the rods and discs. It is noteworthy that despite the common diaryl ether moiety present among the molecules, they are well spread across the roddisc axis, thereby demonstrating the diversity achieved by the Dçtz macrocyclization approach. As well as diversity in shape-space, the polar surface area (PSA) of a small molecule is a significant descriptor in terms of diverse bioactive molecules that are involved in ligand–receptor binding. As mentioned earlier, rigid scaffolds that have diverse PSAs interact differently by hydrogen bonding, electrostatic, and other key noncovalent interactions. This is further exemplified by reports of diverse biologi-

afford the desired products 12–16 in 42–68 % yield (Scheme 5). It is noteworthy that dimeric macrocycles 15 and 16 were generated rather serendipitously. We assume the chain lengths of the expected monomeric macrocycles 15 a/16 a were not long enough for intramolecular cyclization; however, macrocyclization occurred to afford the dimerized compounds 15 and 16. Along with structural diversity, we designed a second diversity element into our library in a “postpairing phase”. Subtle alterations in functional groups and shape of the scaffolds can result in substantial changes to binding affinities. Accordingly, we envisioned that it would be imperative to take some of the scaffolds assembled by the B/C/P strategy and perform functional group transformations to produce new fragments. The result of these changes would be to generate functional group diversity within the scaffold library. Thus, reduction of olefins in scaffolds 12–14 were targeted to generate 17–19 and subsequent ozonolysis of 17 afforded 20 (Scheme 6). Hence, with 20 in hand, we assume critical functional group diversity can be introduced into the macrocyclic derivatives in a simple way through variety of reactions, that is, imine formation and reduction, reduction of an aldehyde and alkylation, derivatization of a phenolic OH group and so on.

Scheme 6. Postpairing. DMSO = dimethyl sulfoxide.

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tral nervous system, a PSA of approximately 60 2 is usually needed.[20] Surface electrostatic profiles were calculated by projecting the Gasteiger–Marsili charge distribution onto a Connolly surface generated by the MOLCAD tool in SYBYL.[19]

Conclusions In this report we have demonstrated a short and efficient synthetic route to diaryl ether macrocycles by applying a Dçtz benzannulation strategy. The macrocyclic library has reasonable diversity in shape-space as deduced by PMI analysis. A range of 30 2 of PSA demonstrates a wide degree of diversity. A representative ozonolysis of the furan moiety of 17 led to functional handles which can be used for further diversification.

Figure 1. Shape space analysis by PMI plot. NPR = normalized principal moment of inertia ratios.

Experimental Section

cal activity of small molecules with varied PSAs resulting from different orientations of heteroatoms. Accordingly, PSA the distribution of macrocyles 12-20 was plotted (Figure 2). PSAs ranging from 53–83 2 further demonstrate the degree of diversity achieved from this protocol. It is noteworthy that for molecules to penetrate the blood-brain barrier and, hence, act on receptors in the cen-

General Remarks All reactions were carried out under an atmosphere of nitrogen in flame-dried glassware with a magnetic stirrer. Reactive liquids were transferred by syringe or cannula and were charged to the reaction flask through rubber septa. Chromium hexacarbonyl, palladium chloride, diisopropyl azodicarboxylate, propargyl alcohol, 3-butyl-1-ol, 4-pentyn-1ol, and 5- hexyn-1-ol were obtained from Sigma–Aldrich Chemical Company and used without purification. Compounds 5 and 6 were prepared by a standard literature protocol.[16] Furan was obtained from Spectrochem Ltd. and used without purification. 4-Hydroxybenzaldehyde was obtained from Loba Chemie and used without purification. Triphenylphosphine was obtained from Merck Co. Inc. and used without purification Tetrahydrofuran was freshly distilled prior to use from sodium and benzophenone ketyl under nitrogen and methylene chloride was freshly distilled from calcium hydride under nitrogen. Analytical thin layer chromatography was performed with Merck silica gel plates (0.25 mm thickness) with PF254 indicator. Compounds were visualized under UV lamp or by iodine treatment. Column chromatography was carried out on 60–120 mesh silica gel with technical grade solvents, which were distilled prior to use. 1 H NMR spectra were recorded on Bruker 300 UltrashieldTM at 300 MHz. 13C NMR spectra were obtained on the same instrument at 75.5 MHz in CDCl3 solution with tetramethylsilane (1H NMR spectra spectra) and [D6]DMSO or CDCl3 (13C NMR spectra) as an internal reference, unless otherwise stated. Chemical shifts (d) are re-

Figure 2. Polar surface area of 12–20.

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tane); 1H NMR (300 MHz,CDCl3): d = 7.97ACHTUNGRE(s, 1 H), 7.79 (s, 1 H), 7.73– 7.66 (m, 2 H), 7.23–7.12 (m, 2 H), 6.69–6.67 (m, 1 H), 6.53 (s, 1 H), 6.47 (s, 1 H), 4.36–4.32(t, J=6 Hz, 2 H) 2.70–2.60 (m, 2 H), 2.05–2.03 ppm (t, J = 3 Hz, 1 H); 13C NMR (300 MHz, CDCl3): d = 223.8, 215.6, 165.8, 164.7, 159.2, 150.9, 143.2, 132.6, 128.9, 122.8, 117.9, 112.9, 112.3, 79.5, 7.4, 61.8, 18.5 ppm.

ported in ppm. All 13C NMR spectra were measured with complete proton decoupling. Data are reported as follows: s = singlet, d = doublet, t = triplet, m = multiplet. Elemental analysis was recorded on a CEC440HA instrument. General Procedure for the Synthesis of 3-(4-Hydroxyphenyl) Acrylic Acid Alkynyl Ester

Carbene 8

The alkynol and triphenylphosphine were added to a solution of 3-(4-hydroxyphenyl) acrylic acid in THF at room temperature under nitrogen atmosphere. Diisopropyl azodicarboxylate was then added to this mixture dropwise at 0 8C. The reaction mixture was then stirred overnight at room temperature, and filtered through celite to give crude 3-(4-hydroxyphenyl) acrylic acid alkynyl ester upon solvent evaporation. The crude product was further purified by chromatography on a silica gel column with ethyl acetate/hexane (1:5) to give the desired 3-(4-hydroxyphenyl) acrylic acid alkynyl ester as white to off-white solid.

The reaction of tetramethylammonium salt 1 (0.25 g, 0.83 mmol), dichloromethane (7.3 mL), acetyl bromide (0.102 g, 0.83 mmol), NaH (0.043 g, 1.1 mmol), and 3 (0.25 g, 0.83 mmol) in THF (5 mL) yielded carbene 8 (0.25 g, 0.5 mmol, 62 %). TLC: Rf = 0.42(30 % EtOAc/heptane); 1H NMR (300 MHz,CDCl3): d = 7.90 (s, 1 H), 7.69 (s, 1 H), 7.64– 7.58 (m, 2 H), 7.16 (s, 1 H), 7.06–7.05 (m, 1 H), 6.62–6.60 (m, 2 H), 6.44– 6.38 (m, 1 H), 4.29–4.25 (m, 2 H), 2.32–2.27 (m, 2 H), 1.94–1.84 ppm (m, 2 H); 13C NMR (300 MHz,CDCl3): d = 224.3, 216.2, 166.7, 165.3, 159.7, 151.5, 143.4, 133.3, 129.5, 123.3, 118.8, 113.5, 112.9, 83.1, 69.1, 63.2, 27.7, 15.3 ppm.

Compound 2 The reaction of 3-(4-hydroxyphenyl) acrylic acid (0.19 g, 0.88 mmol), THF (8 mL), but-3-yne-1-ol (0.051 g, 0.73 mmol), triphenylphosphine (0.19 g, 0.73 mmol), and diisopropyl azodicarboxylate (0.14 g, 0.73 mmol) yielded 3-(4-hydroxyphenyl) acrylic acid but-3-ynyl ester (0.2 g, 0.92 mmol, 75 %). TLC: Rf = 0.43 (30 % EtOAc/heptane); 1 H NMR (300 MHz, CDCl3): d = 7.66 (d, J = 15.9 Hz, 1 H), 7.43 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H), 6.31 (d, J = 15.9 Hz, 1 H), 5.33 (bs, 1 H), 4.31 (t, J = 6.8 Hz, 2 H), 2.61 (m, 2 H), 2.03 ppm (m, 1 H); 13C NMR (300 MHz, CDCl3): d = 51.4, 59.7, 73.6, 77.9, 112.4, 113.5, 127.6, 130.4, 142.6, 154.0, 164.9 ppm.

Carbene 9 The reaction of tetramethylammonium salt 1 (0.106 g, 0.35 mmol), dichloromethane (2.3 mL) acetyl bromide (0.043 g, 0.35 mmol), NaH (0.018 g, 0.45 mmol), and 4 (0.10 g, 0.42 mmol) in THF (2.1 mL) yielded carbene 9 (0.084 g, 0.16 mmol, 46.6 %). TLC: Rf = 0.40 (30 % EtOAc/ heptane); 1H NMR (300 MHz,CDCl3): d = 7.90 (s, 1 H), 7.63–7.46 (m, 2 H), 7.16–7.06 (m, 3 H), 7.05 (m, 1 H), 6.62–6.60 (m, 1 H), 6.43–6.38 (m, 1 H),4.21–4.16 (t, J = 6.3 Hz, 2 H), 2.25–2.18 (m, 2 H), 1.92–1.91 (m, 1 H), 1.83–1.74 (m, 2 H), 1.63–1.58 ppm (t, J1 = 2.94 Hz, J2 = 7 Hz, 4 H); 13 C NMR (300 MHz,CDCl3): d = 224.6, 215.1, 165.6, 158.5, 150.3, 142.1, 132.1, 128.1, 122.1, 120.9, 117.8, 112.3, 111.7, 82.7, 67.6, 62.9, 26.6, 23.8, 16.9 ppm.

Compound 3 The reaction of 3-(4-hydroxyphenyl) acrylic acid (0.3 g, 1.8 mmol), THF (10 mL), pent-4-yne-1-ol (0.12 g, 1.5 mmol), triphenylphosphine (0.39 g, 1.5 mmol), and diisopropyl azodicarboxylate (0.3 g, 1.5 mmol) yielded 3(4-hydroxyphenyl)-acrylic acid pent-4-ynyl ester (0.3 g, 1.3 mmol, 70 %). TLC: Rf = 0.44 (30 % EtOAc/heptane); 1H NMR (300 MHz,CDCl3): d = 7.57(d, J=15.9 Hz, 1 H), 7.36 (d, J = 8.6 Hz, 2 H), 6.79 (d, J = 8.6 Hz, 2 H), 6.23 (d, J = 15.9 Hz, 1 H), 5.33 (bs, 1 H), 4.24 (t, J = 6.2 Hz, 2 H), 2.28 (m, 2 H), 1.89 ppm (m, 3 H); 13C NMR (300 MHz, CDCl3): d = 18.1, 27.8, 64.0, 68.7, 83.9, 115.5, 115.9, 127.2, 130.0, 144.6, 157.7, 167.6 ppm.

Carbene 10 The reaction of tetramethylammonium salt 1 (0.106 g, 0.35 mmol), dichloromethane (2.3 mL) acetyl bromide (0.043 g, 0.35 mmol), NaH(0.018 g, 0.45 mmol), and 5 (0.09 g, 0.5 mmol) in THF (2.1 mL) yielded carbene 10 (0.110 g, 0.25 mmol, 70 %). TLC: Rf = 0.60 (30 % EtOAc/heptane); 1H NMR (300 MHz, CDCl3): d = 7.92 (s, 1 H), 7.15– 7.18 (m, 3 H), 6.95–7.06 (m, 2 H), 4.07–4.16 (t, J = 8 Hz, 2 H), 2.39–2.48 (t, J1 = 6 Hz, J2 = 8 Hz, 2 H), 1.98–2.05 ppm (m, 3 H); 13C NMR (300 MHz, CDCl3): d = 224.6, 216.1, 165.1, 157.8, 152.5, 150.9, 123.3, 115.3, 113.3, 112.9, 84.1, 68.9, 67.9, 28.7, 24.1, 18.2 ppm.

Compound 4 The reaction of 3-(4-hydroxyphenyl) acrylic acid (0.1 g, 0.6 mmol), THF (8 mL), hex-5-yne-1-ol (0.049 g, 0.5 mmol), triphenylphosphine (0.13 g, 0.5 mmol), and diisopropyl azodicarboxylate (0.1 g, 0.5 mmol) yielded 3(4-hydroxyphenyl)-acrylic acid hex-5-ynyl ester (0.1 g, 0.4 mmol, 71 %). TLC: Rf = 0.46 (30 % EtOAc/heptane); 1H NMR (300 MHz,CDCl3): d = 7.62(d, J=18.4 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 2 H), 6.79 (d, J = 8.5 Hz, 2 H), 6.23 (d, J = 15.9 Hz, 1 H), 5.61 (bs, 1 H), 4.16 (t, J = 6.4 Hz, 2 H), 2.20 (m, 2 H), 1.91 (s, 1 H), 1.76 (m, 2 H), 1.53 ppm (m, 2 H); 13C NMR (300 MHz, CDCl3): d = 18.1, 25.0, 27.8, 64.0, 68.7, 83.9, 115.5, 115.9, 127.2, 130.0, 144.6, 157.7, 167.6 ppm.

Carbene 11 The reaction of tetramethylammonium salt 1 (0.21 g, 0.69 mmol), dichloromethane (5 mL) acetyl bromide (0.09 g, 0.69 mmol), NaH(0.04 g, 0.9 mmol), and 6 (0.22 g, 0.81 mmol) in THF (2.1 mL) yielded carbene 11 (0.22 g, 0.33 mmol, 54 %). TLC: Rf = 0.62 (30 % EtOAc/heptane. 1 H NMR (300 MHz, CDCl3): d = 7.98 (s, 1 H), 7.11–7.15 (m, 3 H), 6.95– 7.02 (m, 2 H), 6.62–6.70 (m, 1 H), 3.99–4.06 (t, J = 8 Hz, 2 H), 2.11–2.18 (m, 2 H), 1.88–2.05 (m, 3 H), 1.65–1.71 ppm (m, 2 H); 13C NMR (300 MHz, CDCl3): d = 224.6, 216.3, 165.1, 157.7, 152.6, 151.1, 123.3, 115.4, 113.3, 112.9, 83.3, 68.9, 66.8, 29.7, 28.1, 26.1, 15.2 ppm.

General Procedure for the Synthesis of [(Aryloxy)ACHTUNGRE(furyl)carbene]chromium(0)

General Procedure for the Synthesis of Macrocyclic Diaryl Ethers

Acetyl bromide was added to a solution of tetramethylammonium salt 1 in CH2Cl2 at room temperature. The deep purple reaction mixture was immediately treated with a solution of the appropriate sodium phenolate 2 a–6 a (prepared by adding NaH to a THF solution of phenol 2–6). When the reaction mixture turned completely red the solvent was removed in vacuum and the crude product was purified by chromatography on a silica gel column with EtOAc/hexane (1:20) to yield the desired carbene as a red solid.

A Schlenk reaction vessel was charged with the appropriate carbene complex and tetrahydrofuran. The reaction mixture was then freezethaw degassed in three cycles and maintained under a positive-pressure nitrogen atmosphere. The reaction mixture was heated to 60 8C with stirring. When the starting material was consumed (TLC, 12–15 h), the reaction flask was cooled to room temperature and stirred open to the air for 0.5 h. Then the reaction mixture was filtered through celite and purified by chromatography on a silica gel column with hexanes/ethyl acetate as eluent.

Carbene 7 The reaction of tetramethylammonium salt 1 (0.139 g, 0.46 mmol), dichloromethane (4.3 mL), acetyl bromide (0.057 g, 0.46 mmol), NaH (0.014 g, 0.6 mmol), and 2 (0.12 g, 0.55 mmol), in THF (3.4 mL) yielded carbene 7 (0.16 g, 0.36 mmol, 79 %). TLC: Rf = 0.5(30 % EtOAc/hep-

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Compound 12 Carbene 7 (0.05 g, 0.102 mmol) in THF (5 mL) was heated to 60 8C. Chromatographic purification with ethyl acetate/hexanes (1:1) gave 12

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(0.014 g, 42.40 %). TLC: Rf = 0.18 (50 % EtOAc/hexanes); 1H NMR (300 MHz,[D6]DMSO): d = 9.78 (s, 1 H), 7.71 (s, 1 H) 7.43–7.41 (d, J = 9 Hz, 2 H), 7.37–7.32 (d, J = 15 Hz, 1 H) 7.10 (s, 1 H), 6.71 (s, 1 H), 6.68– 6.65 (d, J = 9 Hz, 2 H), 6.24–6.19 (d, J = 15 Hz, 1 H), 4.45–4.42 (t, J = 4.5 Hz, 2 H), 2.94–2.91 ppm (t, J = 4.5 Hz, 2 H); 13C NMR (300 MHz,CDCl3): d = 165.9, 160.1, 145.4, 145.4, 144.6, 143.5, 130.3, 130.1, 127.8, 120.3, 118.8, 115.9, 115.1, 105.1, 29.5, 28.9 ppm. Elemental analysis: calcd (%) for C19H14O5 : C 70.8, H 4.4, O 24.8; found: C 70.8, H 4.3.

a silica gel column (2–3 % methanol in CH2Cl2) to generate the desired compound. Compound 17 Macrocycle 12 (0.11 g, 0.33 mmol) in THF (8 mL) with cat. Pd/C was heated to reflux at 60 8C. Chromatographic purification with ethyl acetate/hexanes (1:1) gave 17 (0.1 g, 87 %). TLC: Rf = 0.35 (25 % EtOAc/ hexanes). 1H NMR (300 MHz,[D6]DMSO): d = 9.85 (s, 1 H), 7.61–7.58 (m, 1 H) 7.51- 7.21 (m, 2 H), 7.11 (s, 1 H), 6.75–6.55 (m, 3 H), 4.48–4.41 (m, 2 H), 2.95–2.75 (m, 2 H), 2.79–2.51 ppm (m, 2 H); 13C NMR (300 MHz, CDCl3): d = 174.6, 153.4, 152.4, 146.1, 145.4, 144.8, 142.1, 132.0, 120.1, 119.1, 118.9, 115.1, 113.2, 29.6, 17.1 ppm. Elemental analysis: calcd (%) for C19H16O5 : C 70.4, H 5.0, O 24.7; found: C 70.2, H 4.9.

Compound 13 Carbene 8 (0.10 g, 0.20 mmol) in THF (10 mL) was heated to 60 8C. Chromatographic purification with ethyl acetate/hexanes (1:1) gave 13 (0.029 g, 43.20 %). TLC: Rf = 0.17 (50 % EtOAc/hexanes); 1H NMR (300 MHz, [D6]DMSO): d = 9.65 (s, 1 H), 7.91 (s, 1 H), 7.62–7.59 (d, J = 9 Hz, 2 H), 7.56 (s, 1 H), 7.23 (s, 1 H), 6.96–6.93 (d, J = 9 Hz, 2 H), 6.63 (s, 1 H), 6.42–6.37 (d, J = 15 Hz, 1 H), 4.01–3.98 (t, J = 4.5 Hz, 2 H), 2.82– 2.80 (m, 2 H), 2.13–2.05 ppm (m, 2 H); 13C NMRACHTUNGRE(300 MHz,[D6]DMSO): d = 166.4, 158.8, 145.6, 144.6, 144.4, 143.9, 132.1, 130.3, 128.5, 119.4, 119.1, 117.1, 116.9, 105.1, 26.5, 26.4, 20.7 ppm. Elemental analysis: calcd (%) for C20H16O5 : C 71.4, H 4.8, O 23.8; found: C 71.3, H 4.8.

Compound 18 Macrocycle 13 (0.16 g, 0.33 mmol) in THF (8 mL) with cat. Pd/C was heated to reflux at 60 8C. Chromatographic purification with ethyl acetate/hexanes (1:1) gave 18 (0.14 g, 90 %). TLC: Rf = 0.38 (25 % EtOAc/ hexanes). 1H NMR (300 MHz,[D6]DMSO): d = 9.65 (s, 1 H), 7.9 (s, 1 H), 7.75–7.55 (m, 2 H), 7.25 (s, 1 H), 7.01- 6.81 (m, 2 H), 6.61 (s, 1 H), 4.10– 3.91 (m, 2 H), 3.35–3.15 (m, 2 H), 2.98–2.71 (m, 4 H), 2.15–2.05 ppm (m, 2 H); 13C NMR (300 MHz, CDCl3): d = 181.0, 160.1, 159.0, 144.1, 143.40, 134.1, 132.0, 130.4, 120, 55.2, 27.1, 20.1, 1.1 ppm. Elemental analysis: calcd (%) for C20H18O5 : C 71.0, H 5.4, O 23.6; found: C 71.0, H 5.2.

Compound 14 Carbene 9 (0.084 g, 0.16 mmol) in THF (8.4 mL) was heated to 60 8C. Chromatographic purification with ethyl acetate/hexanes (1:1) gave 14 (0.019 g, 33.33 %). TLC: Rf = 0.15 (50 % EtOAc/hexanes); 1H NMR (300 MHz,[D6]DMSO): d = 9.60 (s, 1 H), 7.79 (s, 1 H), 7.62–7.59 (d, J = 9 Hz, 2 H), 7.55 (s, 1 H), 7.14 (s, 1 H), 6.88 (s, 1 H), 6.82–6.80 (d, J = 8.7 Hz, 2 H), 6.44–6.40 (d, J = 16.1 Hz, 1 H), 4.11–4.08 (t, J = 4.6 Hz, 2 H), 2.69–2.65 (m, 2 H), 2.21–2.16 (m, 2 H), 2.01–1.97 ppm (m, 2 H); 13C NMR (300 MHz,CDCl3): d = 167.4, 158.8, 146.5, 144.9, 144.8, 144.4, 132.5, 130.1, 127.8, 121.6, 121.2, 118.7, 115.6, 115.4, 104.9, 28.8, 25.1, 24.3, 17.1 ppm. Elemental analysis: calcd (%) for C21H18O5 : C 72.0, H 5.2, O 22.8; found: C 71.9, H 5.2.

Compound 19. Macrocycle 14 (1.75 g, 0.33 mmol) in THF (8 mL) with cat. Pd/C was heated to reflux at 60 8C. Chromatographic purification with ethyl acetate/hexanes (1:1) gave 14 (0.15 g, 91 %). TLC: Rf = 0.41 (25 % EtOAc/ hexanes). 1H NMR (300 MHz,[D6]DMSO): d = 9.65 (s, 1 H), 7.81 (s, 1 H), 7.65–7.51 (m, 2 H), 7.15 (s, 1 H), 6.91- 6.65 (m, 3 H), 4.18–4.05 (m, 2 H), 3.75–3.35 (m, 2 H), 3.15–3.05 (m, 2 H), 2.81–2.61 (m, 4 H), 2.15–2.05 (m, 2 H), 2.01–1.85 ppm (m, 2 H); 13C NMR (300 MHz, CDCl3): d = 174.0, 147.1, 134.1, 132.0, 130.4, 122.0, 118.4, 115.1, 105.1, 39.2, 31.1, 28.1 ppm. Elemental analysis: calcd (%) for C21H20O5 : C 71.6, H 5.7, O 22.7; found: C 71.6, H 5.7.

Compound 15

Ozonolysis of 17 to Generate 20

Carbene 10 (0.046 g, 0.08 mmol) in THF (5 mL) was heated to 60 8C. Chromatographic purification with ethyl acetate/hexanes (1:1) gave 15 (0.017 g, 40 %). TLC: Rf = 0.45 (50 % EtOAc/hexanes); 1H NMR (300 MHz, [D6]DMSO): d = 7.48–7.45 (m, 1 H), 6.79–6.75 (m, 3 H), 6.65 (s, 1 H), 6.64–6.61 (m, 2 H), 3.69–3.65 (m, 2 H), 2.95–2.89 (m, 2 H), 2.18– 2.16 ppm (m, 2 H); 13C NMR(300 MHz,CDCl3): d = 152.6, 148.9, 148.0, 147.1, 140.1, 130.3, 129.4, 122.6, 120.1, 117.5, 107.1, 75.1, 30.9, 21.7 ppm. LC-MS calc. for C34H28O8 : 565.2 [M+H] + ; found: 565.2.

Compound 17 (140 mg, 0.324 mmol) in anhydrous CH2Cl2 (8 mL) was cooled to 78 8C, and ozone was bubbled through the solution for 10 min. The reaction mixture was stirred with Ph3P for 2 h and then diluted with water (5 mL), washed with CH2Cl2 (3 25 mL), and evaporated at reduced pressure. chromatography on a silica gel column gave 20 (55 mg, 50 %). 1H NMR (300 MHz,[D6]DMSO): d = 10.98 (s, 1 H), 9.79 (s, 1 H), 7.25–7.05 (m, 2 H), 6.81- 6.61 (m, 3 H), 4.65–4.55 (m, 2 H), 3.61– 3.21 (m, 2 H), 3.05–2.88 (m, 2 H), 2.75–2.45 ppm (m, 2 H); 13C NMR (300 MHz, CDCl3): d = 197.0, 177.1, 155.1, 154.0, 146.7, 145, 135.0, 122.4, 121.0, 118.4, 117.1, 29.2, 19.8, 18.1 ppm. Elemental analysis: calcd (%) for C18H16O6 : C 65.9, H 4.9, O 29.2; found: C 65.7, H 4.6.

Compound 16 Carbene 11 (0.096 g, 0.16 mmol) in THF (7 mL) was heated to 60 8C. Chromatographic purification with ethyl acetate/hexanes (1:1) gave 16 (0.029 g, 39.5 %). TLC: Rf = 0.51 (50 % EtOAc/hexanes); 1H NMR (300 MHz, [D6]DMSO): d = 7.45–7.41 (m, 1 H), 6.79–6.75 (m, 3 H), 6.68 (s, 1 H), 6.63–6.61 (m, 2 H), 4.10–3.98 (m, 2 H), 3.21–3.18 (m, 2 H), 2.31– 2.21 ppm (m, 4 H); 13C NMR(300 MHz, [D6]DMSO): d = 153.1, 147.9, 147.0, 146.1, 140.1, 131.3, 129.8, 122.1, 121.1, 117.8, 106.9, 75.1, 30.9, 27.9, 21.7 ppm. Elemental analysis: calcd (%) for C36H32O8 : C 73.0, H 5.4, O 21.6; found: C 73.0, H 5.3.

Acknowledgements We thank GVK Bioscience for financial support.

General Procedure for Hydrogenation of Macrocyclic Diaryl Ethers 12– 14

[1] E. M. Driggers, S. P. Hale, J. Lee, N. K. Terret, Nat. Rev. Drug Discovery 2008, 7, 608 – 624. [2] E. Marsault, L. M. Peterson, J. Med. Chem. 2011, 54, 1961 – 2004. [3] a) S. J. Stachel, C. A. Coburn, S. Sankaranarayan, E. A. Price, B. L. Pietrak, Q. Huang, J. Lineberger, A. S. Espeseth, L. Jin, J. Ellis, M. K. Holloway, S. Munshi, T. Allison, D. Hazuda, A. J. Simon, S. L. Graham, J. P. Vacca, J. Med. Chem. 2006, 49, 6147 – 6150; b) R. J. Cherney, L. Wang, D. T. Meyer, C. B. Xue, Z. R. Wasserman, K. D. Hardman, P. K. Welch, M. B. Covington, R. A. Copelan, E. C. Arner, W. F. DeGrado, C. P. Decicco, J. Med. Chem. 1998, 41, 1749 – 1751; c) K. X. Chen, F. G. Njoroge, A. Arasappan, S. Venka-

A flask was charged with the appropriate carbene, and then evacuated with argon thrice. The appropriate volume of tetrahydrofuran then a catalytic amount of Pd/C (10 % w/w). The solution was subjected to 10 bar pressure of H2 and stirred at reflux for 12 h. Once TLC indicated complete consumption of the starting material, the reaction was exposed to air and was filtered through a bed of celite. The filtrate was diluted with ethyl acetate and was washed with water. The organic layer was dried over anhydrous magnesium sulfate and was evaporated under vacuum to obtain the crude product, which was purified by chromatography on

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FULL PAPER Macrocycles Subhabrata Sen,* Rajanikanth Mamidala, Rambabu Gundla, M. T. Charya

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Diversity Oriented Synthesis of Macrocyclic Diaryl Ethers by Dçtz Benzannulation

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Further reading: The synthesis of a proof-of-concept library of macrocyclic diaryl ethers is accomplished by diversity oriented synthesis through an intramolecular Dçtz benzannulation

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strategy. Computational methods were used to assess the extent of diversity present in the library and to examine the polar surface area of the generated compounds.

