Phospha-adamantane ligands for cross-coupling of CSP3 boronates

Abstract

Disclosed are compositions and methods for performing cross-coupling reactions at Csp3- hybridized boronates. Also disclosed are methods of deprotecting silyl-protected cross-coupling products comprising the oxidation of C-Si bonds.

Description

[0001] UIX-05325

[0002] PHOSPHA-ADAMANTANE LIGANDS FOR CROSS¬ COUPLING OF CSP3 BORONATES

[0003] RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 737,939, filed December 23, 2024.

[0005] STATEMENT OF GOVERNMENT SUPPORT

[0006] This invention was made with government support under 1955838 and 2019897 awarded by the National Science Foundation. The government has certain rights in the invention.

[0007] BACKGROUND

[0008] Chemical reaction development has progressed substantially over the past several years, driven largely by automated experimentation and machine learning techniques. It remains a major challenge, however, to rationally develop new chemical reactivity when the starting point, even after attempts at screening, chemical design, and best guessing, is 0% yield. For such cold-start problems, it is not possible to generate datasets with the dynamic range of reaction yields needed to drive human and / or machine learning. A representative cold start problem of interest is the stereospecific cross-coupling of secondary Csp3pinacol boronic esters with unactivated vinyl halides, a reaction which could in theory enable automated modular synthesis of thousands of polyketide natural products and derivatives which comprise a large and especially functionally rich area of chemical space. In view of the foregoing, there is an unmet need to develop new methods for performing the stereospecific cross-coupling of secondary Csp3pinacol boronic esters with unactivated vinyl halides.

[0009] SUMMARY OF THE INVENTION

[0010] In certain aspects, the present disclosure provides compounds of formula (I):

[0011]

[0012] (I),UIX-05325

[0013] or a salt thereof;

[0014] wherein:

[0015] R1is H, alkyl, alkoxyl, -O-alkaryl, aralkyl, or aryl; and

[0016] R2is H, alkoxyl, or haloalkyl.

[0017] In further aspects, the present disclosure provides compounds of formula (II):

[0018]

[0019] or a salt thereof;

[0020] wherein:

[0021] RAis selected from the group consisting of H,

[0022]

[0023]

[0024] RBis selected from the group consisting of H,

[0025]

[0026] provided that if RBis H, then RAis not

[0027]

[0028]

[0029] ,

[0030] In yet further aspects, the present disclosure provides methods of making a compound of formula (III):

[0031]

[0032] (III);

[0033] comprising combining under suitable conditions a compound of formula (IV):

[0034] X1— A

[0035] (IV);

[0036] a compound of formula (V):UIX-05325

[0037]

[0038] (V);

[0039] a compound of the present disclosure; and a transition metal salt or a transition metal complex; thereby producing the compound of formula (III);

[0040] wherein:

[0041] A is aryl, heteroaryl, or alkenyl;

[0042] n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0043] R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0044] R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0045] R5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; and

[0046] X1is a halogen.

[0047] In still further aspects, the present disclosure provides methods of making a compound of formula (VI):

[0048]

[0049] (VI);

[0050] comprising combining under suitable conditions a compound of formula (IV):

[0051] X1— A

[0052] (IV);

[0053] a compound of formula (VII):

[0054]

[0055] (VII);

[0056] a compound of the present disclosure; and a transition metal salt or a transition metal complex; thereby producing the compound of formula (VI);

[0057] wherein:UIX-05325

[0058] A is aryl, heteroaryl, or alkenyl;

[0059] n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0060] R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0061] R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0062] R5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; and

[0063] X1is a halogen.

[0064] In certain aspects, the present disclosure provides methods of making a compound of formula (VIII):

[0065]

[0066] (VIII);

[0067] comprising combining under suitable conditions a compound of formula (III):

[0068]

[0069] (III);

[0070] or a compound of formula (VI):

[0071]

[0072] an oxidizing agent; and at least one base; thereby producing the compound of formula (VIII); wherein:

[0073] A is aryl, heteroaryl, or alkenyl;

[0074] n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0075] R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0076] R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; andUIX-05325

[0077] R5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl.

[0078] In further aspects, the present disclosure provides methods of making a compound of formula (I):

[0079]

[0080] comprising combining a compound of formula (X):

[0081]

[0082] with a transition metal salt or a transition metal catalyst, at least one base, and 1 ,3,5,7- tetramethyl-2,4,6-trioxa-8-phosphaadamantane; thereby producing the compound of formula (I);

[0083] wherein:

[0084] R1is H, alkyl, alkoxyl, -O-alkaryl, aralkyl, or aryl;

[0085] R2is H, alkoxyl, or haloalkyl; and

[0086] X2is a halogen.

[0087] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A shows that stereospecific Csp3 cross-coupling enables access to polyketide structures. 2D t-SNE representing Jaccard similarity of 300,056 natural product Morgan (ECFP6) fingerprints.

[0088] FIG. IB is a reaction schematic showing that cross-coupling of secondary alkyl organoboron nucleophiles with unactivated vinyl halides represents a cold start problem.

[0089] FIG. 1C depicts the coevolution of the buff-tailed sicklebill hummingbird and the centropogon flower.

[0090] FIG. ID is a schematic depicting the strategy underlying the directed coevolution of chemicals. LI = RuPhos.UIX-05325

[0091] FIG. 2A depicts a mechanistic hypothesis proposing that electrophile electronics tune the electrophilicity of the palladium oxidative addition complex leading to disparate reactivities.

[0092] FIG. 2B shows 2D t-SNE representing Jaccard similarity of polyketide natural product Morgan (ECFP6) fingerprints representing vinyl-a-methyl-b-hydroxyl-containing polyketides that cover 38% of polyketide space (2868 / 7553 molecules).

[0093] FIG. 2C depicts DFT-calculated NPA charge analysis of polyketide extracted electrophiles to select intermediate substrates. NPA charge of bromine-bound carbon atoms was computed at wB97X-D / cc-pVTZ level of theory.

[0094] FIG. 2D shows the incremental reduction in productive ligand chemical space (horizontal axis) tracking from substrates 1 to 4 (horizontal dashed lines). Yields are represented by color.

[0095] FIG. 2E depicts the exploitation of overlaps in sets of productive ligands between coevolution substrates. Vertical axes show yield with a given substrate for different ligands (ligand space is horizontal axis shared between the four plots). Vertical dotted arrows indicate non-zero yield for a less-activated substrate when using a ligand that gave best yield for the more activated neighbor in the coevolution sequence.

[0096] FIG. 2F is a reaction scheme depicting a cross-coupling of pinacol siloxaborolate (6a) and the small molecule synthesizer used for automated reactions.

[0097] FIG. 2G depict GC or HPLC yields for ligands tested. See Examples section for all ligand structures and yields. Data point color represents the halide with which the reaction was performed. Data points that follow the top ligand for a halide represent the yield when that ligand was tested on the following electrophile.

[0098] FIG. 2H shows that evolved ligands L31 and L37 produce non-zero yields on the initially unreactive 2b.

[0099] FIG. 3A shows a conceptual illustration of the search for general reactivity. For each of the halides 2a - 2d, the zone of >50% yield in the space of ligands (horizontal axis) and conditions (vertical axis) is bounded by an ellipse. Intersection of four ellipses is the zone of general reactivity. Basic coevolution strategy keeps conditions fixed and therefore moves from right to left along the x-axis to arrive at a ligand within productive chemical space for halide 2b, but not with overlapping with productive spaces for 2a, 2c, and 2d. In contrast, coevolution of general reaction conditions requires a strategy for searching productive ligand space while maintaining reactivity for previous substrates.UIX-05325

[0100] FIG. 3B shows a conceptual illustration of coevolution with selective pressure for general reactivity. Plots show general behaviour of yield in the space of ligands. Each bellshaped curve corresponds to a halide. Coevolution algorithm is modified to search for maxima of the mean yield of two or more halides (black curves).

[0101] FIG. 3C is a reaction scheme depicting a cross -coupling of secondary alkyl b-aryloxysilyl pinacol boronic esters: ACS Catal. 2022 conditions. 4-Bromoanisole (2e) was employed as the electrophile for better visibility by HPLC with UV-detection.

[0102] FIG. 3D shows that Direct Injection HPLC reveals decreasing the water content increases the reaction rate and yield.

[0103] FIG. 3E Homogeneous base screen shows TMSOK provides maximum rate and yield.

[0104] FIG. 3F shows that selective pressure for generality yields general reactivity across electrophiles 2a - 2d. See SM pages X-Y for all reactions and yields. Data point color represents which halides the reactions were performed on. Data points at color transitions represent yield of the top condition from the previous hill when applied on the next halide. ± represents standard deviation.

[0105] FIG. 4A is a reaction scheme depicting the stereoretentive cross-coupling of stereoisomerically enriched secondary alkyl b-aryloxysilyl pinacol boronic esters and subsequent Tamao oxidation to obtain a-methyl-b-hydroxyl-containing products. Yield of step 1 by GC or HPLC and yield of step 2 represents purified product isolated after silica gel column chromatography.

[0106] FIG. 4B is a reaction scheme depicting a representative cross-coupling with ligand L31.

[0107] FIG. 4C shows the polyketide-extracted electrophile scope covering a-methyl-b-hydroxyl-containing polyketide space represented by 2D t-SNE of Morgan ECFP6 fingerprints. Representative natural products containing extracted halides shown in 3D. R in compound 2f represents -(C^jsCChEt.

[0108] DETAILED DESCRIPTION OF THE INVENTION

[0109] Chemical reaction development has progressed substantially over the past several years, driven largely by automated experimentation and machine learning techniques. It remains a major challenge, however, to rationally develop new chemical reactivity when the starting point, even after attempts at screening, chemical design, and best guessing, is 0% yield. For such cold-start problems, it is not possible to generate datasets with the dynamic range ofUIX-05325

[0110] reaction yields needed to drive human and / or machine learning. A representative cold start problem of interest is the stereospecific cross-coupling of secondary Csp3pinacol boronic esters with unactivated vinyl halides, a reaction which could in theory enable automated modular synthesis of thousands of polyketide natural products and derivatives which comprise a large and especially functionally rich area of chemical space. In view of the foregoing, there is an unmet need to develop new methods for performing the stereospecific cross-coupling of secondary Csp3pinacol boronic esters with unactivated vinyl halides.

[0111] Nature routinely develops new functions via the process of coevolution, in which two or more evolvable units apply reciprocal selective pressure on one another. The curved bill of the buff-tailed sicklebill hummingbird and the shape of the centropogon flower is a classic example (Fig. 1C). Building on the pioneering work of Arnold and coworkers in area of in vitro directed evolution, Zhao and coworkers creatively developed in vitro directed coevolution to solve cold start problems in biochemistry. This now generalized approach sequentially optimizes enzyme activity on a series of systematically morphed intermediates that lie in between substrates with accessible and inaccessible reactivity. That is, the enzymes and substrates are intentionally co-evolved. Key to this process is that each new substrate must have non-zero reactivity with an enzyme optimized on the previous substrate in the series. It was questioned whether this concept could be translated to solve cold start problems in chemistry. Specifically, it was sought to discover a new phosphine ligand capable of promoting a targeted Csp3cross-coupling reaction via a directed co-evolution campaign that starts with known phosphine LI and reactive substrate 2a (Fig. ID).

[0112] To identify intermediate substrates that could potentially bridge the gap between 2a and 2b, it was hypothesized that reactivity differences were attributable to differences in transmetalation rates between the corresponding palladium oxidative addition complexes 5 and siloxaborolate 6. The latter was suggested by earlier studies to be the likely intermediate for transmetalation when coupling beta-aryloxysilyl Csp3boronic esters 1. Specifically, it was reasoned that the more electron poor aryl halide 2a renders the corresponding palladium oxidative addition complex 5a more electrophilic and thus more reactive towards transmetalation with 6 (Fig.2A). Notably, similar effects have been identified for electron poor versus rich phosphines, and electron-poor vinyl halides tend to be activated relative to their electron-rich counterparts in cross-couplings with other types of secondary alkyl organoboron nucleophiles. Thus, it was anticipated that a calculable electronic parameter, such as natural population analysis (NPA) charge, could capture reactivity trends and enable rational selection of intermediate substrates for the coevolution campaign. Density functional theory (DFT)UIX-05325

[0113] calculations were performed, (wB97X-D functional, cc-pVTZ basis set) and identified that the NPA charge at the bromine-bearing carbon atom for 2a is -0.131 e, and that of 2b is -0.286 e. This provided a quantitative definition of the gap this study aimed to bridge.

[0114] To maximize the synthetic utility of whatever methods we could develop, bridging efforts were focused on candidate vinyl halide motifs that also represent substructures of polyketide natural products. To generate such candidates, an open access, interactive digital tool was developed that represents >300,000 natural products and derivatives from the Dictionary of Natural Products database. All compounds were annotated according to their molecular fingerprinting (Morgan ECFP6), 2D t-distributed stochastic nearest- neighbor embedding (t-SNE) of Jaccard similarities, and the Reymond group’s Faerun package. The polyketide family was then filtered to identify molecules containing the targeted acyclic vinyl-a-methyl-b-hydroxyl motifs (Fig. 2B). 230 vinyl bromide structures were extracted and DFT calculations were again used to calculate NPA charges at the bromine-bearing carbon atoms (Fig. 2C). Readily accessible intermediate substrates tert-butyl (E)-3-bromo-2-methylacrylate 2c (NPA charge -0.214 e) and (£)-3-bromo-A,A,2-trimethylacrylamide 2d (NPA charge — 0.260 e) were chosen to bridge the NPA charges, and hopefully, the reactivities of 2a and 2b.

[0115] It was theorized that directed coevolution of phosphine ligands and organohalides when moving from highly reactive substrate 2a to the initially unreactive vinyl halide 2b would track along a narrowing productive ligand space (Fig. 2D). This concept assumes at least partial continuity of yields across the chemical space, because yields are expected to be similar for similar ligands and similar substrates. This analysis suggests that navigating the narrowing path of high yield (Fig. 2D) is most practical when the productive ligands are optimized in small steps along the way. Thus, the proposed approach provides the best chance for some ligands that are highly productive with a more activated substrate to be somewhat productive with the next, less activated substrate (Fig. 2E). Alternatively stated, if the jumps in either coevolution partner are too big, there would be no overlapping reactivities to bridge the gaps. Choosing a more closely spaced sequence of substrates may partially alleviate this constraint, but since such a sequence is discrete by nature, there is also a physical limit to how similar neighboring substrates can be.

[0116] With these concepts in mind, it was planned to serially test phosphine ligands for maximized yields of organohalides 2c, 2b, and 2d until non-zero yields for the next targeted substrates were observed and to use structural features of the top performing ligands from each preceding optimization to guide ligand design for the next. To ensure that the discovered reaction conditions would be compatible with modular automated synthesis, increaseUIX-05325

[0117] experimental throughput, and maximize the reproducibility of the coupling reactions, a small molecule synthesizer able to perform 20 simultaneous Csp3cross-coupling reactions and their workups under an argon atmosphere was constructed based on previous designs. (Fig.2F). Key to the proposed coevolution process, reactions were performed in batches of 5-10 ligands at a time allowing for on-the-fly decisions on structural modifications, enabling the custom synthesis of ligands, and maximizing the impact of fewer data points. This is analogous to active machine learning where more frequent model updates with relatively smaller data batch sizes can yield model convergence with fewer data points. This is different than high throughput experimentation where a higher number of experiments, except with mostly commercially available ligands, would be performed.

[0118] Starting with the previously reported optimal ligand for aryl halides, ortho-substituted aryl phosphine RuPhos (LI), the cross-coupling of siloxaborolate 6a and bromobenzene 2a was tested on the automated synthesizer and provided 80% yield. Under these conditions, the corresponding yield with unactivated vinyl halide 2b was 0%, with no detection of the targeted product even by mass spectrometry (MS) of the crude reaction mixture. The gap in reactivity was too large. Alternatively, application of these same conditions to the coupling of 11 provided a non-zero yield of 12% (Fig. 2G). Building on the ortho-substituted aryl phosphine framework, a variety of modified phosphine ligands were tested for their capacity to improve reaction with 2c. Common ligands such as SPhos, XPhos, tricyclohexylphosphine, and triphenylphosphine were relatively unproductive. In contrast, a yield of 65% was observed with exhaustively ortho-substituted ligand tri-o-tolylphosphine. This observation stimulated the synthesis and testing of a variety of tri-o-tolylphosphine variants. Most of these structures performed worse than tri-o-tolylphosphine, but two performed better with top ligand tri-o-methyl- -methoxylphenyl phosphine L10 providing 83% yield.

[0119] At this stage it was again attempted to jump directly to unactivated vinyl halide 2a using the five top performing phosphine ligands for 2c, but all reactions failed to generate any MS-detectable product. Thus, experiments on the next intermediate electrophile 2d commenced. The same five top performing phosphine ligands were tested for their capacity to couple 6a with 2d, and L10 provided 18% yield. Additional modification of the tri-o-tolyl phosphine scaffold, including modifications that break C3 symmetry, yielded a novel phosphine containing two o-tolyl groups and one o-benzylphenyl group (L30) that increased yields to 34%. Continued explorations along this C3-symmetry-breaking theme yielded a novel phosphine containing an o-isopropoxy-substituted aryl group and the other two positionsUIX-05325

[0120] occupied with a phosphaadamantane (L31) motif (29). This was the top performer providing 41% yield of the coupled product.

[0121] At this stage, the top five ligands for coupling 2d were tested on 2b with only one ligand, the top performer with halide 2d, L31, providing a MS hit on the crude reaction mixture. This was the first time we had observed any of the targeted Csp3coupling with unactivated vinyl halide 2b. Work up and purification of this reaction revealed a yield of 24%. Further evolving the structure of L31 via synthesis and testing of additional o-substituted aryl phosphaadamantane phosphines led to another novel L37 containing an o-benzylaryl group, which provided an improved yield of 34%. Notably, the phosphaadamantane ligands found to be productive for 2b are not represented commercially, nor are they included in the Kraken database, suggesting that they would not have been identified via high throughput screening or currently available data science-centric methods.

[0122] While the directed coevolution campaign led to a ligand L37 that enabled the coupling of 5 and 2a for the first time, it was noted that this ligand offered a markedly lower yield for the original coupling between 1 and 2a (Fig. 2G). A specific solution for 2b was evolved at the cost of coupling 2a and other more electron-deficient vinyl halides. It was next questioned if the selective pressures driving a directed coevolution campaign could be tuned to yield general conditions that work for all four substrates 2a-2d and thus most of the polyketide natural product derived electrophiles that they collectively represent (Fig. 2B). Alternatively stated, a hypothetical location in reaction condition space was sought where productivities for all these substrates overlap (Fig. 3A). It was proposed this might be achieved by performing a second coevolution campaign during which we intentionally apply selective pressure for generality by converting the objective function into the average yield of all previous as well as each new intermediate (Fig 3B).

[0123] To increase our chances of discovering such generality, the search space was expanded to also include solvent, base, additives, and temperature as variables. To explore this space, studies were performed in situ under catalytic heterogenous conditions the coupling of secondary alkyl b-aryloxysilyl pinacol boronic ester 1 with aryl halide 4-bromoanisole (2) (which yields product with strong UV / Vis absorption) using information-rich Directlnjection HPLC (Fig.3C). We held the ligand LI constant and sampled many different combinations of these variables. One key observation was that decreasing the water content increased reaction rate (Fig. 3D). This prompted the consideration of testing anhydrous homogenous conditions promoted by soluble bases as recently reported by the Denmark group. TMSOK emerged as the fastest and highest yielding base (Fig. 3E). The optimized conditions, deemed TMSOKUIX-05325

[0124] (anh), were compared to the starting conditions, CsOH (aq), across several halide electrophiles inspired by the previous report that represented a broad electronic range as confirmed by NPA charge calculations. Product yield increased in all cases and some electrophiles that underwent minimal to no conversion to the desired coupling product under the CsOH (aq) conditions were productive coupling partners under TMSOK (anh) conditions. TMSOK (anh) conditions reduced byproduct profiles in most cases, with protodehalogenated electrophile and arylated phosphine ligand constituting two characterized byproducts. Additionally, TMSOK (anh) conditions decreased average reaction time from 12+4 to 4+1 hours.

[0125] Transfer of these conditions to the coupling of 1 and 2b proved to be unsuccessful, resulting in no detectable product, suggesting that modification of ligand structure was required regardless of optimization of other reaction parameters. Thus, the directed coevolution for generality campaign was undertaken. Initial testing of the TMSOK (anh) RuPhos LI conditions with 2c provided a low yield of 5%. Leveraging these learnings from the first coevolutionary walk, the TMSOK (anh) conditions were combined with newly discovered productive ligand scaffolds in the coupling with 1 and 2c. Under anhydrous conditions, only the phosphaadamantane ligand class was competent for both 2a and 2c, revealing three ligands with average yields of >60% with L31 affording the highest average yield of 87+6%. (Fig.3F). Yet, application of these top three conditions to 2d resulted in only 20-25% yield, with the highest average yield across 2a, 2c, and 2d being 66+36%. Strategic implementation of Directlnj ection HPLC for time course analysis revealed the reaction completed in 1.5 h, leading to the speculation that the 12 h reaction time employed on the automated synthesizer could be leading to product decomposition. By shortening reaction time to 1 h, the coupling yield for 2d increased to 74% and the average yield across 2a, 2c, and 2d to 80+5%. Gratifyingly, these conditions transferred to the unactivated vinyl halide 2b, giving rise to a general set of conditions with an average yield across 2a-2d of 80+5%, and showcasing how the coevolution process can be tuned to yield unique outcomes by incorporating different selection criteria.

[0126] To test the stereochemical outcome and generality of the conditions, stereoisomerically enriched syn- and r / / ? / z-b-aryloxysilyl pinacol boronic esters 1-syn and 1-anti were prepared and submitted to cross-coupling conditions with 2a - 2d followed by Tamao oxidation and showed perfect stereochemical retention in all cases to yield the key polyketide a-methyl-b-hydroxyl motif (Fig. 4A). Notably, both stereochemistry of the sp3carbon atom involved in coupling as well as olefin geometry were retained. To probe the reactivity-based generality and applicability of these conditions across our targeted polyketide chemical space, the substrate scope was designed to comprise representative polyketide-extracted electrophiles and collectedUIX-05325

[0127] full kinetic profiles via Directlnj ection HPLC analysis (Fig. 4B). To select representative polyketide structures, >230 electrophiles were analyzed, extracted from vinyl-a-methyl-b-hydroxyl-containing polyketides (Fig. 2C) and 12 commercially available or synthesizable electrophiles were selected from the extracted candidate vinyl bromide set (Fig. 4C).

[0128] Independent embedding of the 230 vinyl halide structures using a custom metric that equally weights Morgan ECFP6 fingerprints and NPA charges, followed by visualization by 2D t-SNE, suggests the selected electrophiles cover the range of structural and electronic characteristics. Notably, the top 3 vinyl bromides (2k, 2b, and 21) are present in 1157 polyketides representing 40% of the desired chemical space, whereas all 12 vinyl halides are present in 1741 polyketides (68% of desired chemical space). To rapidly access the generality of these conditions, full kinetic profiles were obtained for the couplings of 1 with the selected electrophiles. Under the general cross-coupling conditions, all electrophiles showed complete conversion, and even when protodehalogenated side product formation was observed for 2f the reaction still provided 58% yield of desired product. Importantly, these results suggest that the strategic selection of coevolution substrates, and the modified coevolution approach, enabled development of conditions that are general across the broad target polyketide space.

[0129] In summary, directed coevolution of chemicals overcame a cold start problem in chemistry, the discovery of a Csp3Suzuki-Miyaura cross-coupling reaction between secondary alkyl boronic esters and unactivated vinyl halides, enabling stereospecific access to important natural product-like chemical matter. Additionally, this approach was tuned to affect different optimization outcomes such as general instead of selective reaction conditions. A roadmap for obtaining data-science-driven, complex-molecule-extracted substrate scopes was developed, along with a manner for rapidly assessing reaction conditions across the chemical space of interest via automated collection of kinetic profiles. It was speculated that directed coevolution of chemicals could be even more powerful when paired with higher throughput experimentation and AI / ML.

[0130] Compounds of this Disclosure

[0131] In certain aspects, the present disclosure provides compounds of formula (I):

[0132]

[0133] UIX-05325

[0134] (I),

[0135] or a salt thereof;

[0136] wherein:

[0137] R1is H, alkyl, alkoxyl, -O-alkaryl, aralkyl, or aryl; and

[0138] R2is H, alkoxyl, or haloalkyl.

[0139] In certain embodiments, R1is H. In further embodiments, R1is alkoxyl. In yet further

[0140] embodiments, R1is selected from the group consisting

[0141]

[0142] . In

[0143] still further embodiments, R1is -O-alkaryl. In certain embodiments, R1is

[0144]

[0145] . In further embodiments, R1is alkyl. In yet further embodiments, R1is methyl. In still further embodiments, R1is aralkyl. In certain embodiments, R1is benzyl. In further embodiments, R1is aryl. In yet further embodiments, R1is phenyl. In still further embodiments, R2is H. In certain embodiments, R2is haloalkyl. In further embodiments, R2is trifluoromethyl. In yet further embodiments, R2is alkoxyl. In still further embodiments, R2is methoxy.UIX-05325

[0146] In certain embodiments, the compound is selected from the group consisting of:

[0147]

[0148] In further aspects, the present disclosure provides compounds of formula (II):

[0149]

[0150] (II),

[0151] or a salt thereof;

[0152] wherein:

[0153]

[0154] UIX-05325

[0155] RBis selected from the group consisting of H,

[0156]

[0157] ,

[0158] provided that if RBis H, then RAis not

[0159]

[0160]

[0161] In certain embodiments, the compound is selected from the group consisting of:

[0162]

[0163] Methods ofC-C Bond Formation

[0164] In yet further aspects, the present disclosure provides methods of making a compound of formula (III):

[0165]

[0166] comprising combining under suitable conditions a compound of formula (IV):

[0167] X1— A

[0168] (IV);

[0169] a compound of formula (V):

[0170]

[0171] UIX-05325

[0172] (V);

[0173] a compound of the present disclosure; and a transition metal salt or a transition metal complex; thereby producing the compound of formula (III);

[0174] wherein:

[0175] A is aryl, heteroaryl, or alkenyl;

[0176] n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0177] R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0178] R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0179] R5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; and

[0180] X1is a halogen.

[0181] In certain embodiments, the methods further comprise at least one base. In further embodiments, the at least one base is potassium trimethylsilanolate. In yet further embodiments, the transition metal salt or the transition metal complex is used in an amount of about 1 mol% to about 30 mol% relative to the compound of formula (V). In still further embodiments, the transition metal salt or the transition metal complex is used in an amount of about 1 mol% to about 10 mol% relative to the compound of formula (V). In certain embodiments, the transition metal salt or the transition metal complex is used in an amount of about 5 mol% relative to the compound of formula (V). In further embodiments, the compound of the present disclosure is used in an amount of about 1 mol% to about 50 mol% relative to the compound of formula (V). In yet further embodiments, the compound of the present disclosure is used in an amount of about 10 mol% to about 25 mol% relative to the compound of formula (V). In still further embodiments, the compound of the present disclosure is used in an amount of about 20 mol% relative to the compound of formula (V).

[0182] In still further aspects, the present disclosure provides methods of making a compound of formula (VI):

[0183]

[0184] (VI);

[0185] comprising combining under suitable conditions a compound of formula (IV):

[0186] X1— AUIX-05325

[0187] (IV);

[0188] a compound of formula (VII):

[0189]

[0190] (VII);

[0191] a compound of the present disclosure; and a transition metal salt or a transition metal complex; thereby producing the compound of formula (VI);

[0192] wherein:

[0193] A is aryl, heteroaryl, or alkenyl;

[0194] n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0195] R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0196] R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0197] R5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; and

[0198] X1is a halogen.

[0199] In certain embodiments, the methods further comprise at least one base. In further embodiments, the at least one base is potassium trimethylsilanolate. In yet further embodiments, the transition metal salt or the transition metal complex is used in an amount of about 1 mol% to about 30 mol% as compared to the compound of formula (VII). In still further embodiments, the transition metal salt or the transition metal complex is used in an amount of about 1 mol% to about 10 mol% relative to the compound of formula (VII). In certain embodiments, the transition metal salt or the transition metal complex is used in an amount of about 5 mol% relative to the compound of formula (VII). In further embodiments, the compound of the present disclosure is used in an amount of about 1 mol% to about 50 mol% relative to the compound of formula (VII). In yet further embodiments, the compound of the present disclosure is used in an amount of about 10 mol% to about 25 mol% relative to the compound of formula (VII). In still further embodiments, the compound of the present disclosure is used in an amount of about 20 mol% relative to the compound of formula (VII). In certain embodiments, the transition metal complex is Pd2(dba)s. In further embodiments, X1UIX-05325

[0200] is bromine. In yet further embodiments, the compound of formula (IV) is selected from the group consisting of:

[0201]

[0202] In certain aspects, the present disclosure provides methods of making a compound of formula (VIII):

[0203]

[0204] comprising combining under suitable conditions a compound of formula (III):

[0205]

[0206] or a compound of formula (VI):

[0207]

[0208] (VI);

[0209] an oxidizing agent; and at least one base; thereby producing the compound of formula (VIII); wherein:

[0210] A is aryl, heteroaryl, or alkenyl;

[0211] n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0212] R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;

[0213] R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; and

[0214] R5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl.UIX-05325

[0215] In certain embodiments, the oxidizing agent is urea’EhCh. In further embodiments, the at least one base is potassium bicarbonate, potassium fluoride, or a combination thereof. In yet further embodiments, the at least one base is a combination of potassium bicarbonate and potassium fluoride.

[0216] Methods of Making Phospha-Adamantanes

[0217] In further aspects, the present disclosure provides methods of making a compound of formula (I):

[0218]

[0219] (i);

[0220] comprising combining a compound of formula (X):

[0221]

[0222] (X);

[0223] with a transition metal salt or a transition metal catalyst, at least one base, and 1 ,3,5,7- tetramethyl-2,4,6-trioxa-8-phosphaadamantane; thereby producing the compound of formula (I);

[0224] wherein:

[0225] R1is H, alkyl, alkoxyl, -O-alkaryl, aralkyl, or aryl;

[0226] R2is H, alkoxyl, or haloalkyl; and

[0227] X2is a halogen.

[0228] In certain embodiments, the at least one base is potassium carbonate. In further embodiments, the transition metal catalyst is Pd(PPhs)4. In yet further embodiments, X2is bromo. In still further embodiments, the compound of formula (X) is selected from the group consisting of:UIX-05325

[0229]

[0230] Definitions

[0231] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0232] The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.

[0233] The term “alkyl” as used herein is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer, or 10 or fewer. In certain embodiments, the term “alkyl” refers to a C1-C10 alkyl group. In certain embodiments, the term “alkyl” refers to a Ci-Ce alkyl group, for example a Ci-Ce straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C12 branched-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-Cs branched-chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0234] The term “cycloalkyl” means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (Cs-Cvjcycloalkyl, which represents a monocyclic saturated carbocyclic ring, having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl,UIX-05325

[0235] cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged monocyclic rings and fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (z.e., a bridging group of the form -(CH2)W-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

[0236] The term “(cycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more cycloalkyl groups. An example of cycloalkylalkyl is cyclohexylmethyl group.

[0237] The term “heterocycloalkyl” as used herein refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl, dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl, azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, trithianyl, and 2-UIX-05325

[0238] azobicyclo [3.1.0] hexane. A heterocycloalkyl group is optionally substituted by one or more substituents as described below.

[0239] The term “(heterocycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.

[0240] The term “alkenyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l -heptenyl, and 3-decenyl. The unsaturated bond(s) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

[0241] The term “alkynyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0242] The term “alkylene” is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In one embodiment an alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. That is, in one embodiment, a “substituted alkyl” is an “alkylene”.

[0243] The term “amino” is a term of art and as used herein refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

[0244]

[0245] wherein Ra, Rt>, and Rceach independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)X-Rd, or Raand Rt>, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; Rd represents an aryl, a heteroaryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and x is zero or an integer in theUIX-05325

[0246] range of 1 to 8. In certain embodiments, only one of Raor Rb may be a carbonyl, e.g., Ra, Rb, and the nitrogen together do not form an imide. In other embodiments, Raand Rb (and optionally Rc) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)X-Rd. In certain embodiments, Raand Rb are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl, any of which may be further substituted (e.g., by halogen, alkyl, alkoxy, hydroxy, and so forth). In certain embodiments, the term “amino” refers to -NH2.

[0247] In certain embodiments, the term “alkylamino” refers to -NH(alkyl).

[0248] In certain embodiments, the term “dialkylamino” refers to -N(alkyl)2.

[0249] The term “amido”, as used herein, means -NHC(=O)-, wherein the amido group is bound to the parent molecular moiety through the nitrogen. Examples of amido include alkylamido such as CHsC(=O)N(H)- and CHsCH2C(=O)N(H)-.

[0250] The term “acyl” is a term of art and as used herein refers to any group or radical of the form RCO- where R is any organic group, e.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0251] The term “aminoalkyl” as used herein refers to an alkyl group substituted with one or more one amino groups. In one embodiment, the term “aminoalkyl” refers to an aminomethyl group, i.e., -CH2NH2.

[0252] The term “aminoacyl” is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.

[0253] The term “aminothionyl” as used herein refers to an analog of an aminoacyl in which the O of RC(O)- has been replaced by sulfur, hence is of the form RC(S)-.

[0254] The term “phosphoryl” is a term of art and as used herein may in general be represented by the formula:

[0255]

[0256] wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl; for example, -P(O)(Ome)- or -P(O)(OH)2. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:UIX-05325

[0257] Q50 Q50

[0258] - Q51 — p - o - - Q51 — P— OR59

[0259] OR59 OR59

[0260] wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N; for example, -O-P(O)(OH)Ome or -NH-P(0)(0H)2. When Q50 is S, the phosphoryl moiety is a “phosphorothioate.”

[0261] The term “aminophosphoryl” as used herein refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(0)(0H)Nme2.

[0262] The term “azide” or “azido”, as used herein, means an -N3 group.

[0263] The term “carbonyl” as used herein refers to -C(=O)-.

[0264] The term “thiocarbonyl” as used herein refers to -C(=S)-.

[0265] The term “alkylphosphoryl” as used herein refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(O)(OH)Me.

[0266] The term “alkylthio” as used herein refers to alkyl-S-. The term “(alkylthio)alkyl” refers to an alkyl group substituted by an alkylthio group.

[0267] The term “carboxy”, as used herein, means a -CO2H group.

[0268] The term “aryl” is a term of art and as used herein refers to includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example, benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group contains from 6-10 carbon ring atoms (i.e., (Ce-Cio)aryl). The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. In certain embodiments, the term “aryl” refers to a phenyl group.

[0269] The term “heteroaryl” is a term of art and as used herein refers to a monocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl,UIX-05325

[0270] benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo [3, 4-d] pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The “heteroaryl” may be substituted at one or more ring positions with one or more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls.

[0271] The term “aralkyl” or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group.

[0272] The term “heteroaralkyl” or “heteroarylalkyl” is a term of art and as used herein refers to an alkyl group substituted with a heteroaryl group, appended to the parent molecular moiety through the alkyl group.

[0273] The term “alkoxy” as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0274] The term “alkoxyalkyl” refers to an alkyl group substituted by an alkoxy group.

[0275] The term “alkoxycarbonyl” means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(=O)-, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and / c / V-butoxycarbonyl.

[0276] The term “alkylcarbonyl”, as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1 -oxopropyl, 2, 2-dimethyl-l -oxopropyl, 1 -oxobutyl, and 1 -oxopentyl.UIX-05325

[0277] The term “arylcarbonyl”, as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

[0278] The term “alkylcarbonyloxy” and “arylcarbonyloxy”, as used herein, means an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and / -butylcarbonyloxy. Representative examples of arylcarbonyloxy include, but are not limited to phenylcarbonyloxy.

[0279] The term “alkenoxy” or “alkenoxyl” means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propen-l-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-0-).

[0280] The term “aryloxy” as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0281] The term “-O-alkaryl” as used herein means an aralkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0282] The term “heteroaryloxy” as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0283] The term “carbocyclyl” as used herein means a monocyclic or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl). Examples of carbocyclyl groups include 1 -cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1 -cyclopentenyl, 3-cyclohexyl, 1 -cyclohexenyl and 2-cyclopentenylmethyl.

[0284] The term “cyano” is a term of art and as used herein refers to -CN.

[0285] The term “halo” is a term of art and as used herein refers to -F, -Cl, -Br, or -I.

[0286] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms.

[0287] The term “hydroxy” is a term of art and as used herein refers to -OH.

[0288] The term “hydroxyalkyl”, as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.UIX-05325

[0289] The term “silyl”, as used herein, includes hydrocarbyl derivatives of the silyl (HsSi-) group (i.e., (hydrocarbyl Si-), wherein a hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS), tertbutyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy] methyl (SEM) .

[0290] The term “silyloxy”, as used herein, means a silyl group, as defined herein, appended to the parent molecule through an oxygen atom.

[0291] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and / / v -isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0292] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0293] It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0294] The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described hereinUIX-05325

[0295] above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0296] In certain embodiments, the optional substituents contemplated in this invention include halogen, azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyl, alkoxyl, amino, aminoalkyl, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether (e.g., -alkylene-O(alkyl)), alkylthio, sulfonyl, sulfonamide, ketone (e.g., -CO(alkyl)), aldehyde (-C(O)H), ester (e.g., -COO(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano.

[0297] As used herein, the term “optionally substituted” or “substituted or unsubstituted” when it precedes a list of chemical moieties means that the list of chemical moieities that follow are each substituted or unsubstituted. For example, “substituted or unsubstituted aryl, heteroaryl, and cycloalkyl” or “optionally substituted aryl, heteroaryl, and cycloalkyl” means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

[0298] The phrase “protecting group”, as used herein, means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nded.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.

[0299] For purposes of the invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67thEd., 1986-87, inside cover.

[0300] Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.UIX-05325

[0301] The term “pharmaceutically acceptable salt” as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I. As another example, the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I per molecule of tartaric acid.

[0302] The terms “carrier” and “pharmaceutically acceptable carrier” as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington’s Pharmaceutical Sciences by E.W. Martin, herein incorporated by reference in its entirety.

[0303] As used herein, the term “oxidizing agent” refers to a reagent that accepts one or more electrons from a substrate. Certain oxidizing agents may also induce the formation of new bonds to oxygen. Illustrative examples of oxidizing agent include, but are not limited to, oxygen, ozone, hydrogen peroxide, periodic acid, sodium periodate, Dess-Martin periodinane, peracetic acid, meto-chloroperbenzoic acid, fluorine, chlorine, bromine, iodine, nitric acid, potassium nitrate, potassium chlorate, peroxydisulfuric acid, peroxymonosulfuric acid, sodium hypochlorite, interhalogen compounds (such as Icl), chromic acids, chromium trioxide, pyridinium chlorochromate, sodium dichromate, potassium permanganate, manganese heptoxide, sodium perborate, nitrous oxide, nitrogen dioxide, dinitrogen tetroxide, ceric ammonium nitrate, and ceric sulfate.

[0304] As used herein, the term “reducing agent” refers to a reagent that donates one or more electrons to a substrate. Illustrative examples of reducing agents include, but are not limited to, lithium, sodium, potassium, magnesium, aluminum, iron, tin, copper, zinc, sodium hydride, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodiumUIX-05325

[0305] tetraacetoxyborohydride, NaAlH2(OCH2CH2OCHs)2, Na(Hg), Zn(Hg), diborane, nickel boride, sodium dithionate, diisobutylaluminum hydride, and ascorbic acid.

[0306] EXAMPLES

[0307] Now being generally described, the invention will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

[0308] Example 1: Exemplary Synthesis of Compounds of this Disclosure

[0309] General Procedure A: Manual cross-coupling of inacol siloxaborolates

[0310] In an argon filled glove box, palladium source (0.01 mmol, 10 mol%), ligand (0.02 mmol, 20 mol%), and base (0.3 mmol, 3.0 equiv.) were added to a 7 mL glass vial followed by a rare earth stir bar (oval, diam. 5 mm, L 10 mm). Solid nucleophile was added at this time (0.2 mmol, 2.0 equiv.). The vial was sealed with an open top screw cap fitted with a Teflon septum, removed from the glove box, and placed under positive argon pressure via a needle attached to a Schlenk line. The electrophiles (0.1 mmol, 1.0 equiv.) were added as 0.5 mL of 0.2 M anhydrous and air-free (argon sparged) dioxane solution. Argon sparged H2O (0.5 mL) was added. The cap was sealed with electrical tape and then the reaction was stirred at 500 rpm in a heat block for 12 hours at 80 °C. After cooling, 3 mL of water was added to the mixture and then it was extracted 3x with 2 mL CH2Q2. The organic layer was passed through a 3 x 1cm silica plug, rinsed with 3 mL CH2Q2, dried with anhydrous sodium sulfate, and concentrated in a 20 mL vial by rotary evaporation. The crude mixture was placed under high vacuum for at least 1 h.

[0311] General Procedure B: Fleming-Tamao oxidation

[0312] After performing the cross coupling, a stir bar, anhydrous and argon sparged THF (2 mL) and methanol (2 mL) were added to the reaction mixture (0.05 M relative to limiting aryl halide electrophile used in General Procedure A). KHCO3 (6.0 equiv.), KF (11 equiv.), and ureaFLCh (15 equiv.) are added to the solution. The vial is sealed with a Teflon cap, electrical taped to seal, and then stirred at 60 °C for 12-14 hours. After allowing the reaction mixture to cool to room temperature, 3 mL of saturated aqueous sodium thiosulfate solution is added, and the mixture is stirred for 20 minutes. To this mixture is added 3 mL H2O. The solution isUIX-05325

[0313] extracted with 5 mL CH2CI2 3x, dried with anhydrous sodium sulfate, and concentrated. Secondary alcohol products were either purified by silica gel column chromatography or analyzed via gas chromatography.

[0314] General Procedure C: Automated cross-coupling of siloxaborolates under aqueous conditions In an argon filled glove box, palladium source (0.005 mmol, 5 mol%) and ligand (0.02 mmol, 20 mol%) were added to a 7 mL borosilicate vial with a stir bar. Solid nucleophile was added at this time (0.2 mmol, 2.0 equiv.). The vial was sealed with an open top screw cap fitted with a Teflon septum, removed from the glove box, placed on the machine, and fixed with two needles: one attached to the solenoid box for positive argon pressure, and another attached to a valve and syringe pump sequence for transfer of liquids. The electrophile (0.1 mmol, 1.0 equiv.) was added as 0.5 mL of a 0.2 M anhydrous and argon sparged dioxane solution through the Teflon septum by the synthesizer machine. Argon sparged H2O (0.5 mL) was added by the machine. The reaction mixture was stirred at 500 rpm in a heat block for a specified time at 80 °C. After cooling, the workup sequence commenced. 2 mL CH2CI2 was added by the machine. The machine then pulled the reaction solution into a syringe pump and pushed it through a plug of 0.5 g silica and 2.0 g anhydrous sodium sulfate packed in an empty Luknova flash column (part # 50-918-463) into a 40 mL scintillation vial through its teflon septum cap via a needle. The machine then performed the same workup again, repeating a total of 3 times. Internal standard (0.1 mmol, 0.1 M in CH2CI2) was added to the reaction solution and then 1 mL of the solution was transferred to a 1.5 mL HPLC vial for HPLC or GC analysis.

[0315] General Procedure D: Anhydrous automated cross-coupling of P- aryloxy silyl pinacol boronic esters

[0316] In an argon filled glove box, palladium source (0.005 mmol, 5 mol%), ligand (0.02 mmol, 20 mol%), and base (0.3 mmol, 3.0 equiv.) were added to a 7 mL borosilicate vial with a stir bar. The vial was sealed with an open top screw cap, fitted with a Teflon septum, removed from the glove box, placed on the machine, and fixed with two needles: one attached to the solenoid box for positive argon pressure, and another attached to a valve and syringe pump sequence for transfer of liquids. The nucleophile (0.2 mmol, 2.0 equiv.) was added by the synthesis machine as 0.5 mL of a 0.4 M anhydrous and argon sparged dioxane solutions via syringe pump through the Teflon septum. The electrophile (0.1 mmol, 1.0 equiv.) was added as 0.5 mL of a 0.2 M anhydrous and argon sparged dioxane solution via syringe pump through the Teflon septum. The reaction mixture was stirred at 500 rpm in a heat block for a specifiedUIX-05325

[0317] amount of time at 80 °C. After cooling, the workup sequence commenced. 2 mL CH2Q2 was added by the machine. The machine then pulled the reaction solution into a syringe pump and pushed it through a plug of 0.5 g silica and 2.0 g anhydrous sodium sulfate packed in an empty Luknova flash column (part # 50-918-463) into a 40 mL scintillation vial through its teflon septum cap via a needle. The machine then performed the same workup again, repeating a total of 3 times. Internal standard (0.1 mmol, 0.1 M in CH2CI2) was added to the reaction solution and then 1 mL of the solution was transferred to a 1.5 mL HPLC vial for HPLC or GC analysis.

[0318]

[0319] An oven dried 40 mL vial equipped with a stir bar was brought into an argon filled glovebox. Pd(PPhs)4 (2 mol%) and K2CO3 (2.0 equiv.) were added. 32 wt% solution of racemic l,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane in xylenes (1.0 equiv.) was added by weight using a pipette. The vial was sealed with a septum lined cap and removed from the glovebox. The reaction vial was placed under positive pressure of argon via a needle fixed to a Schlenk line, m-xylene (0.54 M) followed by the halide (1.0-1.5 equiv.) were added by syringe. The reaction vial was disconnected from the Schlenk line and placed into an aluminum heating well pre-heated to 110 °C and stirred for 2 days. Afterwards, the reaction mixture was cooled to room temperature and filtered through a celite plug with ether. The eluent was concentrated by rotary evaporation until only xylenes remained. The crude product mixture was purified by silica gel column chromatography using a gradient of 0 to 20% ether in hexanes to afford the expected product as a white solid. After taking a31P NMR, if only one signal was present at approximately -40 ppm, the compound was used without further purification. If multiple phosphorus signals were present, the compound was recrystallized from minimal hot ethanol.

[0320] INCORPORATION BY REFERENCE

[0321] All US patents and US and PCT patent application publications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0322] EQUIVALENTS

[0323] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. TheUIX-05325

[0324] full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

UIX-05325CLAIMSWe claim:

1. A compound of formula (I):(I),or a salt thereof;wherein:R1is H, alkyl, alkoxyl, -O-alkaryl, aralkyl, or aryl; andR2is H, alkoxyl, or haloalkyl.

2. The compound of claim 1, wherein R1is H.

3. The compound of claim 1, wherein R1is alkoxyl.The compound of claim 3, wherein R1is selected from the group consisting of5. The compound of claim 1, wherein R1is -O-alkaryl.

6. The compound of claim 5, wherein R1is7. The compound of claim 1, wherein R1is alkyl.

8. The compound of claim 7, wherein R1is methyl.UIX-053259. The compound of claim 1, wherein R1is aralkyl.

10. The compound of claim 7, wherein R1is benzyl.

11. The compound of claim 1, wherein R1is aryl.

12. The compound of claim 11, wherein R1is phenyl.

13. The compound of any one of claims 1-12, wherein R2is H.

14. The compound of any one of claims 1-12, wherein R2is haloalkyl.

15. The compound of claim 14, wherein R2is trifluoromethyl.

16. The compound of any one of claims 1-12, wherein R2is alkoxyl.

17. The compound of claim 16, wherein R2is methoxy.UIX-0532518. The compound of claim 1, wherein the compound is selected from the group consisting(ID,or a salt thereof;wherein:UIX-05325RBis selected from the group consisting of H,0,provided that if RBis H, then RAis not21. A method of making a compound of formula (III):(iff);UIX-05325comprising combining under suitable conditions a compound of formula (IV):X1— A(IV);a compound of formula (V):(V);a compound of any one of claims 1-20; and a transition metal salt or a transition metal complex; thereby producing the compound of formula (III);wherein:A is aryl, heteroaryl, or alkenyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;R5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; andX1is a halogen.

22. The method of claim 21, further comprising at least one base.

23. The method of claim 22, wherein the at least one base is potassium trimethylsilanolate.

24. The method of any one of claims 21-23, wherein the transition metal salt or the transition metal complex is used in an amount of about 1 mol% to about 30 mol% relative to the compound of formula (V).UIX-0532525. The method of claim 24, wherein the transition metal salt or the transition metal complex is used in an amount of about 1 mol% to about 10 mol% relative to the compound of formula (V).

26. The method of claim 24 or 25, wherein the transition metal salt or the transition metal complex is used in an amount of about 5 mol% relative to the compound of formula (V).

27. The method of any one of claims 21-26, wherein the compound of any one of claims 1-20 is used in an amount of about 1 mol% to about 50 mol% relative to the compound of formula (V).

28. The method of claim 27, wherein the compound of any one of claims 1-20 is used in an amount of about 10 mol% to about 25 mol% relative to the compound of formula (V).

29. The method of claim 27 or 28, wherein the compound of any one of claims 1-20 is used in an amount of about 20 mol% relative to the compound of formula (V).

30. A method of making a compound of formula (VI):(VI);comprising combining under suitable conditions a compound of formula (IV):X1— A(IV);a compound of formula (VII):(VII);UIX-05325a compound of any one of claims 1-20; and a transition metal salt or a transition metal complex; thereby producing the compound of formula (VI);wherein:A is aryl, heteroaryl, or alkenyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;R5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; andX1is a halogen.

31. The method of claim 30, further comprising at least one base.

32. The method of claim 31, wherein the at least one base is potassium trimethylsilanolate.

33. The method of any one of claims 30-32, wherein the transition metal salt or the transition metal complex is used in an amount of about 1 mol% to about 30 mol% as compared to the compound of formula (VII).

34. The method of claim 33, wherein the transition metal salt or the transition metal complex is used in an amount of about 1 mol% to about 10 mol% relative to the compound of formula (VII).

35. The method of claim 33 or 34, wherein the transition metal salt or the transition metal complex is used in an amount of about 5 mol% relative to the compound of formula (VII).

36. The method of any one of claims 30-35, wherein the compound of any one of claims 1-20 is used in an amount of about 1 mol% to about 50 mol% relative to the compound of formula (VII).UIX-0532537. The method of claim 36, wherein the compound of any one of claims 1-20 is used in an amount of about 10 mol% to about 25 mol% relative to the compound of formula (VII).

38. The method of claim 36 or 37, wherein the compound of any one of claims 1-20 is used in an amount of about 20 mol% relative to the compound of formula (VII).

39. The method of any one of claims 21-38, wherein the transition metal complex is Pd2(dba)3.

40. The method of any one of claims 21-39, wherein X1is bromine.

41. The method of any one of claims 21-40, wherein the compound of formula (IV) is selected from the group consisting of:

42. A method of making a compound of formula (VIII):(VIII);comprising combining under suitable conditions a compound of formula (III):(ill);or a compound of formula (VI):UIX-05325(VI);an oxidizing agent; and at least one base; thereby producing the compound of formula (VIII); wherein:A is aryl, heteroaryl, or alkenyl;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;R3is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl;R4, independently for each occurrence, is selected from the group consisting of H, alkyl, aryl, -O-aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl; andR5is selected from the group consisting of H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, and heteroaryl.

43. The method of claim 42, wherein the oxidizing agent is urea’FhCh.

44. The method of claim 42 or 43, wherein the at least one base is potassium bicarbonate, potassium fluoride, or a combination thereof.

45. The method of claim 44, wherein the at least one base is a combination of potassium bicarbonate and potassium fluoride.

46. A method of making a compound of formula (I):(i);comprising combining a compound of formula (X):UIX-05325(X);with a transition metal salt or a transition metal catalyst, at least one base, and 1 ,3,5,7- tetramethyl-2,4,6-trioxa-8-phosphaadamantane; thereby producing the compound of formula (I);wherein:R1is H, alkyl, alkoxyl, -O-alkaryl, aralkyl, or aryl;R2is H, alkoxyl, or haloalkyl; andX2is a halogen.

47. The method of claim 46, wherein the at least one base is potassium carbonate.

48. The method of claim 46 or 47, wherein the transition metal catalyst is Pd(PPh3)4.

49. The method of any one of claims 46-48, wherein X2is bromo.

50. The method of claim 46, wherein the compound of formula (X) is selected from the group consisting of:

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