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Published in final edited form as: Angew Chem Int Ed Engl. 2015 Jun 19;54(32):9203–9208. doi: 10.1002/anie.201504337

Total Synthesis and Structural Revision of Antibiotic CJ-16,264**

K C Nicolaou 1, Akshay A Shah 2, Henry Korman 3, Tabrez Khan 4, Lei Shi 5, Wisuttaya Worawalai 6, Emmanuel A Theodorakis 7
PMCID: PMC4530996  NIHMSID: NIHMS711219  PMID: 26096055

Abstract

The total synthesis and structural revision of antibiotic CJ-16,264 is described. Starting with citronellal, the quest for the target molecule featured a novel bis-transannular Diels–Alder reaction that casted stereoselectively the decalin system and included the synthesis of six isomers before demystification of its true structure.

Keywords: natural products, antibiotic, total synthesis, structural revision, transannular Diels–Alder reaction

Isolated from fungus CL39457, antibiotic CJ-16,2641 (1, Figure 1a) was reported to exhibit impressive activities against drug resistant Gram-positive bacteria such as Staphylococcus aureus 01A1120 (MIC = 0.78 μg/mL) and Gram-negative bacteria such as Moraxella catarrhalis 87A1055 (MIC = 0.39 μg/mL) and Escherichia coli 51A1051 with altered permeability (MIC = 6.25 μg/mL). The assigned structure of this molecule is intriguing in that it is amongst the most complex of its relatives, CJ-16,367 [2, Figure 1a, stereochemistry unassigned, isolated from the same fungus (CL39457)]1, UCS1025A (3, Figure 1a)2 and UCS1025B (4, Figure 1a)2, 21-(S)- and 21-(R)-myceliothermophins C (5a)3,4 and D (5b)3,4 (Figure 1b), and the most recently reported antibiotic pyrrolizilactone5 (1a, Figure 1a). Antibiotic CJ-16,264 (1) possesses a challenging tetramethylated decalin system, whose relative and absolute configurations differ from those of its less complex siblings UCS compounds (3 and 4), and the myceliothermophins C (5a) and D (5b) (see Figure 1). Antibiotic CJ-16,264 also appears dissimilar to its close relative antibiotic 1a. In view of the biological properties of CJ-16,264 (1), the doubts over the correctness of its structure raised by the stereochemical differences from its siblings and the incomplete assignment of its absolute configuration1,6, and the challenge presented by its unique polysubstituted decalin system, we embarked on its total synthesis in the hope of solving the puzzle presented by its molecular structure. In this report we describe our synthetic endeavors that led to the total synthesis and structural revision of this target molecule which set the stage for design, synthesis and biological evaluation of its analogs and structural elucidations within this emerging class of antibiotics.

Figure 1.

Figure 1

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Molecular structures of antibiotic CJ-16,264 and other natural products containing varying substituted decalin systems and pyrrolizidinone (a) or pyrrolidinone moieties (b).

Our retrosynthetic analysis of antibiotic CJ-16,264 (structure 1, Scheme 1a) pointed to (S)-citronellal, the more expensive7 of the two enantiomeric forms of this convenient starting material. Mindful of the cost and given our doubts about the structure of our target molecule, we opted to use the less costly (R)-citronellal as the starting material for our initial studies, which were directed toward the total synthesis of the antipode of 1 (i.e. ent-1, Scheme 1a) and the confirmation of the relative stereochemical configuration of the molecule, if not its absolute configuration. At that point we would have the option to apply our developed strategy using (S)-citronellal as a starting material in order to obtain the correct enantiomer of CJ-16,264 should our findings dictated the endeavor. Thus, disconnection of ent-1 (Scheme 1a) through the Reformatsky-type reaction employed by Lambert and Danishefsky in their synthesis of UCS1025A (3)8,9 led to TBS-protected iodide 6 (ideally racemic in order to obtain both diastereoisomers of the final product) and aldehyde 7, the latter being traced back to (R)-citronellal (12) through tricyclic lactone 8 (transannular Diels–Alder reaction10; see endo transition state TS-9, Scheme 1a) and hydroxy acid 11a [macrolactonization, (Z)-α,β-unsaturated as required for the stereochemical relationship of the C1- and C2-substituents of the initially targeted ent-1].

Scheme 1.

Scheme 1

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Retrosynthetic analysis for ent-CJ-16,264 (ent-1) and synthesis of (2Z)- and (2E)-hydroxy acids 11a and 11b. b. Reagents and conditions: a) CBr4 (2.0 equiv), PPh3 (4.0 equiv), CH2Cl2, 0 °C, 3 h, 98%; b) nBuLi (3.0 equiv), THF, −78 °C, 2 h, 95%; c) K2CO3, 13, MeOH, 25 °C, 10 h, 85%; d) O3, CH2Cl2:MeOH (1:1), −78 °C, 2 h; then NaBH4 (1.1 equiv), −78→25 °C, 4 h, 85%; e) Cp2ZrCl2 (1.1 equiv), AlMe3 (4.0 equiv), ClCH2CH2Cl, 25 °C, 5 h; then I2, THF, −20 °C, 2 h, 84%; f) SO3•py (2.0 equiv), Et3N (4.0 equiv), CH2Cl2:DMSO (3:1), 0 °C, 1 h, 91%; g) LiHMDS (1.2 equiv), 18-crown-6 (5.0 equiv), 16 (1.2 equiv), THF, 0 °C, 2 h, 92% (≥95% Z:E dr); h) CuTC (6.0 equiv), 18 (3.0 equiv), DMF, 0→25 °C, 2 h, 85%; i) LiOH (35.0 equiv), THF:H2O (1:1), 60 °C, 18 h, 99%. c. Reagents and conditions: j) SO3•py (2.0 equiv), Et3N (4.0 equiv), CH2Cl2:DMSO (3:1), 0 °C, 1 h; then 20, 25 °C, 4 h; 90%; k) CuTC (6.0 equiv), 18 (3.0 equiv), DMF, 0→25 °C, 2 h, 88%; l) LiOH (35.0 equiv), THF:H2O (1:1), 60 °C, 20 h, 99%. Abbreviations: TBS = tert-butyldimethylsilyl; Cp = cyclopentadienyl; LiHMDS = lithium bis(trimehtlysilyl)amide; CuTC = copper(I)-thiophene-2-carboxylate.

Scheme 1b summarizes the construction of the required hydroxy acid 11a starting from (R)-citronellal (12). Reaction of 12 with the ylide generated from Ph3P and CBr4 gave the expected 1,1-dibromoolefin (98% yield) whose exposure to n-BuLi led to the corresponding terminal acetylene 14 (95% yield)11. Alternatively, acetylene 14 could be prepared from 12 by reaction with the Bestmann–Ohira reagent12 (85% yield) as shown in Scheme 1b. The latter compound was then converted to vinyl iodide 15 through reductive ozonolysis (O3; then NaBH4, 85% yield) followed by a sequence involving carboalumination/iodination13 (Cp2ZrCl2-AlMe3; then I2, overall 84% yield). Subsequent oxidation of 15 (SO3•py14, 95% yield) was then followed by selective (Z)-olefination of the resulting aldehyde with bis-trifluoroethoxy phosphonate 1615 in the presence of KHMDS and 18-crown-6 to furnish (Z)-α,β-unsaturated ethyl ester 17 (92% yield, ≥20:1 Z:E dr). The vinyl iodide 17 was then coupled with hydroxy vinylstannane 18 using CuTC16 to afford hydroxy ester 19 (88% yield) which, upon hydrolysis (aq. LiOH), provided the desired (Z)-hydroxy acid 11a (99% yield). We note here that attempted use of palladium-catalyzed17 coupling reactions to unite vinyl iodide 17 with stannane 18 led to significant amounts of homo-coupling side-products.

With (Z)-hydroxy acid 11a readily available, its macrolactonization was then attempted under various conditions18, including Yamaguchi19, Keck20 and Shiina21 protocols, all of which failed to produce any of the desired 13-membered macrolide 10 (see Scheme 2). Instead, and under high dilution Shiina conditions (MNBA, Et3N, DMAP cat.), we observed the formation of the 26-membered macrolide 22 (37% yield plus 8% yield of the corresponding triolide). That the (2Z)-olefinic bond of 11a had isomerized to the (2E)-olefinic bond within the diolide 22 was evident from the 1H NMR spectrum of the latter (Jα,β = 15.7 Hz). A Michael addition/bond rotation/elimination of DMAP22 or Et3N23 under the reaction conditions may account for this observed isomerization of the (2Z)-olefinic bond of 11a to the (2E)-olefinic bond within the diolide 22. The same macrolide (22) was prepared from (2E)-α,β-unsatured hydroxy acid 11b (synthesized from hydroxy vinyl iodide 15 in three steps and 79% overall yield as shown in Scheme 1c) by the same procedure as that used for the macrodimerization of 11a in 40% yield (plus 8% yield of the corresponding triolide).

Scheme 2.

Scheme 2

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Transannular Diels–Alder reaction to provide cis-fused decalin 25 and syntheses of C1-epimeric aldehydes 7 and 29. Reagents and conditions: a) conditions included several standard macrolactonization protocols including Yamaguchi, Keck and Shiina conditions; b) MNBA (1.5 equiv), Et3N (2.0 equiv), DMAP (0.1 equiv), CH2Cl2, 25 °C, 10 h, 37–40% for diolide (22), 8% for triolide; c) m-xylene (0.021 M), 220 °C, 12 h, 48%; d) NaOMe (10.0 equiv), THF: wet MeOH (9:1), 65 °C, 14 h, 85% [ca 3:2 dr at C1 (8:26)]; e) LAH (1.5 equiv), THF, −78 °C, 1 h, 98%; f) TPBSCl (1.6 equiv), Ag2O (2.5 equiv), KI (0.2 equiv), CH2Cl2, 25 °C, 20 h, 63% (79% brsm); g) TBSCl (2.0 equiv), imidazole (3.0 equiv), CH2Cl2, 0→25 °C, 15 h, 90%; h) LiEt3BH (4.0 equiv), THF, microwave, 80 °C, 10 min, 82%; i) TBAF (1.5 equiv), THF, 25 °C, 1.5 h, 91%; j) DMP (2.5 equiv), CH2Cl2, 0→25 °C, 2 h, 81%; k) LiOH (50.0 equiv), THF:MeOH:H2O (4:2:1), 80 °C, 24 h, 93% [ca 2:1 dr at C1 (26:8)]; l) MeI (1.5 equiv), K2CO3 (2.0 equiv), DMF, 25 °C, 2 h, 85%; m) MsCl (2.0 equiv), Et3N (3.0 equiv), CH2Cl2, 0 °C, 2 h, 90%; n) NaI (10.0 equiv), activated Zn dust (20.0 equiv), DME, 95 °C, 2 h, 83%; o) DIBAL-H (1.5 equiv), hexane, −78 °C, 1 h, 93%; p) DMP (2.3 equiv), CH2Cl2, 0→25 °C, 1 h, 87%. Abbreviations: MNBA = 2-methyl-6-nitrobenzoic anhydride; DMAP = 4-(dimethylamino)pyridine; LAH = lithium aluminum hydride; DIBAL-H = di-iso-butylaluminum hydride; TBSCl = tert-butyldimethylsilyl chloride; MsCl = methanesulfonyl chloride; TPBSCl = 2,4,6-tri-iso-propylbenzenesulfonyl chloride; DME = 1,2-dimethoxyethane; TBAF = tetra-n-butylammonium fluoride; DMP = Dess–Martin periodinane.

Our inability to produce the targeted Diels–Alder precursor 10 coupled with the failure of hydroxy acids 11a and 11b to undergo intramolecular [4+2] cycloaddition24–27, led us to attempt the double intramolecular Diels–Alder reaction of the now readily available macrolide 22. The anticipated incorrect configuration of the product at C1/C1′ (see structure 25, Scheme 2) was expected to be invertable through epimerization. Pleasantly, upon heating 22 in m-xylene at 220 °C for 12 h, 10-membered ring macrodiolide 25 was obtained exclusively and in 48% yield, presumably through the exo transition state exo-TS-24 (Scheme 2). The racemic form of 25 [i.e. (±)-25a, obtained from racemic citronellal via the 6,6′-anti diolide 22a (not shown)] crystallized nicely from hexane (colorless crystals, m.p. 119–123 °C) yielding to X-ray crystallographic analysis28 (see ORTEP representation, Scheme 2), which confirmed the relative configurations of the decalin moiety as depicted in 25.29

Exposure of diolide 25 to NaOMe in THF: wet MeOH at 65 °C led to the formation of γ-lactone 8 (epimerized at C1, colorless crystals, m.p. 103–105 °C, diethyl ether, see ORTEP representation, Scheme 2)28 as the major product and hydroxy acid 26 (not epimerized at C1) as the minor product (85% yield, 8:26 ca 3:2, chromatographically separated) (see Scheme 2). The desired diastereoisomer (8) for the synthesis of ent-1 was then converted to TBS ether decalin system 27 through a four-step sequence involving (i) LAH reduction (diol, 98% yield); (ii) selective reaction of the less hindered hydroxyl group with the bulky 2,4,6-tri-iso-propylbenzenesulfonyl chloride (TPBSCl) in the presence of Ag2O30 and catalytic amounts of KI [to afford the corresponding sulfonate at the less hindered site (appendage at C2), 63% yield, 79% yield based on 80% conversion]; (iii) silylation (TBSCl, imidazole, 90% yield) of the remaining hydroxyl moiety (on C1 appendage); and (iv) reductive removal of the sulfonate group (LiEt3BH31, 82% yield). The latter compound (i.e. 27) was then desilylated (TBAF, 91% yield) and the resulting alcohol was oxidized with DMP32 to the targeted aldehyde 7 in 81% yield as shown in Scheme 2.

Coupling of aldehyde 7 with racemic pyrrolizidinone iodide 6 under the influence of BEt3 (via the corresponding boron enolate of 6)8 proceeded stereoselectively as shown in Scheme 3a furnishing a mixture of alcohols 30 and 31 (87% yield, 30:31 ca 3.5:1 dr, chromatographically separated). The absolute stereochemical configuration of compound 30 (colorless crystals from ethyl acetate-hexane, m.p. 175–178 °C) was confirmed by X-ray crystallographic analysis (see ORTEP representation, Scheme 3a)28. Removal of the TBS group (TASF, 81% yield) from the targeted diastereoisomer 30 (major) followed by DMP oxidation of the secondary alcohol of the resulting diol (32) then furnished corrected-ent-1 (epimerized at C7′, scheme 3a, 83% yield). While the mass spectrum of synthetic corrected-ent-1 matched that reported for natural CJ-16,264, its 1H- and 13C-NMR data differed significantly from those reported for the natural product, suggesting that the originally assigned structure was in error. The observed epimerization at C7′ in corrected-ent-1 upon oxidation at C8′ of its precursor (i.e. 32) confirmed by NMR spectroscopy (J7′,7′a = 0 Hz for corrected-ent-1; J7′,7′a = 4.1 Hz for 32) is noteworthy. Manual molecular modeling of corrected-ent-1 reveals a dihedral angle closer to 90° in its most sterically favorable conformation (anti relationship of H7′ and H7′a; see ref. 2b for model study and ref. 5 for structural assignment of pyrrolizilactone 1a) whereas similar modeling of 32 shows its most sterically favorable conformation exhibiting a dihedral angle of closer to 30° (syn relationship of H7′ and H7′a; see ref. 2 for model study). The latter conformation is supported by the X-ray analysis of 30 (see ORTEP representation, Scheme 3a, X-ray dihedral angle for H7′-C7′-C7′a-H7′a = 38.6°). It is presumed that thermodynamics spontaneously drive this epimerization to the most stable diastereoisomer (i.e. corrected-ent-1).

Scheme 3.

Scheme 3

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Syntheses of the enantiomer of the originally assigned structure of CJ-16,264 (corrected-ent-1) (a) and its diastereoisomers 34 (a), 38 (b), and 40 (b). a. Reagents and conditions: a) BEt3 (3.5 equiv), 6 (3.5 equiv), toluene, −78 °C, 2 h, 87% (30:31 ca 3.5:1 dr); b) TASF (2.0 equiv), THF, 0 °C, 1 h, 81% for 32, 73% for 33; c) DMP (1.5 equiv), CH2Cl2, 0→25 °C, 2 h, 80% for corrected-ent-1, 83% for 34. b. Reagents and conditions: d) BEt3 (3.5 equiv), 6 (3.5 equiv), toluene, −78 °C, 2 h, 83% (35:36 ca 2.5:1 dr); e) TASF (2.0 equiv), THF, 0 °C, 1 h, 78% for 37, 91% for 39; f) DMP (1.5 equiv), CH2Cl2, 0→25 °C, 2 h, 83% for (−)-38, 82% for 40. Abbreviations: TASF = tris(dimethylamino)sulfoniumdifluoro trimethylsilicate.

Faced with this predicament, and in order to decipher the true structure of antibiotic CJ-16,264, we then opted to synthesize the diastereoisomeric structure of corrected-ent-1, isomer 34 (Scheme 3a) derived from enantiomerically pure 7, and the antipode of the shown enantiomer of 6 via intermediate 31 as shown in Scheme 3a. Thus, chromatographically separated diastereoisomer 31 was converted to 34 through the same two-step sequence used for the conversion of 30 to corrected-ent-1, and in similar yields, as depicted in Scheme 3a. However, the spectroscopic data of 34 again failed to match those reported for natural CJ-16,264, prompting us to target the remaining two diastereoisomers of this series of compounds, namely those reachable from hydroxy acid 26 (Scheme 2).

To this end, reaction conditions were first optimized to obtain the desired hydroxy acid 26 as the major product of the hydrolysis of 25 (Scheme 2). Thus, treatment of 25 with LiOH in THF: MeOH: H2O furnished a mixture of 26 and 8 (93% yield) in which the desired hydroxy acid 26 predominated (26:8 ca 2:1, chromatographically separated). The required aldehyde 29 (anti C1/C2) was then synthesized from hydroxy acid 26 through a sequence involving selective methylation of the carboxylic acid moiety (K2CO3, MeI, 85% yield), mesylation of the hydroxyl group (MsCl, Et3N, 90% yield), and reduction of the resulting mesylate methyl ester with Zn dust33 in the presence of NaI to afford tetramethylated decalin system 28 (83% yield). The methyl ester of the latter was then reduced (DIBAL, 93% yield) and the resulting alcohol was oxidized (DMP, 87% yield) to afford the desired aldehyde 29 as shown in Scheme 2.

Coupling of the now readily available aldehyde 29 with racemic pyrrolizidinone iodide 6 under BEt3-mediated Reformatsky-type coupling8, as shown in Scheme 3b, again proceeded stereoselectively, providing a mixture of crystalline alcohols 35 (colorless crystals from ethyl acetate-hexane, m.p. 142–145 °C) and 36 (colorless crystals from ethyl acetate-hexane, m.p. 130–134 °C) (83% yield, 35:36 ca 2.5:1 dr, chromatographically separated). Both 35 and 36 yielded to X-ray crystallographic analysis28 (see ORTEP representations, Scheme 3b) that proved their configurational arrangements as shown in Scheme 3b. The syn arrangement of H7′ and H7′a in 35 and 36 was consistent with their 1H-NMR data (J7′,7′a = 3.9 Hz) as it was for their diastereoisomeric counterpart 30 (J7′,7′a = 4.0 Hz). Subsequent removal of the TBS group from intermediates 35 and 36 provided diols 37 and 39, respectively (TASF, 78% yield for 37, 91% yield for 39). The targeted diastereoisomeric structures of CJ-16,264 were then obtained from 37 and 39 through DMP oxidation to afford (−)-38 and 40 in 83% and 82% yield, respectively. Again, we observed epimerization at C7′ in both final products (−)-38 and 40 as evidenced by the J7′,7′a = 0 Hz coupling constants between H7′ and H7′a for both compounds. The same argument and supporting evidence provided above for corrected-ent-1 and 32 apply here for (−)-38 and 40 and their precursors 37 and 39, respectively. To our delight, the spectroscopic data (1H- and 13C-NMR) and mass spectrum of structure (−)-38 were found to be in agreement with the data reported for the natural CJ-16,264,1 suggesting a structural revision for the antibiotic CJ-16,264. The optical rotation of 38 ([α]D = −9.8° in MeOH), however, was found to be of the opposite sign to that reported for the natural product ([α]D = +27.3° in MeOH)1, pointing to the enantiomer of (−)-38 as the true structure of antibiotic CJ-16,264. With this information in our possession, we then sought to synthesize the antipode of (−)-38, compound (+)-38 (Scheme 4) in order to fully confirm the absolute configuration and obtain a synthetic sample of the naturally occurring antibiotic CJ-16,264.

Scheme 4.

Scheme 4

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Synthesis of the revised structure of antibiotic CJ-16,264 [(+)-38] and its diastereoisomer ent-40. Reagents and conditions: a) see Schemes 1–3; b) BEt3 (3.5 equiv), 6 (3.5 equiv), toluene, −78 °C, 2 h, 86% (ent-35:ent-36 ca 2.3:1 dr); c) TASF (2.0 equiv), THF, 0 °C, 1 h, 76% for ent-37, 88% for ent-39; d) DMP (1.5 equiv), CH2Cl2, 0→25 °C, 2 h, 83% for (+)-38, 82% for ent-40.

The final drive toward the targeted molecule [(+)-38] (via intermediates ent-29 plus 6, ent-35 and ent-37) proceeded from (S)-citronellal (41) along the same lines and in similar yields as the synthesis of (−)-38 (Scheme 3b) as summarized in Scheme 4. The 1H- and 13C-NMR spectroscopic and spectrometric data for synthetic CJ-16,264 matched those reported1 and provided by Dr. Y. Sugie for the natural product and so did the sign of optical rotation ([α]D = +7.7° in MeOH). Attempts to recrystallize (+)-38 from a variety of solvents thus far led to partial formation of the C7′-C8′ enol (enol proton, δ = 12.72 ppm, keto:enol ca 4:1) form and semicrystallization. The enolization of (+)-38 could be completely reversed by passage of the mixture through a silica gel column (EtOAc: hexanes, hexanes→50% EtOAc in hexanes). The deuterated form (deuteration at C7′) of (+)-38 was also detected through a 1H-NMR experiment (benzene-d6, D2O exchange) in which the C7′ proton signal decreased significantly. The corresponding diastereoisomer of (+)-38, compound ent-40, was also synthesized from intermediate ent-36, formed in the coupling of ent-29 and racemic 6, via ent-39 (see Scheme 4). Interestingly, the proven structure of antibiotic CJ-16,264 [(+)-38] resembles closely that proposed for antibiotic 1a (pyrrolizilactone, Figure 1a), although the latter was not precisely defined with regard to the relative stereochemistry between the decalin and pyrrolizidinone domains and the absolute stereochemistry of the molecule (structure 1a represented four stereostructures: two enantioisomers and two diastereoisomers)5.

The reported chemistry led to an enantioselective total synthesis and structural revision of antibiotic CJ-16,264 as structure (+)-38 and sets the foundation for the full structural elucidation of other members of this growing class of antitumor antibiotics. The devised synthetic strategy features a novel macrolactonization/dimerization and a stereoselective intramolecular bis-[4+2] cycloaddition to forge the highly-substituted decalin system of the molecule in its proper stereochemical configuration. A total of six isomeric structures of the antibiotic have been rendered readily available for biological investigations, underscoring the importance of total synthesis to both biology and structural elucidation. Most significantly, the reported total synthesis of antibiotic CJ-16,264 paves the way for analog design, synthesis, and biological evaluation within this class of natural products.

Supplementary Material

Supporting Information

Footnotes

**

K.C.N. thanks Drs. D. H. Huang (TSRI), L. Pasternack (TSRI), L. B. Alemany (Rice) and Q. Kleerekoper (Rice) for NMR spectroscopic assistance, Drs. G. Siuzdak (TSRI) and C. Pennington (Rice) for mass spectrometric assistance, and Drs. R. K. Chadha (TSRI) and J. D. Korp (University of Houston) for X-ray crystallographic assistance. This work was supported by the National Institutes of Health (USA) (grant AI055475), the Cancer Prevention & Research Institute of Texas (CPRIT) and The Welch Foundation. H.K. thanks financial support from the National Science Foundation Graduate Research Fellowship Program (Grant No. DGE-1144086). T.K. acknowledges Fulbright India for a Fulbright-Nehru Postdoctoral Fellowship.

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201xxxxxx.

Contributor Information

Prof. Dr. K. C. Nicolaou, Department of Chemistry, BioScience Research Collaborative Rice University, 6100 Main Street, Houston, TX 77005 (USA)

Dr. Akshay A. Shah, Department of Chemistry, BioScience Research Collaborative Rice University, 6100 Main Street, Houston, TX 77005 (USA)

Dr. Henry Korman, Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 (USA)

Dr. Tabrez Khan, Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)

Dr. Lei Shi, Department of Chemistry, BioScience Research Collaborative Rice University, 6100 Main Street, Houston, TX 77005 (USA)

Dr. Wisuttaya Worawalai, Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 (USA)

Prof. Dr. Emmanuel A. Theodorakis, Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 (USA)

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Supporting Information
NIHMS711219-supplement-Supporting_Information.pdf (6.4MB, pdf)

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