A radical-polar conjunctive reagent and methods for introducing ACYL phosphonates for molecular diversification

Abstract

The subject matter contained herein relates generally to methods for the radical-mediated introduction of the acyl phosphonate group via use of a radical-polar conjunctive reagent. In certain embodiments, the methods provide direct one carbon homologation of carboxylic acids to diverse carbonyl compounds via acyl phosphonates. In certain embodiments, the methods provide introduction of the acyl phosphonate group via the C–H functionalization of small molecules and polyolefins. The subject matter described herein provides the ability to efficiently and selectively insert the acyl phosphonate group to diverse hydrocarbon substrates ranging from small molecules to polymers with >3500 carbon atoms. The ability to both perform direct one carbon homologations of carboxylic acids and to introduce the acyl phosphonate as a diversifiable moiety via C–H functionalization holds significant promise in both medicinal and synthetic chemistry.

Description

[0001] A RADICAL-POLAR CONJUNCTIVE REAGENT AND METHODS FOR INTRODUCING ACYL PHOSPHONATES FOR MOLECULAR DIVERSIFICATION

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] [1] This application claims the benefit of priority to United States Provisional Patent Application No. 63 / 715,402, filed on November 1, 2024, the content of which is incorporated by reference herein in its entirety for all purposes.

[0004] STATEMENT OF GOVERNMENT SUPPORT

[0005] [2] This invention was made with government support under Grant No. GM131708 awarded by National Institutes of Health. The government has certain rights in the invention.

[0006] FIELD OF THE INVENTION

[0007] [3] The subject matter contained herein relates generally to the synthesis of acyl phosphonate compounds via decarboxylative and C-H bond functionalization, and methods employing the compounds.

[0008] BACKGROUND

[0009] [4] Carboxylic acids are among the most widely available, broadly useful building blocks in chemical synthesis, and are common functionality in biologically active drugs and natural products. However, while carboxylic acids constitute many bioactive molecules, direct homologation of carboxylic acids is unknown. Homologation — lengthening the carboxylic acid chain via a single carbon atom — remains a major technical challenge in synthetic chemistry.

[0010] [5] Yet, if the technical challenges could be overcome, the ability to perform direct one carbon homologations of carboxylic acids holds significant promise in both medicinal and synthetic chemistry. The subject matter described herein addresses the shortcomings in this field. BRIEF SUMMARY

[0011] [6] In certain embodiments, the subject matter described herein is directed to a compound having the structure:

[0012] 1

[0013]

[0014] [7] In certain embodiments, the subject matter described herein is directed to a mixture comprising, a compound having the structure:

[0015] 1

[0016]

[0017] and a compound of Formula II:

[0018]

[0019] wherein,

[0020] Rxis an optionally substituted linear or branched Ci-io alkyl or optionally substituted Ce-io aryl;

[0021] Rla, Rlband Rlcare each independently selected from the group consisting of hydrogen, C2-C8 alkenyl, C2-C8 alkynyl, -C1-C3 alkyl-Ci-Cs alkoxy-, C3-8 carbocyclyl, Ce-io aryl, C3-8 heteroaryl, C2-8 heterocyclyl, -Ci- C3 alkyl-Cs-8 carbocyclyl, -C1-C3 alkyl-Ce-io aryl, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a,

[0022] wherein, Q is O or is absent;

[0023] R10ais hydrogen or C1-6 alkyl; and wherein, the carbocyclyl, aryl, heteroaryl, heterocyclyl and alkyl can each be independently optionally substituted;

[0024] and,

[0025] R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of Ci-6 alkyl, halo-C 1-6 alkyl, halo, -CN, and -NO2.

[0026] [8] In certain embodiments, the subject matter described herein is directed to a method of preparing a homologated substrate, comprising:

[0027] i. in the presence of a compound 1 having the structure:

[0028] BrLp,o

[0029]

[0030] MeO OMe

[0031] and,

[0032] a compound of Formula II has the following structure:

[0033]

[0034] wherein,

[0035] Rxis an optionally substituted linear or branched C1-10 alkyl or optionally substituted Ce-io aryl;

[0036] Rla, Rlband Rlcare each independently selected from the group consisting of hydrogen, C2-C8 alkenyl, C2-C8 alkynyl, -C1-C3 alkyl-Ci-Cs alkoxy-, C3-8 cycloalkyl, Ce-io aryl, C3-8 heteroaryl, C2-8 heterocyclyl, -Ci- C3 alkyl-Cs-8 cycloalkyl, -C1-C3 alkyl-Ce-io aryl, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a,

[0037] wherein, Q is O or is absent;

[0038] R10ais hydrogen or C1-6 alkyl; and

[0039] wherein, the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl can each be independently optionally substituted;

[0040]

[0041] R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of Ci-6 alkyl, halo-C 1-6 alkyl, halo, -CN, and -NO2;

[0042] ii. allowing the substrate comprising a COOH group to contact the nitrogencentered radical to form a substrate radical;

[0043] iii. allowing the substrate radical to contact compound 1, wherein, a COOH group on the substrate is functionalized to form an acyl phosphonate having a structure:

[0044]

[0045] [9] In certain embodiments, the subject matter described herein is directed to a method of functionalizing a substrate, comprising:

[0046] i. in the presence of compound 1 having the structure:

[0047]

[0048] and a substrate, contacting a compound of Formula II to form a mixture, wherein the mixture is at a temperature from about 25 °C to about 250 °C, wherein a nitrogencentered radical is prepared, and wherein:

[0049] the substrate comprises a C-H bond; and,

[0050] the compound of Formula II has the following structure:

[0051]

[0052] wherein,

[0053] Rxis an optionally substituted linear or branched C1-10 alkyl or optionally substituted Ce-io aryl;

[0054] Rla. Rlband Rlcare each independently selected from the group consisting of hydrogen, C2-C8 alkenyl, C2-C8 alkynyl, -C1-C3 alkyl-Ci-Cs alkoxy-, C3-8 cycloalkyl, Ce-io aryl, C3-8 heteroaryl, C2-8 heterocyclyl, -Ci- C3 alkyl-Cs-8 cycloalkyl, -C1-C3 alkyl-Ce-io aryl, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a,

[0055] wherein, Q is O or is absent;

[0056] R10ais hydrogen or C1-6 alkyl; and

[0057] wherein, the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl can each be independently optionally substituted;

[0058] and,

[0059] R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of C1-6 alkyl, halo-Ci-6 alkyl, halo, -CN, and -NO2;

[0060] ii. allowing the substrate comprising a C-H bond to contact the nitrogencentered radical to form a substrate radical;

[0061] iii. allowing the substrate radical to contact compound 1, wherein, a C-H bond in the substrate is functionalized to form a C-X bond, wherein X is:

[0062]

[0063]

[0010] In certain embodiments, the subject matter described herein is directed to a method of preparing a homologated substrate, comprising:

[0064] i. forming a mixture comprising a compound of claim 1, a photoredox catalyst and a substrate; wherein, the substrate comprises a COOH group;

[0065] ii. subjecting the mixture to light energy to form a radical:

[0066] iii. allowing the substrate comprising a COOH group to contact the radical to form a substrate radical; and,

[0067] iv. allowing the substrate radical to contact the compound of Formula I, wherein, a COOH group on the substrate is functionalized to form an acyl phosphonate having a structure:

[0068]

[0069]

[0011] In certain embodiments, the subject matter described herein is directed to a functionalized substrate prepared by any method above.

[0012] Still further embodiments are as described herein.

[0070] DETAILED DESCRIPTION

[0071]

[0013] Homologations of organic molecules that add a carbon atom to the substrate are useful in modulating drug potency and accessing molecules which otherwise present a synthetic challenge. Carboxylic acids are one of the most widely available building blocks for chemical synthesis and constitute many bioactive molecules, yet their direct homologation is unknown. Disclosed herein is the direct homologation of carboxylic acids using an easily prepared, shelf-stable (1 -phosphoryl)vinyl sulfonate reagent under mild conditions. Complementary protocols involving either radical-chain transfer or organic photoredox catalysis deliver modular acyl phosphonates in situ which are directly transformed to a wide array of derivatives. The homologation is exceptionally functional group tolerant in applications involving both small molecule building blocks and complex natural products and addresses a longstanding challenge in organic synthesis.

[0072]

[0014] Carboxylic acids are among the most widely available, broadly useful building blocks in chemical synthesis, and are common functionality in biologically active drugs and natural products (7-3). Transformations of synthetically versatile carboxylic acids are invaluable in modem organic synthesis, ranging from classic amide synthesis-the most common reaction in drug development-to catalytic, decarboxylative cross couplings (4 5). Despite the enormous breadth of transformations available, there is a simple transformation of carboxylic acids which remains a major synthetic challenge-lengthening the carboxylic acid chain via single-atom homologation. The ability to perform direct one carbon homologations of carboxylic acids holds significant promise in both medicinal and synthetic chemistry, and the need for such a transformation in medicinal chemistry has been specifically mentioned (6). For example, one-carbon homologs of bioactive carboxylic acid lead compounds can exhibit remarkably enhanced physicochemical and pharmacological properties (7). Furthermore, the ability to directly homologate the vast number of commercially available alkyl carboxylic acids offers access to a wealth of alternative chemical building blocks that are either expensive or unavailable. Exemplary substrates for homologative functionalization include:

[0073]

[0074]

[0015] The challenge of carboxylic acid homologation is somewhat surprising given the well-developed homologations of related carbonyl compounds such as aldehydes and ketones. For example, methylenation of aldehydes followed by hydrolysis is a facile approach to aldehyde homologation (5), and diazomethane insertions enable ketone homologation (9). While protocols to achieve carboxylic acid homologation exist, all require initial functional group interconversion and multiple synthetic steps (10-12). The most common approach is the Amdt-Eistert protocol, first reported in 1935 involving the synthesis of alpha diazocarbonyl compounds via acyl chlorides, followed by silver-mediated Wolff rearrangement (Scheme 1) (10). While this protocol does find use-most notably in the synthesis of P-amino acids (73)-a three-step sequence is required involving reactive and hazardous intermediates, limiting applications with complex, functional group-rich substrates. An alternative protocol is the radical-mediated Barton carboxylic acid homologation; however, this is also a three-step sequence and involves light-sensitive thiopyridone esters (11). Recently, a three-step homologation of carboxylic acids via the redox active ester was reported, but this approach is limited to homologated ester synthesis (14). The significant drawbacks to these strategies limits the synthetic viability of carboxylic acid homologation for synthetic and medicinal chemistry’.

[0075]

[0016] As described herein, development of a suitable radical trapping agent and a repurposed O-alkeny Ihydroxamate reagent (75) allows direct, homologative diversification of carboxylic acids (Scheme 1). The capability of / Bu amidyl radicals to promote decarboxylations of carboxylic acids via direct O-H HAT in a decarboxylative xanthylation using 7V-xanthylamides is known (76). However, utilizing an O-alkeny Ihydroxamate reagent 2- initially applied to aliphatic C-H diversification (75)-described herein is radicalchain decarboxylative homologation. The methods required the development of a new somophile reagent for trapping of a putative carbon-centered radical in a chain process that also yielded a reactive acyl electrophile for polar addition of a nucleophile. This shelfstable vinyl sulfonate reagent 1 and derivatives thereof can achieve these goals and enable the first direct homologative diversification of carboxylic acids. Reagent 1 has properties of a bifunctional reagent (77) displaying both radical and polar reactivity by initially participating in an Sn2’ addition to generate an acyl phosphonate in situ, which allows for subsequent broad homologative diversification. Scheme 1 depicts comparison of direct homologative diversification to the classic Amdt-Eistert approach.

[0076]

[0077] Scheme 1.

[0078]

[0017] As described herein, (l-phosphoryl)vinyl sulfonates

[0079]

[0080] bifunctional reagent 1

[0081] permits a unique synthesis

[0082] for molecular diversification

[0083] facilitate the homologative diversification of a broad range of alkyl carboxylic acids and functionalization of C-H bonds

[0084]

[0018] The homologations can be straightforwardly performed by heating a mixture of the carboxylic acid substrate with reagents 1 and 2, followed immediately by addition of the desired nucleophile and DBU to deliver the homologated product (18). A representative scope of the methods using a range of carboxylic acid building blocks includes those shown below in Table 1. Alcohols are representative nucleophiles yielding homologated esters. Primary carboxylic acids (3-6); secondary carboxylic acids (7-14) and tertiary carboxylic acids are exemplar}7substrates. The homologations of tertiary7carboxy lic acids were also efficient (15-16), and the reaction of a 2- / Bu oxazolidine substrate (19) occurred exclusively on the a-face away from the / Bu group (20) to deliver 16 which sen es as a diversifiable building block for the synthesis of quaternary P-amino acids (21 22). The homologation of a benzothiazole-substituted aryl acetic acid substrate, such as 17 is and example of the homologation to substrates containing Lewis-basic heterocycles. Functionalized strained ring carbocycles are useful small molecule building blocks in medicinal chemistry, enabling the positioning of molecular functionality7in unique vector space and serving as bioisosteres for other classes of compounds (23). As many strained ring carboxylic acids are commercially available or readily accessed, the direct homologation of these compounds is an attractive route to new molecular building blocks featuring these systems, such as 18-22, including a functionalized cyclopropane 18, spirocyclobutane 19, bicyclo[2.2.2]octane 20, [l.l.l]bicyclopentane (BCP, 21), and a cubane derivative (22). These types of transformations provide direct access to unique strained ring derivatives that would otherwise pose a significant synthetic challenge.

[0085]

[0019] A valuable feature of the current protocol is the broad range of nucleophiles amenable to the homologation via sequential addition to the acyl phosphonate intermediate. With respect to oxygen-based nucleophiles, the addition of NaOH or alcohols provide access to the carboxylic acid (23) or ester homolog (24), respectively. Addition of a range of primary7or secondary7amines can provide amide homologs (25-29), with (+)-pseudoephedrine delivering a product (29) primed for subsequent stereoselective alkylation (24).

[0086]

[0087]

[0020] Because carboxylic acid functionality’ is widely present in complex natural products and bioactive small molecules, the methods desenbed herein provide a practical, single-step homologative diversification as an attractive late-stage transformation, a broad range of complex substrates are also amenable. Transformations of diverse 1° substrates (30-33) allow for chemoselectivity of the reaction, having tolerance of common hydrogen bonding functionality such as ureas, alcohols, and amides. Homologations of complex secondary acids (34-36) exhibit potential for high diastereoselectivity with cyclic substrates. Importantly, the O-H HAT of carboxylic acids by the reactive amidyl radical proceeds preferentially over C-H HAT of the relatively weak benzylic C(sp3)-H sites such as in ibuprofen (34). Transformations of bezafibrate and isosteviol as examples can yield quaternary homologs (37-38), with excellent diastereoselectivity. Exemplary complex substrates include:

[0088]

[0089]

[0021] As described herein, homologative diversification offers a broadly applicable tool to streamline the synthesis of carbonyl compounds that would otherwise require multistep synthetic sequences. Representative examples are depicted in Schemes 2A-C. Scheme 2A depicts a two-step lactone homologation facilitates the synthesis of (+)-ambreinolide. Scheme 2B depicts homologation of a commercially available spirocyclobutane enables a concise, two-step synthesis of an NAMPT modulator. Scheme 2C depicts representative catalytic homologations using an acridinium photoredox catalyst.

[0090]

[0091] Scheme 2A.

[0092]

[0093] Scheme 2C.

[0094]

[0022] Exemplary catalytic homologations include:

[0095]

[0096]

[0023] In contrast to the homologative ring expansion of cyclic ketones via the insertion of diazo compounds, the homologation of lactones typically requires a multistep sequence (25). Described herein is a straightforward two-step approach to the homologation of lactones via initial hydrolysis followed by tandem homologation / cyclization, for example, the transformation of commercially available and inexpensive (+)-sclareolide to the natural product (+)-ambreinolide (26 27) is easily performed by hydrolysis followed by homologative lactonization (Scheme 2A). A previous approach to (+)-ambreinolide required 14 steps from linalool and proceeded in low overall yield (28–30). As a second example, the synthesis of nicotinamide phosphoribosyltransferase (NAMPT) modulator 40 involves the homologation of the spirocyclobutane carboxylic acid 41 via a 7-step sequence (31). Using the homologative diversification, 41 can be synthesized from commercially available acid 39 in two steps, highlighting the utility in the preparation of new drug analogs (Scheme 2B).

[0097]

[0024] Scheme 3 depicts photoredox on exemplary substrates:

[0098]

[0099] Scheme 3.

[0100]

[0025] Without being bound to theory, an outline of the reaction mechanism is provided in Scheme 4. Following initiation and amidyl radical formation, O-H HAT of the carboxylic acid substrate leads to decarboxylation and formation of a carbon-centered radical. This intermediate then adds to the (1 -phosphoryl)vinyl sulfonate 1 in a SH2’ process (37) leading to the acyl phosphonate and aryl sulfonyl radical. The sulfonyl radical then adds to reagent 2, leading to chain transfer. The acyl phosphate is stable under these reaction conditions and is primed for subsequent diversification upon the addition of DBU and the nucleophile of choice.

[0101]

[0102] Scheme 4.

[0103]

[0026] The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0104] I. Definitions

[0105]

[0027] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0106]

[0028] A dash

[0107]

[0108] that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through or perpendicular across the end of a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0109]

[0029] The prefix “Cu-Cv" indicates that the following group has from u to v carbon atoms. For example, “Ci-Ce alkyf’ indicates that the alkyl group has from 1 to 6 carbon atoms.

[0110]

[0030] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 50%. In certain other embodiments, the term “about” includes the indicated amount ± 20%. In certain other embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. In certain other embodiments, the term “about” includes the indicated amount ± 0.5% and in certain other embodiments, 0.1%. Such variations are appropriate to perform the disclosed methods or employ the disclosed compositions. Also, to the term “about x” includes description of “x”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g, reference to “the compound” includes a plurality of such compounds.

[0111]

[0031] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 12 carbon atoms (i.e., C1-C12 alkyl), 1 to 8 carbon atoms (i.e., Ci-Cs alkyl), 1 to 6 carbon atoms (i.e., Ci-Ce alkyl), 1 to 4 carbon atoms (i.e.. C1-C4 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH₂)₃CH₃, sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tertbutyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH₂)₂CH₃ and isopropyl (i.e., -CH(CH3)2).

[0112]

[0032] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene"’ group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0113]

[0033] “Alkenyl"’ refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (z.e., C2-C20 alkenyl), 2 to 8 carbon atoms (z.e., C2-C8 alkenyl), 2 to 6 carbon atoms (z. e., C2-C6 alkenyl) or 2 to 4 carbon atoms (z. e., C2-C4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0114]

[0034] “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (z.e., C2-C20 alkynyl), 2 to 8 carbon atoms (z.e., C2-Cs alky nyl), 2 to 6 carbon atoms (z.e., C2-C6 alkynyl) or 2 to 4 carbon atoms (z.e., C2-C4 alkynyl). The term “alky nyl” also includes those groups having one triple bond and one double bond.

[0115]

[0035] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, such as, methylene — CH2 —, ethylene — CH2CH2 —, and the like. As an example, a “hydroxy-methylene” refers to HO — CH2 — *, where * is the attachment point to the molecule.

[0116]

[0036] “Alkoxy” refers to the group “alkyl-O-” (e.g.. C1-C3 alkoxy or Ci-Ce alkoxy). Examples of alkoxy groups include, e.g, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[0117]

[0037] “Alkoxy-alkyl” refers to the group “-alkyl-alkoxy” and the like. The term “C1-C3 alkoxy-Ci-C3 alkyl” refers to a one to three carbon alkyl chain where one hydrogen on any carbon is replaced by an alkoxy group having one to three carbons, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having one to three carbons. The term, “Ci-Ce alkoxy-Ci-Cs alkyl” refers to a one to three carbon alkyl chain where one hydrogen on any carbon is replaced by an alkoxy group having one to six carbons, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having one to six carbons. Non-limiting examples of alkoxy-alkyl are -CH2OCH3, -CH2OC(CH3)3, and -CH₂CH(OH)OCH₃.

[0118]

[0038] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g, monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (z.e., C6-C20 aryl), 6 to 12 carbon ring atoms (z.e., C6-C12 aryl), or 6 to 10 carbon ring atoms (i.e., Ce-Cio aryl). Examples of ary l groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of the point of attachment. If one or more ary l groups are fused yvith a heterocyclyl, the resulting ring system is heterocyclyl regardless of the point of attachment.

[0119]

[0039] The term “phenyl” or “Ph” refers to an aryl ring of the formula of CeHs where the point of attachment to another group or moiety is one of the carbons. The phenyl may be substituted on the aromatic ring. In one embodiment, 0, 1, 2, 3, 4, or 5 atoms of the and group may be substituted by a substituent.

[0120]

[0040] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-” and the like, such as (Ce-Cio aryl)-Ci-C3 alkyl-. As used herein, “(Ce-Cio aryl)-Ci-C3 alkyl” refers to a one to three carbon alkyl chain where one of the hydrogen atoms on any carbon is replaced by an ary l group having six to ten carbon atoms, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an ary l group having six to ten carbon atoms. A non-limiting example of arylalkyl is benzyl.

[0121]

[0041] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-C20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-C12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-C10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., Cs-Cs cycloalkyl), 3 to 7 ring carbon atoms (i.e., C3-C7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-C6 cycloalky l). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bridged and / or fused rings, such as bicyclo[2.2. l]heptanyl, bicyclo[2.2.2]octanyl, bicyclofl. l.l]pentan-l-yl, adamantyl. norbomyl. decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. Further, the term cycloalkyl is intended to encompass any ring or ring system comprising a non-aromatic alkyl ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecany 1.

[0042] “Cycloalkylalky ’ refers to the group “cycloalkyl-alkyl-” and the like, such as (C3-C6 cycloalkyl)-Ci-C3 alkyl. As used herein, “(C3-C6 cycloalkyl)-Ci-C3 alkyl’7refers to a one to three carbon alkyl chain where one of the hydrogen atoms on any carbon is replaced by a cycloalkyl group having three to six carbon atoms, in particular, one hydrogen on one carbon of the chain is replaced by a cycloalkyl group having three to six carbon atoms.

[0122]

[0043] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).

[0123] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above that is a substituted alkyl, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen. For example, halo-Ci-C3 alkyl refers to an alkyl group of 1 to 3 carbons wherein at least one hydrogen atom is replaced by a halogen. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0124]

[0044] “Hydroxyalkyl” refers to an alkyl group as defined above that is a substituted alkyl, wherein one or more (e.g., 1 to 6. or 1 to 3) hydrogen atoms are replaced by a hydroxy group (e.g., hydroxy-C1-C3-alkyl, hydroxy-Ci-Ce-alkyl). The term “hydroxy-Ci-Cs alkyl” refers to a one to three carbon alkyl chain where one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. The term “hydroxy-Ci-Ce alkyl” refers to a one to six carbon alkyl chain where one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. Nonlimiting examples of hydroxyalkyl include -CH2OH, -CH2CH2OH, and -C(CHs)2CH2OH.

[0125]

[0045] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. In certain embodiments, the heteroalkyl can have 1 to 3 carbon atoms (e.g., C1-C3 heteroalkyl) or 1 to 6 carbon atoms (e.g., Ci-Ce heteroalkyl), and one or more (e.g., 1, 2, or 3) heteroatoms or heteroatomic groups. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms of the alkyl group in the “heteroalkyl” may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-. -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc ), thioethers (e.g., -CH2SCH3. -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CHs, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2O CH3, etc.) and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyC H3, etc., where Ryis hydrogen, alkyd, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). In certain embodiments, heteroalky 1 can have 1 to 20 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0126]

[0046] '‘Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroary l includes 1 to 20 ring carbon atoms (i.e., C1-C20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-C12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-C8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 9-10 membered ring systems (i.e., 9-10 membered heteroaryl). 5-10 membered ring systems (i.e., 5-10 membered heteroaryl), 5-7 membered ring systems (i.e., 5-7 membered heteroaryl), 5-6 membered ring systems (i.e., 5-6 membered heteroaryl). or 4-6 membered ring systems (i. e., 4-6 membered heteroary l), each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1 -oxidopyrazinyl, 1-oxidopyridazinyl. phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl. pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo [d] imidazolyl, pyrazolo[l,5-a]pyridinyl and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring or ring system, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0127]

[0047] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”, such as (5- to 10-membered monocyclic heteroaryl)-Ci-Cs alkyl. As used, herein, “(5- to 10-membered monocyclic heteroaryl)-Ci-C3 alkyl” refers to a one to three carbon alkyl chain where one or more hydrogens on any carbon is replaced by a monocyclic heteroaryl group having 5-to 10- members, in particular, one hydrogen on one carbon of the chain is replaced by a (5-to 10-membered monocyclic heteroaryl group.

[0128]

[0048] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e.. the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass a ring or ring system comprising any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. The term heterocyclyl is also intended to encompass a ring system comprising a cycloalkyl ring which is fused to a heteroaryl ring, regardless of the attachment to the remainder of the molecule. Additionally, the term heterocyclyl is intended to encompass a ring system comprising a cycloalkyl ring which is fused to a heterocyclyl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-C20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-C12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-C10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-C8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-C12 heterocyclyl), 3 to 8 ring carbon atoms (i.e.. C3-C8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-C6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. When the heterocyclyl ring contains 4- to 6- ring atoms, it is also referred to herein as a 4- to 6-membered heterocyclyl. Also disclosed herein are 5- or 6-membered heterocyclyls, having 5 or 6 ring atoms, respectively, and 5- to 10-membered heterocyclyls, having 5 to 10 ring atoms. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazohdinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. In certain embodiments, the term “heterocyclyl” can include “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-l-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1.2.3, 4-tetrahydroisoquinolinyl, 4, 5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0129]

[0049] “Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-.”

[0130]

[0050] The terms '‘optional'’ or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0131]

[0051] The term “substituted” used herein means any of the above groups (i.e., alkyd, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) wherein at least one (e.g, 1 to 5. 1 to 4, or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide or -Si(Ry)3, wherein each Ryis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

[0132]

[0052] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more (e.g, 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgS(=O)i-2Rh, -C(=O)Rg, -C(=O)ORg, -OC(=O)ORg, -OC(=O)Rg, -C(=O)NRgRh, -OC(=O)NRgRh, -ORg, -SRg, -S(=O)Rg, -S(=O)2Rg, -OS(=O)i-2Rg, -S(=O)i-2ORg, -NRgS(=O)i-2NRgRh, =NSO2Rg, =NORg, -S(=O)i-2NRgRh, -SF5, -SCF3 or -OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g, 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl.

[0133]

[0053] In certain embodiments, “substituted” also means any of the above groups, in particular a substituted alkyl, cycloalkyl, aryl, heteroary 1, or heterocyclyl, in which one or more (e.g, 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalky l, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyL heterocycly lalkyl, heteroaryl, and / or heteroary lalkyl, or two of Rgand Rhand R1are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alky l optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy. In certain embodiments, “substituted” also means any of the above groups, in particular a substituted alkyl, cycloalkyl, aryl, heteroary 1, or heterocyclyl, in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, nitro, halo, alkoxy, alkylamino, cycloalkyl, heterocyclyl. aryl or heteroaryl. In certain embodiments, "substituted" also means any of the above groups, in particular a substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, nitro, halo, alkoxy, or alkylamino.

[0134]

[0054] Structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted’’ may describe other chemical groups defined herein.

[0135]

[0055] As used herein, the term “small molecule” refers to a chemical compound with a low molecular weight (< 900 Daltons). In certain embodiments, the small molecule may be an active pharmaceutical ingredient and / or may regulate biological processes by engaging with biological targets.

[0136]

[0056] As used herein, “polymer” refers to the product of a polymerization reaction in which one or more monomers and / or repeat units are linked together. As used herein, “copolymer” refers to a polymer resulting from the polymerization of two or more chemically distinct monomers. A “block copolymer” refers to a polymer comprising blocks of monomers.

[0137]

[0057] The term “substrate radical” refers to an intermediate in the processes described herein whereby the substrate, e.g. a PI or PC feedstock, is converted to a reactive species. The radical can be generated by any known methods.

[0138]

[0058] As used herein, the term “post-industrial” or “PI” refers to a stream of polyolefin-based polymer feedstock for the processes described herein. In certain embodiments, the post-industrial polymer is obtained from production waste. As used herein, the term “postconsumer” or “PC” refers to a stream of polyolefin-based polymer feedstock for the process described herein. In certain embodiments, the post-consumer polymer is obtained from post-consumer products. Regardless of the feedstock, the polymer can be in a form produced by regrinding. The feedstocks can contain primarily polypropylene (PP), polyethylene (PE) and mixed polyolefins (MPO). However, feedstocks can include any PC or PI polymers that include, but are not limited to, polyethylene (PE), low-density polyethylene (LPDE), linear low density (LLDPE), high density (HDPE), polypropylene, polyvinylchloride, polystyrene, and polyethylene terephthalate. The term "‘substrate” refers to any of the feedstock materials.

[0139]

[0059] As used herein, the ‘‘contacting” refers to reagents in close proximity so that a reaction may occur. As used herein, the term “modified” refers to covalently transforming the starting material, whereby the resulting product has a measurable change in a chemical or physical property.

[0140]

[0060] As used herein, the term “photoredox catalyst” refers to any known compound capable of a catalytic role under lower energy radiation, such as visible light.

[0141]

[0061] Additional definitions may be set forth below.

[0142] II. Compounds and Methods

[0143]

[0062] In certain embodiments, the subject matter described herein is directed to a compound having the structure:

[0144]

[0145]

[0063] In certain embodiments, the subject matter described herein is directed to a mixture comprising, compound 1 and a compound of Formula II:

[0146]

[0147] wherein,

[0148] Rxis an optionally substituted linear or branched Ci-io alkyl or optionally substituted Ce-io aryl; Rla, Rlband Rlcare each independently selected from the group consisting of hydrogen. C2-C8 alkenyl, C2-C8 alkynyl, -C1-C3 alkyl-Ci-Cs alkoxy-, C3-8 carbocyclyl, Ce-io aryl, C3-8 heteroaryl, C2-8 heterocyclyl, -Ci- C3 alkyl-Cs-8 carbocyclyl, -C1-C3 alkyl-Ce-io aryl, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a.

[0149] wherein, Q is O or is absent;

[0150] R10ais hydrogen or C1-6 alkyl; and

[0151] wherein, the carbocyclyl, aryl, heteroary l, heterocyclyl and alkyl can each be independently optionally substituted;

[0152] and,

[0153] R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of C1-6 alkyl, halo-C 1-6 alkyl, halo, -CN, and -NO2.

[0154]

[0064] In certain embodiments, the subject matter described herein is directed to a method of preparing a homologated substrate, comprising:

[0155] i. in the presence of compound 1 having the structure:

[0156]

[0157] and a substrate, contacting a compound of Formula II to form a mixture, wherein the mixture is at a temperature from about 25 °C to about 250 °C, wherein a nitrogencentered radical is prepared, and wherein:

[0158] the substrate comprises a COOH group;

[0159] and,

[0160] the compound of Formula II has the following structure:

[0161]

[0162] wherein. Rxis an optionally substituted linear or branched Ci-io alkyl or optionally substituted Ce-io aryl;

[0163] Rla, Rlband Rlcare each independently selected from the group consisting of hydrogen, C2-C8 alkenyl, C2-C8 alkynyl, -C1-C3 alkyl-Ci-Cs alkoxy-, C3-8 cycloalkyl, Ce-io ar l, C3-8 heteroaryl, C2-8 heterocyclyl, -Ci- C3 alkyl-Cs-8 cycloalkyl, -C1-C3 alkyl-Ce-io aryl, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a,

[0164] wherein, Q is O or is absent;

[0165] R10ais hydrogen or C1-6 alkyl; and

[0166] wherein, the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl can each be independently optionally substituted;

[0167] and,

[0168] R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of C1-6 alkyl, halo-C 1-6 alkyl, halo, -CN, and -NO2;

[0169] ii. allowing the substrate comprising a COOH group to contact the nitrogencentered radical to form a substrate radical;

[0170] iii. allowing the substrate radical to contact compound 1, wherein, a COOH group on the substrate is functionalized to form an acyl phosphonate having a structure:

[0171]

[0172]

[0065] In certain embodiments, the subject matter described herein is directed to a method of functionalizing a substrate, comprising:

[0173] i. in the presence of compound 1 having the structure:

[0174]

[0175] and a substrate, contacting a compound of Formula II to form a mixture, wherein the mixture is at a temperature from about 25 °C to about 250 °C. wherein a nitrogencentered radical is prepared, and wherein:

[0176] the substrate comprises a C-H bond; and, the compound of Formula II has the following structure:

[0177]

[0178] wherein,

[0179] Rxis an optionally substituted linear or branched C1-10 alkyl or optionally substituted Ce-io aryl;

[0180] Rla, Rlband Rlcare each independently selected from the group consisting of hydrogen. C2-C8 alkenyl, C2-C8 alkynyl, -C1-C3 alkyl-Ci-C3 alkoxy-, C3-8 cycloalkyl, Ce-io ary l. C3-8 heteroaryl, C2-8 heterocyclyl, -Ci- C3 alkyl-C3-8 cycloalkyl, -C1-C3 alkyl-Ce-io aryl, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a,

[0181] wherein, Q is O or is absent;

[0182] R10ais hydrogen or C1-6 alkyl; and

[0183] wherein, the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl can each be independently optionally substituted;

[0184] and.

[0185] R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of Ci-6 alkyl, halo-C 1-6 alkyl, halo, -CN, and -NO2;

[0186] ii. allowing the substrate comprising a C-H bond to contact the nitrogencentered radical to form a substrate radical;

[0187] iii. allowing the substrate radical to contact compound 1, wherein, a C-H bond in the substrate is functionalized to form a C-X bond, wherein X is:

[0188]

[0189]

[0066] In certain embodiments, the subject matter described herein is directed to a method of preparing a homologated substrate, comprising: i. forming a mixture comprising a compound of claim 1, a photoredox catalyst and a substrate; wherein, the substrate comprises a COOH group;

[0190] ii. subjecting the mixture to light energy to form a radical:

[0191] iii. allowing the substrate comprising a COOH group to contact the radical to form a substrate radical; and,

[0192] iv. allowing the substrate radical to contact the compound of Formula I, wherein, a COOH group on the substrate is functionalized to form an acyl phosphonate having a structure:

[0193]

[0194]

[0067] In certain of the above embodiments, compound 1 is a solid at room temperature.

[0195]

[0068] In certain of the above embodiments, a mixture can further comprise a solvent.

[0196]

[0069] In certain of the above embodiments, a mixture can further comprise a substrate.

[0197]

[0070] In certain of the above embodiments, an acyl phosphonate having a structure:

[0198]

[0199] is contacted with a nucleophile to convert the acyl phosphonate to

[0200]

[0201]

[0071] In certain of the above embodiments, the compound of Formula II is present at 1.0 to 3.0 equiv of the compound of Formula I.

[0202]

[0072] In certain of the above embodiments, the method is a one-pot or one-step synthesis.

[0203]

[0073] In certain of the above embodiments, the mixture is at about 50 °C to about 150 °C.

[0204]

[0074] In certain of the above embodiments, light provides activation energy of the catalyst. In certain of the above embodiments, the light is of a wavelength of visible light.

[0205]

[0075] In certain of the above embodiments, the photoredox catalyst is an acridinium photoredox catalyst.

[0206]

[0076] In certain of the above embodiments, the substrate is a polymer or small molecule.

[0207]

[0077] In certain of the above embodiments, the substrate is a polymer, wherein the polymer comprises a unit comprising at least one C-H bond and having the structure: In certain of the above embodiments, the polymer is LLDPE (linear low-density polyethylene), iPP (isotactic polypropylene). HDPE (high-density polyethylene), PIPE (post-industrial polyethylene), PCPE (post-consumer polyethylene), NDPE (narrow dispersity polyethylene).

[0208]

[0078] In certain of the above embodiments, one C-H bond in the unit is functionalized, wherein the unit has the structure:

[0209]

[0210]

[0079] In certain of the above embodiments, the methods further comprise contacting the functionalized unit with a nucleophile to prepare

[0211]

[0212] Nuc

[0213]

[0080] In certain of the above embodiments, Nuc is a residue of the nucleophile. In certain of the above embodiments, useful nucleophiles include water, alcohol, amine and thiol. In certain of the above embodiments, useful nucleophiles include

[0214]

[0215]

[0081] In certain of the above embodiments, the subject matter described herein is directed to a functionalized substrate prepared by any method above.

[0216]

[0082] Compounds disclosed herein may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23. Wiley. N. Y. (1967-2006 ed.), or Beilsteins Handhuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database).

[0083] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing Formula I compounds and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0217]

[0084] The General Procedures and Examples provide exemplary methods for preparing compounds. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted and discussed in the Schemes, General Procedures, and Examples, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry’ well known to those skilled in the art.

[0218]

[0085] In preparing compounds described herein, protection of remote functionality (e.g., primary' or secondary amine) of intermediates may be necessary'. The need for such protection will vary' depending on the nature of the remote functionality' and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, phthalimide (Phth), t-butoxycarbonyl (Boc). benzyloxy carbonyl (Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0219]

[0086] The following examples are offered by way of illustration and not by way of limitation.

[0220] EXAMPLES

[0221]

[0087] General Methods and Procedures

[0222]

[0088] Proton and carbon magnetic resonance spectra (1H NMR and13C NMR) were recorded on either a Bruker AVANCE NEO 400 MHz (1H NMR at 400 MHz and 13C at 101 MHz) or 500 MHz (1H NMR at 500 MHz and13C at 125 MHz) or 600 MHz (1H NMR at 600 MHz and 13C at 151 MHz) NMR spectrometer with solvent resonance as the internal standard (1H NMR: CHC13 at 7.260 ppm. 13C NMR: CDC13 at 77.16 ppm).

[0223] 1H NMR data are reported as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = sextet, hept = heptet, m = multiplet), coupling constants (Hz), and integration. High-resolution mass spectrometry samples were analyzed with a Q exactive HF-X (ThermoFisher, Bremen, Germany) mass spectrometer with samples introduced via an electrospray source (ESI) at a flow rate of 15 pL / min in methanol. Xcalibur (ThermoFisher, Bremen, Germany ) was used to analyze the data. Molecular formula assignments were determined with Molecular Formula Calculator (v 1.2.3). Purification of the reaction products was carried out by flash chromatography using Siliaflash P60 silica gel (40-63 pm) purchased from Silicycle. Tetrahydrofuran, diethyl ether, acetonitrile, and dichloromethane were dried by passage through a column of neutral alumina under nitrogen prior to use. PhCF3 and HFIP were sparged with argon before storage over 4 A molecular sieves in an argon-filled glovebox. All other reagents were obtained from commercial sources and used without further purification, unless otherwise noted. PR 160 LED lights were purchased from Kessil and set to 100% intensity (352mW / cm2 measured from 1 cm distance).

[0224] List of Abbreviations

[0225] Boc tert-butyloxy carbonyl

[0226] BnOH benzyl alcohol

[0227] DBU l,8-diazabicyclo[5.4.0]undec-7-ene

[0228] DCM di chloromethane

[0229] DMSO dimethyl sulfoxide

[0230] EtOAc ethyl acetate

[0231] Et20 diethyl ether

[0232] FA formic acid

[0233] HFIP 1,1,1,3,3.3-hexafluoroisopropanol

[0234] HMDSO hexamethyldisiloxane

[0235] HOBt hydroxy benzotriazole

[0236] zPrOH 2-propanol

[0237] MeCN acetonitrile

[0238] MeOH methanol

[0239] PhCF3 a,a,a-trifluorotoluene

[0240] TEA triethylamine

[0241] TFA trifluoroacetic acid THF tetrahydrofuran

[0242]

[0089] Reagent Preparation

[0243]

[0244]

[0090] l-(Dimethoxyphosphoryl)vinyl 4-biomobenzenesulfonate (1): This compound was prepared in analogy to a published procedure.! To an oven-dried 100 mL round bottom flask containing a magnetic stir bar, acetyd chloride (7.11 mL, 100 mmol, 1.00 equiv) was added and cooled to 0°C. Trimethyl phosphite (11.8 mL, 100 mmol, 1.00 equiv) was then added dropwise over a period of 1 hour. (Note: the addition rate must be monitored due to the possibility of an exotherm.) The colorless solution was then allowed to warm to rt and stirred for an additional 2 hours. The mixture was concentrated under reduced pressure to yield dimethyl acetylphosphonate as a colorless oil, which was used in the next step without further purification. The dimethyl acetylphosphonate as transferred to an oven-dried 1 L round bottom flask containing a magnetic stir bar. THF (300 mL) and 4-bromobenzenesulfonyl chloride (38.3 g, 150 mmol, 1.50 equiv) were then added. The reaction was cooled to 0 °C and DBU (22.4 mL, 150 mmol, 1.50 equiv) was added dropwise. The reaction was allow ed to warm to rt and stirred for 12 hours. The resulting mixture was then filtered directly through a pad of silica using EtOAc as eluent. The mixture was concentrated under reduced pressure. The crude oil was then dissolved in EtOAc (75 mL) in an Erlenmeyer flask. The flask was then sealed with a septum, wrapped with teflon, and placed in the freezer overnight. The solvent was then filtered off and the crystallized solids were washed with cold EtOAc to yield the title compound as an off-white crystalline solid (14.7 g, 40%).

[0245] Note: Stability tests w ere performed by either irradiating or heating a solution of reagent 1 for 3 h and 16 h. 1 -(Dimethoxyphosphoryl)vinyl 4-bromobenzenesulfonate (1) (37.1 mg, 0.100 mmol) was dissolved in 1 mL of PhCF3. Partial decomposition was observed under 40 W 440 nm lights at 3 h (82% returned starting material) and major decomposition was observed under 40 W 440 nm lights at 16 h (38% returned starting material). >95% returned starting material was observed at 90 °C for both 3 h and 16 h. Returned starting material was determined by NMR analysis with addition of internal standard. 1H NMR (600 MHz, Chloroform-d) 57.82 - 7.79 (m, 2H), 7.74 - 7.69 (m, 2H), 6.06 (dd, J = 17.7, 3.0 Hz, 1H), 6.02 (q, J = 3.0 Hz, 1H), 3.65 (d, J = 11.3 Hz, 6H).

[0246] 13C NMR (151 MHz, Chloroform-d) 5 145.53, 144.01, 134.89, 132.68. 130.02, 121.52 (d, J = 23.8 Hz), 53.50, 53.47.

[0247] Rf = 0.60 (EtOAc)

[0248] HRMS (ESI) calculated for [M+Na]+: 394.9148, found 394.9147.

[0249]

[0091] / V-(te / 7-butyl)-'V-hydroxy-3,5-bis(trifluoromethyl)benzamide

[0250]

[0251]

[0092] was prepared according to a published procedure; physical and spectral data were in accordance with literature data. Procedures for the synthesis of compounds of Formula II and all species of Formula II disclosed in PCT / US2022 / 029013 are herein incorporated by reference in its entirety.

[0252]

[0093] / V-(te / 7-butyl)- 'V-((l-pheiiylvinyl)oxy)-3,5-bis(trifluoromethyl)benzamide (2)

[0253]

[0254] was prepared according to a published procedures with several modifications as follows: to a 1 L Erlenmeyer flask were added a magnetic stir bar, V-( / ert-butyl)-A hydroxy-3, 5-bis(trifluoromethyl)benzamide (18.2 g. 55.2 mmol, 1.00 equiv) and DCM (600 mb). Cu(OAc)2 • H2O (11.0 g, 55.2 mmol, 1.00 equiv), pyridine (13.0 mL, 166 mmol, 3.00 equiv), and Na2SO4 (39.2 g, 276 mmol, 5.00 equiv) were then added to the reaction mixture. The reaction was stirred for 12 hours at rt. To the flask was then added (1-phenyl)vinyl boronic acid (16.3 g, 110 mmol, 2.00 equiv). The flask was then covered in a layer of aluminum foil. The reaction was stirred vigorously for 4 days at rt with the flask open to air. Once complete, the mixture was passed through a layer of silica with EtOAc. The filtrate was concentrated under reduced pressure at rt to yield a crude oil. This material was purified via flash column chromatography to yield a pale yellow oil. The oil was diluted with a minimal amount of pentanes and placed in a refrigerator overnight. The product crystallized to yield the title compound as a white, crystalline solid (13.5 g, 57%). Physical and spectral data were in accordance with literature data.

[0255] Note: After boronic acid addition, DCM should be added as needed throughout the 4 days to maintain the original solvent level.

[0256]

[0094] 9-Mesityl-3,6-di- / er / -butyl-10-phenylacridinium tetrafluoroborate (Mes-iBu Acr)

[0257]

[0258] was prepared according to a published procedure; physical and spectral data were in accordance with literature data.

[0259]

[0095] Substrate Preparation

[0260]

[0261] 2>((iR,lR,4a^, S»^)>2~hydFoxy*2,5>5,8»-letr»tnethyldcc»hydr8saphthaleB-i~yl)«vetic acid (Si): A sohition of 3aR)-(^)-seiareolide (1.00 g, 3.99 m ch 1.00 eqniv) in MieOH (40 rnL) was added to a 100 tnL round bottom flask containing a magnetic stir bar and 3M NaOH (26.6 mL.

[0262] 20.0 equiv). The mixture was refluxed for 20 hour??. The reaction was then concentrated to reduce the volume of MeOH. Water was added tnrtii all of the sodium salt dissolved. 2 HCl was then added dropwise until Ste pH reached 4. The mixture was extracted with 3 x 100 m EtOAc. The organic layers were combined, dried over MgSQ*, and subsequently concentrated under reduced pressure. The title compound was obtained as a white, crystalline solid (6,88 g, 82%).

[0263] Note: The pH must be titrated carefully after hydrolysis to avoid acid-induced lactonization. To further reduce potential decomposition from lactonization, the isolated product was kept in the refrigerator for months without degradation.

[0264] lH MR (500 MHz, CMorofo - ) <32.52 (dd, J - 16.3, 5.9 Hz, 1H), 2.35 (dd, J- 16,2,.3 Hz, TH), I.95 (dt, 7 - 12.4, 3.2 Hz, 1H), 1.81 (<ld. J - 6.0, 4.3 Hz, 1H). 1.76 - 1.66 (m, 1H), 1.64 1.53 (in. 2H), 1.53 - 1,42 (m. 2H), 1.42- 1.35 (in. HI). 1.28 { d, 7- 13.5, 3.2 Hz. 1H), l. I9(s, 3H), 1.14 (dd, J- 13.4, 4.1 Hz, 1H), 03-19 (ddd, J ” 14.3, 10.7, 3.3 Hz, 2H). 0.88 (s, 3H), 0.79 (s.

[0265] 6H).

[0266] NMR (151 MHz, Chlorofo -d) u 179.66. 74.04. 57.69, 56.00, 44.55, 41.84, 39.31, 38.71, 33.49, 33.39, 30.30, 23.40, 21.55, 20.61, 18.49, 15.52.

[0267] HUMS (ESI) calculated for [M+ af: 328.2247, found 328.2246.

[0268]

[0269] Methyl (6S,11S -11.(3 ■•(benz>'loxy)-3-oxopropyl>-6-fmethoxycarbonyl).2, dimethyl.4,9,12-trfoxo-3-oxa-^,16,13-tidazapentadecan-15-oate(S2):

[0270] Step 1: A 250 mL round-bottom flask equipped with a magnetic stir bar was charged with a solution of N-(tert-buiyioxycarbonyl>y-benzyl-L-gi»tajruc acid (5.06 g, 15,0 mmol, LOO equiv), glycine methyl ester hydrochloride (2.07 g, 16.5 mmol, 1.10 equiv) and SO wt. % HOBt (2.53 g, 15,0 mmol. 1.00 equiv) in DCM (159 mL) and cooled to 0 -'C. To this solution was added? Pr> EtN (2.87 L, 16.5 mmol, LIO equiv) dropwise over 5 min, and tire resulting mixture was stirred at 0:C for 10 min. To this solution was added H3-dime^yl-aminopropyl>3-ethylcari?odKmide hydrochloride (3.16 g, 16,5 mmol, 1. W eqtriv), and the resulting mixture was warmed to rt. After 16 hours, the reaction, mixture was cooled to 0SC and quenched with IM HC1 (50 mL). The precipitate was filtered off, and the phases were separated. The aqueous phase was farther extracted with DCM (3 x 30 ). The combined organic layers were washed with brine (100 mL). dried over MgSt and concentrated under reduced pressure to afford dipeptide, which was used in the next step without further purification.

[0271] Step 2; To 8 solution of dipepiide. (6,1 g, 15 mmol, 1.0 equiv) iri DCM (75 L) was added TFA (75 L) at rt. The mixture was stirred for 3 hours. The mixture was then concentrated under reduced pressure to afford the dipeptide TFA salt, which was used in the next step without further purification,

[0272] Step 3: A 250 L round-bottom flask equipped with a magnetic stir bar was charged with a solution of die dipepude TFA salt, (4S)-4-(tert-butoxycaib0nylaimno)-5-methoxy-5-oxo-pentanoic acid (3.92 g, 15.0 mmol) anddO t. HHOBt (2,79 g, 16.5 mind, 1,10 equiv) D€M (150 mL) and cooled to 0*C. To this solution was added iPrsEiN (.53 mL, 37.5 mmol, 2.50 equiv) dropwise over 5 in, and the resulting mixture was stirred at 0 ’C for 10 min. To this solution was added 1 -(3-dimeihyl-aminopropyI)-3-ethydcart>odiimide hydrochloride (3,16 g, 16.5 mmol, 1,10 e uiv) and the resulting mixture was warmed to rt After 16 hours, the reaction mixture was cooled to 0 °C and quenched with IM HC1 (IGO ). Hie phases were separated, and the aqueous phase was extracted with 3 x 100 mL DC, The combined organic layers were washed with l x IM HC1, 2 x sat NaHCOj (aq). and i x brine. The material was then dried over bfgSO* and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography (75 -> 100% Et(). Ac / Hex). The title compound was isolated as a white solid (6.5! g, 79%). "!H MR (800 MHz, Chiorofor -d) 87.36 - 7.27 (m. SH). 7.22 (t..1 =* 5.6 Hz, 1H). 6.88 (d, J « 7,7 Hz, 1H), 5.43 ('<!, J - 8.2 Hz, 1H)' 5.09 (d. J - 4.9 Hz, 2H, 4.57 (td. J - 7.7, 5.6 Hz, 1H), 4.26 (dt, J *= 13.5. 6.4 Hz, IH), 3.98 (d. J - 8.5, 5.6 Hz, 2H). 3.70 (d, 3 - 4. S Hz, 6H), 2.56 (dt,.1 - 16.9, 7.4 Hz. 1H). 2.48 (dt, J - 16.9, 7.1 Hz, 1H). 2.28 (t, J - 7.3 Hz, 2H). 2.16 (qd, J - 10.2, 4.4 Hz. 2H>, 2.01 (it, J - 14.4. 6.3 Hz. HI). 1.91 (dq, J - 14.9, 76 Hz, IH), 1.40 (s, 9H).

[0273] «C NMR (151 MHz, Chtoroform- ) § 173.40, 172.96, 1 2 39, 171.66. 170.16, 155.76, 135.80, 128.65, 128.38, 128.32, 80.12, 66.64, 52.94, 52.51, 52.49, 52.37, 1.21.32.14, 30.44, 28.37, 7.45. Rf-0.60 (EtOAc)

[0274] HR. MS (ESI) calculated for [ +: 574.2371..fomd 574.2388.

[0275]

[0276] (S) 4 (fS) 4 ( tert ■batox carbonyl inine) 5 metliexy 5 ■axepeutanamide) -5 ((2 efliuxy 2 <*xa^tliyI)aHKJn>)-5-t>x« e»taaoit.' sit-id S3): A 25 xnL rcusid bctipm Sask equipped with a. magnetic stir bar was charged with a solution of tripeptide S2 (2.8 g, 5.0 mmol, 1.0 eqttiv), 10 wt. H Pd / C (0.53 g, 0.50 mmol, 10 mol%), and MeOH (6.5 mL). The flask was then capped with a rubber septum. Ha atmosphere was generated by attaching a balloon filled with Hj and performing 3 evacuation-refill cycles. The Hash was then allowed to stir overnight. The reaction was then filtered through s pad of Celite and concentrated to afford pure tripeptide S3 as a white solid (1.8 g,?< ).

[0277] !H NM» ($00 MBz, CMoroform-d) S 7.6 (q. J« 8,$ Hz, 1H), 7.19 (d, J - 8.1 Hz. 1H), 5.50 (d, J =» 8.3 Hz. 1H)< 4.72 (t. J - 7.5 Hz, t H), 4.2 (, J - 5.9 Hz. 1H)< 4.08 (dd. J « 17.8. 6.0 Hz, 1 H), 3.97 (dd, J « 17.9, 5.4 Hz, 1H). 3.72 (s, OH), 2.47 {«, J « 17.2. 9.7 Hz. 2H), 2.41 - 2.30 (m. 2H).

[0278] 2.15 t, J - 14.6. 7.2 Hz, 2H). 2.01 - 1.87 in, 2H), 1.41 (s, 9H).

[0279] w€ NM» (151 MHz, Chlurofoim d) S 176.18, 173.07, 172.90, 172.25, 170.33, 156.01, 80.33, 53.05, 52.61, 52.46, 52.22, 41.31, 32.18, 30.08, 28. 1, 28.31, 27.92.

[0280] HRMS (ESI) calculated for [ t-Naf: 484.1902, found 4S4.192O.

[0281]

[0096] Decarboxylative Homologation General Procedures General Procedure A; Amidyl-rad ai mediated Decarboxylative Homologation

[0282] 'Ito a flame-dried I dram vial were added a magnetic stir bar, carboxylic acid substrate (0,200 mol, 1.00 equiv), O-alkenyl hydroxamate 2 (1 9 mg. 0.300 mmol, 1.58 equiv). and (1- pho$phoryl)viayl sulfonate I (148 mg, 0,400 mol. 2.00 equiv). The vial was moved into an argoa-filled glovebox. To the vial were added PhCFs (1.8 ml.) and HFIP (0,2 ). The visl was then sealed with, a cap containing a PTFE septum. Teflon was wrapped around the cap. The vial was removed from the glovebox and set to stir in a fumehood at 90 *C for 1 hour.

[0283] After cooling to rt, MeOH (40.5 pL, 1.00 mmol, 5.06 equiy) or BnOH (103 L, 1.00 mmol, 5.00 equiv) was added via syringe to the vial, followed by DBU (149 L, 1.00 mmol, 5.00 e uiv). The vial was set to stir for 1 hour at rt. The reaction was then coneentrated and filtered through a silica plug with EtQAc. The resulting crude material was purified by flash column chromatography. Cmde 'H MR yields were obtained using HMDSO as internal standard. For reactions with NMR yields, characterization data was obtained via isolation of several pure column fractions.

[0284] General Procedure B: Acridinium catalyzed Decatlioxylatve Homologation To a flame-dried i dram vial were added a. magnetic sin bar, carboxylic acid substrate (0.200 mmol, 1 00 equi ), Cto-diisopropylethylaniine (34.8 uL. 0.200 mmol, 1.06 e uiv), (1- phusphut fiviayl sulfonate 1 (81.7 mg. 0.220 nmiol. 1.10 equiv), and 9-’vtesrtyl-3to-di-tei / - bufyi-16-phenyiacridmium tetrafluoroborate (5.7 mg. 5 raolH). The vial was moved into an argon-fiUed glovebox. To the vial were added MeCN (1.6 L) and HFIP (0,4 L). The vial was then sealed with a cap containing a PTFE septum. Teflon was wrapped around the cap. The vial was removed from the glovebox, and set to stir in a fh ehood for Id hotns with irradiation from two 440 ntn Bl, ED Kessil lamps and fa t cooling.

[0285] MeOH (40.5 uL, 1,00 mmol, 5 equiv) or BnOH (103 pL, 1.00 mol, 5.06 equiv) was then added via syringe to the vial, followed by DBU (149 L, 1.00 mmol.5.00 equiv). The vial was set to stir for 1 hour at rt. Tire reaction was then concentrated and filtered through a silica plug with EtOAc. The resulting crude material was purified by flash column cinematography. CrudeSH NMR yields were obtained using HMDSO as internal standard. For reactions with NMR yields, characterization data was obtained via isolation of several pure column fractions.

[0286] Example 1

[0287]

[0097] 1-benzyl 6-methyl (7?)-2-((Zerf-butoxycarbonyl)amino)hexanedioate (3)

[0288]

[0289] I beazyl 6-meth l (A)-.((Ov'6butoxycarbonyI)smim>) exmiedioare(3) was obtained fess (J?)- S- benzyfo yi^f-fCGtz-btttox csrb u llsminoi-S-oxopentanoic acid (67,5 mg, 0.200 mol, LOO e uiv) asms General Procedure A. The erode pro-duct was purified via Hash column chromatography yielding the title compound as a pale yellow oil (37.4 mg, 51%).

[0290] ’H N R (400 MHz. Chlorofonu d) 67.34 (s, 5H), 5.22 ~ 5.11 (, 2H), 5.07 (d, J~ 3,4 Hz.. 1H).

[0291] 4.34 (q. J « 6.7 Hz, 1 H, 3.64 (s, 3H), 2.30 (tt,.7^ 11.5, 5.8 Hz, 2H), 1.84 (h,.7- 7.1, 5.7 Hz, 1H).

[0292] 1,66 (tt, 12,6, 9.6. 6.7 Hz, 3H), 1.43 (s, 9H).

[0293] »C NMR (151 MHz, Chiorofo -d) 6 173.57, 172.55, 155.48. 135,46, 128.71, 128.54, 128,39, 80,05, 67.21. 53.33, 51.69, 33.45, 33,07, 28.42, 26.79.

[0294] Rf « 0,13 (30% EtOAc / Hex)

[0295] HRMS (ESI) calculated for PM Nap: 388.1731, found 388,1725.

[0296] Example 2

[0297]

[0098] Benzyl 4-(4-chlorophenyl)butanoate (4)

[0298]

[0299] Benzyl 4 (4 ehloi’opii?nyl)l>tta»oate (4)j was obtained from 3~( -chlorophenyi)propanoic acid (36.9 mg, 0.200 ntmol, 1.00 equiv) using both General Procedures A and B. The crude product was purified via flash column chromatography yielding the fide compound as a clear oil, With General Procedure A, the product was isolated (31,1 mg, 54 % yield), and with General Procedure B, a crude *H NMR yield of 38% was obtained.

[0300] JH N R (690 MHz, Chloroform d) 87,40 - 7.31 (m, 5H), 7.24 (d, J -■= 8.2 Hz, 2H), 7.08 (d, J » 7.9 Hz, 2H1, 5.12 (s, 2H), 2,61 (i, J - 7.7 Hz, 2H), 2.37 (t, J « 7.4 Hz. 2H), 1.95 (p. J « 7.5 Hz.

[0301] 2H).

[0302] ,3C NMR (151 MHz, Chloroform- ) S 173.25, 139.89, 136.10, 131,87, 129.97, 128.72, 128,62, 128. 1. 66.37, 34,54, 33.59, 6,52.

[0303] Rf “ 0.56 (20% EtOAc / Hex)

[0304] HRMS (ESI) calculated for

[0305]

[0306] 311.0810, found 311,0816.

[0307] Example 3

[0099] / V-(benzyloxy)-3-(4,4-difluorocyclohexyl)propanamide (5)

[0308]

[0309] A'-(benzyfoxy)-3~(4.4-dlllimi,o<y<-tohexyl)p»opaiia foe (5 was obtained fem 2-(4,4- difitorucyclohmcyl)acetic add (35.6 mg, 0.200 mmol, 1,00 e uiv) using General Procedure A with the fallowing modifications: once the decarboxylation reaction was complete, Q-benzyl hydroxylamme hydrochloride (160 mg, 1.00 xmnol, 5.00 equiv) was added, followed by DBU (299 uL. 2.00 mmol, 10.0 eqniv). The reaction was then completed according to the general procedure. The crude product was purified via flash column chromatography yielding the title compound as a white, crystalline solid (34, 1 g, 57%).

[0310] *H NMR (400 MHz, Chloroform^) 67.80 (m, 1H), 7.39 (m. 5H), 4,87 (in. 2H), 2.41 - 1.93 (m, 4H), 1.72 (m, 3H), 1.61 (ra. 3H). 1.26 (in, 3H).

[0311] ISC X R (151 MHz, CWoroform-d) e 170.78, 135.42, 129.36, 128.98, 128,84, 78.31, 35.26, 33.-16 (dd, J = 25.4, 22,6 Hz), 30.97 (d, 7= 27.3 Hz), 29,53 (d,7= 48.9 Hz). 28.79, 8.73.

[0312] 37,4 Hz).

[0313]

[0314] Tert-bvtyl 3-(3-snetimxy-3-<txopropyi)a2 ridiae~l-i'ttrbexykrie (6) was obtained from 2-(l- (feif-bmoxyearb9nyl)azetidin-3-yl)aeetic acid (43,1 g, 0.200 nmmh 1.00 eqviv) using General Procedure A. The crude product was purified via flash column cinomatography yielding fee title compound as a pale yellow oil (11.1 mg, 23%).

[0315] *H NMR (560 MHz, Chlorofor -d) c 3.99 (t, J=» 8.3 Hz, IH), 3.67 (s, 1HX 3.53 (dd, « 8.6, 5,5 Hz. 1 H),. 2.27 (t, 7- 7.5 Hz, 1H), 1.91 (q, 7- 7.6 Hz, 1H), 1.43 s, 9H).

[0316] 53C NMR (151 MHZ. Cilloroth -O} 8173.49, 1 6.49, 79.44. 54. 1, 51.83, 31,63, 29.59, 28.54, 28.38.

[0317] Note: C(54.31) represents the carbon alpha to die -V-Boc. The signal appears as a bread doublet rather Sum a singlet dee to cmdTonnational isomerism on die NMR timescale. As a result, there is peak broadening and partial separation, giving the appearance of two signals. Furthermore, Ulis signal was initially not apparent when using a dl relaxation time of 3 seconds; the di relaxation time was extended to 6 seconds for sufficient visibility.

[0318] Rf - 0.22 (3-3 1 D€M7Hex / Ei O)

[0319] 1IRMS (ESI) calculated for [M-i-Na]*: 266.1363, found 286.1359.

[0320] Example 5

[0321]

[0101] Benzyl 3-propylhexanoate (7)

[0322]

[0323] Benzyl 3-propylhex noste (7) was obtained from valproic acid (2 mg, 0.200 mmol, 1.00 eqmv) using both General Procedures A and B. The crude product was purified via flash column chromatography yielding the title compound as a dear oil. With General Procedure A. the title compound was isolated (40.2 mg, 81% yield}, and with General Procedure B. a crudelH NMR yield of 70% was obtained.

[0324] Using General Procedure A with slight modification, this reaction was also repeated on 1 mmol scale. To a flame-dried 20 ml. scintillation vial were added a magnetic stir bar, valproic acid (144 mg, 1.00 mmol, 1.00 eqniv), Oalkenyl hydroxamate reagent 2 (647 mg, 1.50 mmol, 1.50 e uiv), and (I-pimsphorvi)vinyl sulfonate 1 (742 mg, 2.00 m ol.2.00 equiv). The vial was then moved into an argon-filled glovebox. To the flask were added PhC'Fi (9.0 ml.) and HFIP (1.0 niL). The vial was then sealed with a cap confining a PTFE septum. Teflon was wrapped around the cap. The flask was removed from the glovebox and set to stir in a fome ood at 50 X for 16 hours. After cooling to rt, BaQH (520 p. L, 5.00 inmol, 5.00 equiv) was added via syringe to the vial, followed by DBU (748 gL, 5.00 mmol, 5.00 equiv). The vial was set to stir for 1 hour at rt. The reaction was then concentrated and filtered through a silica plug with EtOAc. The crude product was purified via flash column chromatography yielding the title compound (192 mg. 77%).5H MR (600 MHz, Chloroform d) S 7.39 - 7.29 (, 5H), 5.12 (s, 2H), 2.29 (d, J - 6.9 Hz, 2H), 1.90 (p. J« 6.1 Hz, IH), 1.34- 1.15 (m, 8H). 0.87 (t, J - 7.0 Hz, 6H).

[0325] ,8C NMR (151 MHz, Chloroform cl) 8 173.62, 136.33, 123,63, 123,37, 128.27. 66.13, 39.40, 36.34, 34.84. 19.80. 14.43.

[0326] Rf- 0.69 (2036 EtOAGHex)

[0327] HRMS (ESI) calculated for [M-f a]*: 271.1669, found 2 1.1675.

[0328] Example 6

[0329]

[0102] Benzyl 2-( let rally dro-2 / / -pyran-3-yl)acet ate (8)

[0330]

[0331] Benzyl l-(t«rahydr»-215r-pyrau-3-yl)acetate (8) was ebiainefi from tetrah.ydro-25d-'pyratr-3- carboxyhc acid {26,0 mg, 0.200 i nol. 1.00 eqaiv) ruing General Procedure A. The crude product was purified via flash column chromatography yielding the title compound as a dear oil (30.9 g, 66%).

[0332] ’H?*MR ($00 MHz, Chloroform-d) S 7.40 - 7.29 (m, 5H), 5.12 (s, 2H), 3.9 - 3.77 (, 2H), 3.44 - 3.34 (m, IH), 3.14 (dd, J - 11.2. 9.2 Hz., IH), 232 - 2.18 (, H). 2.13 (dddd, J - 14.1.

[0333] 9.3, 7.2, 3.6 Hz, IH), 1.87 fdit, J - 14.3. 3.7, 1.9 Hz, IH), 1.68 - 1.55 (m, 2H), 1.31 - 1.18 (m, IH).

[0334] BC MR (151 MHz, Citloroform-d) S 172.21, 1 6.01, 128.71,.126.40, 128.37, 72.57, 68.44, 66.42, 37.36, 33.06. 29,65, 25.35.

[0335] R.r-0.3912034 EtOAdlfex)

[0336] HRMS (ESI calculated for [M-i-Naf: 257.1148. found 257.11 5.

[0337] Example 7

[0338]

[0103] Tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-l-carboxylate (9)

[0339]

[0340] Trrt -butyl 4- (2..m thoxy-2 - xoefliyli i eridine-l carboxylate (9) was obtained fean l-(mr6 buioxycarboayl)piperid e-'3-carboxylic add (45.9 g, 0.200 tn ol, 1.00 eqniv) using General Procedure A. The crude product was purified via flash column cliromsto phs’" yielding the title compm d as a pale yellow oil (37,1 mg, 72%).

[0341] 5H NMR (666 MHz, C roform-d) c- 4.10 - 3.73 (, 2H), 3,66 (s, 3H), 3,01 - 236 (, 2H), 2.25 (dd, J - 15.3, 6.9 Hz, IH), 2.16 (dd, 7- 1,3, 7.3 Hz, IH). 1.95 (ttt, J- 10.7, 7.3, 3.8 Hz, IH), 1.86- l.76(m, 1H), 1.61 (dp,,f« 12.6, 4.1 Hz,. IH), 1.45 (m, 1H), 1.43 (s, 9H), 1.16 (m, IH).

[0342] ,3C:MR (151 MHz, Chior»fona-d) 6172.71, 154,87, 79.49, 51.67, 9.50, 43.88, 38.06, 32.85, 30.64, 28,52, 24.35.

[0343] Rf ~ 0.12 (1094 EtOAc / Hex)

[0344] HRMS (ESI) calculated for M+Na: 280.1520, found 280.1516.

[0345] Example 8

[0346]

[0104] Tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-l-carboxylate (10)

[0347]

[0348] J -butyl 4-(2-meTkoxy-2-oxbethM)piperi i»e-l-cartM> yla (19) was obtained from l- nvr- bti?oxy arfjon¥l)piperid e-4-caxtjox lic acid (45,9 mg. 9,200 mmol. 1.00 eqoiv) using General Procedure A. The crude product was purified via flesh column chromatography yielding the title compound as a pale yellow oil (35,0 mg, 68%),

[0349] SMR (509 MHz. CMoroform-d) 84.05 (s, 2H), 3.65 (s, 3H), 2.69 (t, J- 13.1 Hz, 2H), 2.22 (d, 7- 7.1 Hz, 2H), 1.90 (tit, 7- 10.9, 7.1, 3.7 Hr, 1H), 1.66 (d, 7- 13.1 Hz, 2H), 1.43 (s, 9H).

[0350] 1.13 (qd, 12.4, 4.4 Hz, 2H).

[0351] BC W (151 MHz, E htoroform-d) 5 172.96, 154.90.79.45, 51.60, 44.12, 40.97, 33.17,31.91, 28.55.

[0352] Rf « 0.13 (10% EtOAtTHex)

[0353] HRMS (ESI) calculated for ( ENaf: 280.15.20, found 280.1516.

[0354] Example 9

[0355]

[0105] Methyl 2-(l-(4-chloropicolinoyl)piperidin-4-yl)acetate (11)

[0356]

[0357] (ill

[0358] Methyl 2-(l-(4-cWoropicoliaeyI)pipei'idia-4-yl)scetale (11) was obtained from l-(4- chlaropic01in.oyl)piperidijie-4-carboxyhc acid (53.7 mg. 0.200 mmol, 1.00 etpriv) using General Procedure A. The crude product was purified via flash column cinrsmatogrsphy yielding the title eonrpcnmd as a pale yellow oil (40.5 mg, 68%).

[0359] lH MR (400 MHz, Chtornform-d) 5 8.45 (d, J - 5.4 Hz, 1H), 7.59 (d, J~ 2.0 Hz, 1H), 7.3 (dd, 7- 5.4, 2,1 Hz, IH), 4.68 (ddt, 7- 13.2, 4.6, 2.4 Hz. 1H), 3.85 (ddt J- 13.7, 4.7. 2.4 Hz, 1H), 3.06 (td. 7- 12.7, 2.8 Hz, 1H), 2.80 (id. 4 « 12.9, 3.0 Hz, 1H), 2.34 - 2.20 (m, 2H). 2.06 (dddd, J- 15.6. 11.9, 7.6. 3.8 Hz, 1H), 1.83 (dq, U.8;2.9 Hz, 1H), l.<59 (dt, 7- 12.7, 3.1 Hz, 1H). 1.31 (ddt, J - 22.2, 9.9. 4.1 Hz.2H).

[0360] «C MR (151 MHz, Chl«reform-d) 5 172.73, 166.31. 15.83, 149.39, 145.28, 124.76, 124.19.

[0361] 51.66, 47.32, 42.63, 40.66. 33,12, 32.46, 31.61.

[0362] Rf- 0.23 (50% EtOAc / Hex)

[0363] HRMS (ESI) calculated forOf-bNaf: 319.0820, found 319.0831.

[0364] Example 10

[0365]

[0106] Benzyl 2-((15,47?)-bicyclo[2.2.1]heptan-2-yl)acetate (12)

[0366]

[0367] Benzyl 2-«15,,4jR)-bicycto(2..1]hep n-2-j4)acetete 12) was obtained from 15,42?)-bicyclo[2.2.1.)heptane-2-c3xb©xylic acid (28,{l mg, 0.200 mmol 1.00 eqniv) usisig both General Procedures A and B. The crude product was purified via Sash column cinematography yielding fire title eo poi d as a clear oil. With General Procedure A. the product was isolated (40.1 mg, 82% yield), and with General Procedure B, a crude;H NMR yield of 55% was obtained (only exo isomer observed).

[0368] *H MR (600 MHz, Chloroform d 5 7.41 - 7.29 (. H), 5.11 (, J - 3.5 Hz, 2H), 2.33 ( d, J - 15,1, 7.8 Hz, 1H). 2.23 - 2.15 (m, 2H). 2,00 - 1,90 (, IH), 1.96 - 1.88 (m, IH, 1,35 - 1.41 (m, TH), 1.30 (dp, J - 9.9,.0 Hz, IH), 1.28- 1.19 (m, IH), 1.19 - 1.03 (m, 3H).

[0369] «C NMR (151 MHz, C’hlorof rm-d) S 173.15, 136.31. 12.67. 128.31. 128.27. 66.14, 41.42, 4.29, 38.58, 3.89, 36.88, 35.35, 29.89, 28.67.

[0370] Rf =» 0.64 (20% EtOAc / Hex)

[0371] H MS (ESI) calculated for [MHSta]’: 267.1356, found 267.1.363,

[0372] Note: The observed diastereomer was tentatively assigned in analogy to the observed selectivity for another uoibnniyl radical coupling reaction?

[0373] Example 11

[0374]

[0107] Tert-butyl (5-oxotetrahydrofuran-3-yl)carbamate (13)

[0375]

[0376] butyl (5 oxotetrahydrofuran 3 yDcarbsma (13) was obtained from N-(ten~ butoxyearb jiyI}-L-serisia (41.0 mg, 0.200 mmol. 1.00 eqniv) using General Procedure A with the followin modifies ioa: once the decarboxylation reaction was complete, only DBU(1 9.uL, 1,00 tnoi, 5.00 equiv) was added. The reaction was then completed according to the general procedure. The crude pnxlnct was purified via flash, column chromatography yielding the title compound as a white solid (38.9 mg, 97%).

[0377] JH NMR (600 MHz, Chhmofo -d) 55.05 {»,. 1 H), 4.51 - 4.39 (m, 2H), 4.20 (d,.!«= 7.2 Hz, 1. H), 2.82 (dd, J - 17.9, 7.7 Hz, IH). 2.45 (dd, J « 18.0, 3.8 Hz. IH), 1.43 (s, 9H).

[0378] UG NMR (151 MHz, €hlorofonn-d) 8175.34. 155. IS, 80.61. 73.84, 47,78, 35.1, 28.41.

[0379] R1 « 0.10 (20% EtQAcZHex}

[0380] HR S (ESI) calculated for I -Naf: 224,0894, found 224.0905.

[0381] Example 12

[0382]

[0108] Methyl 3-(l-oxo-3,4-dihydroisoquinolin-2(lH)-yl)butanoate (14)

[0383]

[0384] Methyl 3~(l-»xo-3,4-dihy<h'Oisi>qaiH<>l -2(lIT)-yI)lmtam>ttte (14) was obteixied from 2«(l- xo-3,4-fohydr i 0 ainolm- (L?f)-yl)propauoic add using General Procedure A with the ollowmg modifications: 2 l^xO’3.4-foh fo-oi 0qmnolin’2(L® *yl)pr»p ii0ic acid (21,9 rag. 0.100 mraoL 1.00 eq i ), Oalketryl hydroxsraate 2 (64, 7 mg, 0,150 mol, 1.50 eqtiiv), and (I- ho ph ydlvinyl sulfonate 1 (74.2 g, 0.200 mraoL 2.00 equiv) were added to a 1 dram vial on foe bench. The vis! was then moved into an argon-fill d glovebox. To the vial PhCFj (0.6 mt) and HP1P (0,4 tnL) were added. The vial was then sealed with a cap containing a PTFE septntn and moved back fo the bench. The reaction was heated and stirred at 70 °C for 4 hours.

[0385] Upon cooling the leacticn to.it, MeOH (20.2 pL, 0.500 mmol, 5.00 equiv) was added via syringe, followed by £> BU (74.6 L, 0.509 mol, S. OOeqwiv). The reaction was stirred for 1 hour at rt. The reaction was foen concentrated, filtered wifo MeCN: DMSO< and subjected to preparative liquid chromatography (LC) using a CIS column with 0.136 FA buffer using a - 5 -* 4036 gradient of MeC in water. Solvent was removed from fractions to yield the pure product as a clear oil (1.3 mg, 58%).

[0386] !H NMR(60O MHZ, Chloroform-d) § 8.96 (dd, 7.7, 1.4 Hz. 1H), 7.40 (id, J ~ 7.4, 1.4 Hz.

[0387] 1 H), 7.32 (td, J - 7.6, 1.3 Hz, 1 H). 7.16 (d, J - 7.5 Hz. 1H), 5,18 (dp,.7 - 8.4, 6.8 Hz, 1H), 3.63 (s, 3H), 3.51 - 3.42 (in, 2H), 2.95 (qdd, J - 15.7, HU, 5.5 Hz, 2H), 2.79 (dd, J - 14,7. 8.5 Hz, 1H), 2.56 (dd, 14.7, 6,4 Hz, 1H), 1.30 (d, 7- 6,9 Hz, 3H).

[0388] UC NMR (151 MHz, OllWOfo ^ 5 171,68, 164.27, 13 3. 131.73, 129,88, 128.56, 127.13, 126,86, 51.93, 47.14, 40.98, 39.13. 28.51, 18.05.

[0389] Rf - 0.1 ('3:: 1 DCWHex® O)

[0390] HRMS (ESI) calculated for [MdNaJT 270.1109, found 270, 1108.

[0391] Example 13

[0392]

[0109] Methyl 2-(6-fluorochroman-2-yl)acetate (15)

[0393]

[0394] Methyl 2-(6-fiBOF6chrotnan~2-yl)acetate (15) was obtained from 6«finorochjomane-2~ carboxylic acid (39.2 mg, 0.200 tu oi, 1.00 eqaiv) using both General Procedures A and B, with slight modification to the latter. The irradiation time for the acridmium-catalyzed reaction was 3 hours, after which time the reaction was completed according to the general procedure. With General Procedure A. a erode;H R yield of 90% was obtained, and with General Procedure B, a crude H NMR yield of 96% was obtained.

[0395] 5H NMR («09 MHz, Ch >roform-d) § 6.80 ~ 0.09 (m. 3H), 4.46 - 4,39 (m, 1H), 3.74 (s, 3H), 2. S7 (d,3~ 16.9, 10.9, 5.9 Hz, 1H), 2.79 (dd, J - 15.5. 7.3 Hz, 1H, 2.74 (ddd, J - 16.8, 5,6, 3.3 Hz, 1H),2.61 (dd, J- 15.5, 5.9 Hz, 1H).2.07 (ddt. J- 13.5, 5.9, 2.8 Hz, 1H), l,76 (d dd, J~ 13.4, 11.2, 10.1, 5.6 Hz. Hi.

[0396] xaC (151 MHZ. C&lo eno-df 5 171.25, 156.93 (d, J = 238.1 Hz), 150.54 ((1. J = 2.1 Hz), 122.75 (d, J « 7,5 Hz), 117,82 (d, J « 8.1 Hz), 115.37 (d. J « 22.6 Hz), 1(4.09 (d, J ** 23.0 Hz), 72.43, 51.99, 40.41, 26.97. 24.72,

[0397] 55,F N R (377 MHz, Chl»r»form-d) b -124.34 (td, J~ 8.4, 4.9 Hz).

[0398] Rf - 0.41 (20% EtOAc / Hex)

[0399] HUMS (ESI) calculated for (M+Naf: 247.0741, found 247.0752.

[0400] Example 14

[0401]

[0110] Methyl 3-(((benzyloxy)carbonyl)amino)-3-methylbutanoate (16)

[0402]

[0403] Methyl -(((benzylexy)carbonyl)amiao -3-metiiylbutau<>ate (15) was obtained from 2- (((benzy4oxy)catbon l) mino)-2-nretliylpropauoic acid (47.5 mg, 0.200 mmol, 1.00 e uiv) using General Procedure A. The crude product was purified via flash column clrromatography yielding the tide compound as a pale yellow oil (33.3 mg, 03%).

[0404] JH NMR (609 MHz, Chlmx>fonn--d) 87.41 - 7.30 (m, 5H), 5,24 ($, 1H). 5.08 (s, 2H), 3.66 (s, H), 2.73 (s. 2H, 1.43 (s, 6H).

[0405] WC NMR (151 MHz, CbfoFUform-d) 5 171.74. 154.95, 136.82, 128.59, 128.10, 66.29. 51.60, 51.52, 44.24, 27.42.

[0406] Rf 9.21 (15% OAc / Hex)

[0407] HRMS (ESI) calculated for[MtNa]7427.3183, found 427.3 ISO.

[0408] Example 15

[0409]

[0111] 7)? / 'r-biityl(27?,4>S')-4-(2-(benzyloxy)-2-oxoethyl)-2-(r<’ / 'f-biityl)-4-methyloxazolidine-3-carboxylate

[0410]

[0411] -butyl (SI S)- (2 -fheuzytoxy) 2 nxoethyl) 2 {teH bu 4) 4 netliyi xazolidine-3- earhftxytare {17)| was obtained from {)2P.4. S)-3-(m? MutoxycarboByl -2-(fej'M iiy'l)--4- niethyh>x z<slidine-4-carboxylic acid (57.5 mg, 0.200 mmol, 1.00 equiv), which was prepared according to a published procedure®, using; General Procedure A. The crude product was purified via flash cchmm chromatography yielding the title compound as a clear oil (30.1 mg.38%, >25:1. dr).

[0412] XH AMR (600 MHz, Chloroform-d) <57.39 - 7.29 (m, 5H), 5.09 (m, J - 12.1 Hz, 2H), 4.89 (s, IH), 4.19 (d, J » §.9 Hz, IH), 3.86 (d, J « 9.0 Hz, IH), 3.19 (s, IH), 2.55 (d. J « 13.5 Hz, IH), 1.50 (s, 3H), 1.44 (s, 9H), 0.93 (s.9H).

[0413]

[0414] MHz, ChIorof«rm-d) 8 171.09. 154.39, 135.88, 128.94, 128.63, 128.43, 97.41, 80.66, 76.52, 66.76.62.32, 0.37, 38.92, 28.44, 27.12.24.20.

[0415] Rf - 0.59 (20% EtO crilex)

[0416] HUMS (ESI) calculated for [ + a: 414.2251, found 414.2269.

[0417] Example 16

[0418]

[0112] Benzyl 3-(4-(benzo[rf]thiazol-2-yl)phenyl)propanoate (18)

[0419]

[0420] Benzyl 3-(4-(heazo[ri]thia20i-2-yI)pheByl)prepanoat-e

[0421]

[0422] was obtained from 2-(4-(benzo^thlazol’S-y ffoenyOacefic acid ’using General Procedure A with the following modifications: to a flame-dried 1 dram vial were added a magnetic stir bar.2-(4-(l>eiSzo(<?]thiazol-2-yl)phenyl)scetic acid (53.9 ig, 0,200 mmol l.00 eqmv), 0-alkenyl hydroxamate 2 (129 mg.

[0423] 0.300 msnc, I.50 eqniv). and i-phosph<siyl)vinyl sulfonate 1 (223 mg, 0.600 mined, 3.00 e uiv). The vial was moved into an argun-filled glovebox. To the via were added PhCFs (1,0 L) and HFIP (1.0 mL). The reaction was then completed according to the general procedure. The crude product was purified via flash column chromatography yielding the title compound as an off-white solid (44.3 mg. 59%),

[0424] }H AMR (600 MHz, Chforeform-d) 88.07 (d, J - 8. i Hz, IH), 8.00 (d, J - 8.2 Hz, 2H), 7.90 (d, J - 7.9 Hz, IH), 7.49 {ddd, J - 8-3. 7.1, 1.2 Hz, 1H), 7.42 - 7.28 (in, 8H), 5.12 ts.2H), 3.04 (t. J « 7.7 Hz, 2H). 2.74 (t, J « 7.7 Hz, 2H).

[0425] UC AMR (151 MHz. Chforofor -d) 5172.55, 168.04. 154.29, 143.84, 135.92. 135.12, 131.95, 129.15, 128.70, 128.42, 127.87, 126.42, 125.24, 123.27, 121.73. 6.55, 5.64, 0.95.

[0426] Rf ~ 0.50 (20% EtOAc / Hex)

[0427] HRMS (ESI) calculated for [M t H]*: 374.1209, found 374.1209.

[0428] Example 17

[0429]

[0113] Benzyl 2-(l-phenylcyclopropyl)acetate (19)

[0430]

[0431] Benzyl 3-{i-pt)eiiykye >|>ropyt)aeetare (19)| was obtained fsc-m l-pheayteyclopropajie-l- carboxylic acid (32.4 sag, 0,200 mol, 1.00 equiv) using General Procedure A. Hie crude product was purified via flash column chroniaiography yielding the title compound as a clear oil (44.4 mg, 83%),

[0432] *H NMR (dpi) MHz, Clilmxdm -d) 67.39 - 7.15 (m, I OH), 5.04 (s, 2H), 2.66 (, 2H). 0.99 0.87 (m, 4H).

[0433] UC MR (151 MHz,. Chl«rofi»-m-d) 8171.84, 144.15, 136.07, 128.5S, I2S.55. 12837, 128.26, 128.20, 126.41, 66,19, 4.95, 22.58, 13.68,

[0434] Rf = 0,52 20% EtOAc / Hex)

[0435] HRMS (ESI) calculated for [MTNa: 289.1199, found 289.1208.

[0436] Example 18

[0437]

[0114] Benzyl 2-(6-(( / err-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetate (20)

[0438]

[0439] Benzyl 2-(6-((te^-butoxycai'1>o»yi)amlno)8 ii'o[3.3]heptan~2-yl)a€etate (20 | was obtained fi m 6«((rc?- lHitoxycatboayl)atnino) piro(3.3]heptane-2-carboxylxc acid 41 (51.1 trtg. 0.200 xnul, 1,00 equiy) using General Procedure A. The crude product was purified via flash colunm chromatography yielding the title compound as long, white needles (57.0 mg, 79%).

[0440] *H NMR (5 0 MHz, €hlor«fi>rm-d) 87.25 (h..7- 9,2.7.9 Hz, 5H), 5.01 (s, 2H), 4.60 (d, <7= 20.7 Hz, 1H), 4.01 - 3.83 (hr IK), 2,49 (p, J- 7.9 Hz, IK), 2,36 (t 7- 12.1 Hz, SH), 2.17 (qd, J- 11.5, 5.0 Hz, 2H), 2.06- 1.96 (m, 1H). 1.79 - 1.53 (m.4H). 1.35 (s, 9H).

[0441] UC NMR (151 MHz, Chlorofo -d) S 172,39, 155.05, 136.16, 128,66, 128.29, 128.25, 79.33, 66,18, 44.00.43.61, 41.51, 41.21, 40.56, 39.99, 33.62, 28.51, 27.02.

[0442] Rf- 0.08 ( 34 EtOAc / Hex)

[0443] HRMS (ESI) calculated for [ i Na] 2382.1989. found 382.1984.

[0444] Example 19

[0445]

[0115] Methyl 4-(2-methoxy-2-oxoethyl)bicyclo [2.2.2] octane- 1-carboxylate (21)

[0446]

[0447] Methyl 4-(2-methoxy.-2-uxeethyl)bieycto[2.2.2]oetane-I-earboxylate (21) was obtained from 4-(metfcoxycartx>ayl)bicycto[2.2.2]<>ctane-l •carboxylic add (42.4 mg, 0.200 rnxnol, 1.00 eq y) using General Procedure A. The crude product was purified via flash column ehro atogrophy yieldbig the title compoiuid as a pale ydiw oil (40.4 mg, 84%).

[0448] !H MR (600 MHZ, Chforofonn-d) 5 362 (s. 3H), 3.61 (s, 3H). 2.10 (s, 2H), 1.80 ~ 1.72 (ay 6H). 1.56 - 1.46 (. 6H).

[0449] SC MMR (IM MHz, Chfoxoform d) <i 178.32, 172.28, 51.74, 51.28, 45.52, 38.55, 30.77, 30,49, 28.45.

[0450] Rf •■• 0.25 (10% EtOAdHex)

[0451] HRMS (ESI) calculated for [ 4N-a]~ 263.1254, found 263.1251.

[0452] Example 20

[0453]

[0116] Methyl 3-(2-(benzyloxy)-2-oxoethyl)bicyclo[l.l.l]pentane-l-carboxylate (22)

[0454]

[0455] Methyl 3-( -(benzyfoxy)-2-exoethj'i)bicydo[l.l.llpentsne-l-carbox late (22) was obtained fen 3- niethoxy<ja Ix) yl)b yclo[l..l]pe!iiane-l.-'C rbc>xyUc add (34.0 nig, 0.200 aunol, 1.00 eqdv) using General Procedure A. The crude product was purified via flash column chromatography yielding the title compound as a colorless solid (20.0 nig, 36%).

[0456] ’ll NMR (500 MHz, Chfofofown-d) d 7.39 - 7.30 (m. 5H), 5.11 (s, 2H), 3.66 (s, 3H), 2.58 (s, 2H), 2.04 (s, 6H).

[0457] 1SC N R (151 MHz. Oiteroforin-d) o 170.86. 170.25, 135.95, 128.75, 128.51, 128.49. 66.50.

[0458] 52.65, 51.77, 38.39. 37.17, 36.21.

[0459] Rf - 0.43 (20% EtOAdHex)

[0460] HRMS (ESI) calculated for [M-rNaf: 297.1 OPS, found 297.1109.

[0461] Example 21

[0462]

[0117] Methyl (2 / ',3 / ?,4r,5. V)-4-(2-(benzyloxy)-2-oxoethyl)cubane-l -carboxylate (23)

[0463]

[0464] Methyl (2r R,4r,5S)-4-(2-(be»zytoxy>2-oxoethyl)ctibane-l carboxylate 23)j was obtained from (ls.2A^3r,8S>4-(mefooxycarboB i)cu1 e-l-c8xt>ox lic add (46. mg, 11.206 nsitrol. 1.00 e uiv) using General Procedure A. The crude product was purified via flash column chromatography yielding the title compound as a clear oil (27.6 mg, 4333}.

[0465] JH N (600 MHz, Chiorofo - ) 87.39 - 7.30 (tn, 5H), 5.12 (s, 2H), 4.13 - 4.07 (m. 3H), 3.81 (L J = 4.9 Hz, 3H). 3.70 (s, 3H), 2.71 (s, 21f).

[0466] i3C NMR (151 MHz Chtoruform-d) « 172.90. 171.06, 136.03.. 128.71, 128.45, 128.41, 66.41.

[0467] 56.24, 54.96, 51.63. 46.77, 46.48, 38.09.

[0468] Rf - 0.45 ( 9% EfOAc / Hex)

[0469] HRMS (ESI} calculated for [ t-Na: 333.1098. found 333.1109.

[0470] Example 22

[0471]

[0118] 2-(6-((terr-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetic acid (24)

[0472]

[0473] 2-(6-((O'rAbtttoxycsrbo»yl}aminoyspiro[3.3]heptaa-2-j’l)acctic acid (24) teas obtained front 6- ((mrt-binoxyc?a'bonyl)ami!to)spiro[3,3]hepiruie-2-carboxylic acid 41 (51.1 mg, 0.200 mmoL 1.00 eqniv) using General Procedure A with the following modifications: once the decarboxylation reaction was complete, to the vial was added 2.5 mL of a 2:3 mixture of (IM NaOH): THF. After stirring for 1 hour at rt, the reactfoit was washed with x 5 L ©CM. The aqueous layer was acidified with IM I-IC1 to pH 4. The mixture was then extracted with 3 x 5 mL EtOAc. The organic layers were combined, dried over MgSOg and concentrated under reduced pressure. A crudelH NMR yield of 67% was obtained.

[0474] 41 MR (500 MHz, Chloroform-d) o 5.28-4.47 (m. Hl), 4.06-370 (, 1H), 2.62 2.43 (m, 2H).2.40 (d, J- 7.5 Hz, 2H), 2.2? id, J - 10.5 Hz. 2H), 2,11 (s, IH), 1.8 - 1.62 (tn, 4H), 1.42 (s, 9H).

[0475] MR (151 MHz, Chlnreform-d) 6177.42. 155.10, 79.44, 44.02. 43.65, 1.55. 0.77, 40.56, 39.98, 33.67, 28.54, 26.81.

[0476] Rf = 0.07 (40% EtQAc / Hex)

[0477] HRMS (ESI) calculated for [M+NaF: 292.1520, found 292.152S.

[0478] Example 23

[0479]

[0119] Benzyl-3-(2-(6-((terr-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetoxy)azetidine-l-carboxylate (25)

[0480]

[0481] Benzyl 3 ( 4.fi((frrfibufoxycsrbonyl)ajniHu).spH'0[3.3]liepi»8i-2-yl)acetoxy)szciidine l- carboxylate (25)| was obtained from 6^{zerfrbutoxyearboayl)am o)spiro[3.3]h.eptaue-2-’ carboxylic acid 41 (51.1 mg, 0.209 mol, LOO sqtiv) using General Procedure A with the following modification: once the decarboxylation reaction was complete, benzyl 3- hydKsxyazetidiae-l-cnrb xyla e (207 mg, 1.00 mmol,.5.00 equiv) and DBU (140 pt, 1.00 mmol, 5.00 equiv) were added sequentially to the reaction vial. The reaction was then completed according io ths general procedure. The crude product was purified via flash column chromatography yielding the title compound as a clear oil (72.2 mg, 81%),

[0482] 3H 1 R (600 MHz, €Worofo m-d) 57.37 ••• 7.28 (m, 5H), 5.18 •• 5.06 (m, 3H), 4.62 (s, IH).

[0483] 4.35 - 4.23 (, 2H), 4.05 - 3.87 (in, 3H), 2.52 (hept, J - 8.2 Hz, IH), 2.50 ~ 2.34, 3H), 2.31 - 2.20 (in, 2H), 2.0S (ddd. J - 11.8. 7.3, 4.0 Hz. IH), 1.83 - 1.65 (m, 4H), 1.42 (s. 9H).

[0484] MC NMR(151 MHz, Chforoform -d) 5 172.03, 156.31, 155.02, 136.54, 128.62, 128.25, 128.15, 79.31, 6697, 63.46, 56.51, 43.96. 43.61, 41.48, 40.80. 40.52, 39.92, 33.65. 28.51, 26.84.

[0485] Rf ~ 0.24 (20% EtGAc / ex)

[0486] HUMS (ESI) calculated for [ TNS]*: 481.2350, found '181.2555.

[0487] Example 24

[0488]

[0120] rer / -butyl-(6-(2-((2-(lE7-indol-3-yl)ethyl)amino)-2-oxoethyl)spiro[3.3]heptan-2-yl)carbamate (26)

[0489]

[0490] Terf-b alyl (8~(2 -((2 -(12 / 4ndeL3 -y I tfey l)a unn»)-2~ex»ethyl)spire.3 ] he p tan -2- yl earhamafe (26) was obtained from 6 (?cvr-batoxycari yl)ammo)spir^3.3 «ptaue-2- carboxylie acid 41 (51.1 mg, 0.200 mmol, 1.00 equiv) using General Procedure A with the following modification: after the decarboxylation reaction was complete, a solution of tryptamine (43.1 mg, 0.300 mumi, 1.50 equiv) and DBU (149 L, 1 00 mmol, 5.00 e uiv) ia 0.5 mL DCM was added to the reaction visl. The reaction was then completed according to the general procedure. A crude!H UMR yield of 75% was obtained for this reaction.JH NMR (406 MHz, CMernfor -d) 88.49 (s, IH), 7.59 (d, J - 7.8 Hz, IH), 7,38 (d, J - 8.1 Hz, IH), 7.24 - 7,16 (m, IH), 7,15 - 7,07 (in, IH). 7.02 (d, J- 2.4 Hz, 1H). 5.45 d, J- 5.9 Hz, IH), 4.71 - 4.54 (m, H), 3,$5 (d, J- 9. G Hz, IH), 3,57 (ddt, J- 19.5. 13.5, 6.7 Hz, 2H). 2.95 (t, J- 6.6 Hz, 2H), 2.54 - 2,33 (m, 2H). 2.26 - 2.05 (m, 4H), 1.99 (ddd. - 1.7, 7.8, 3.9 Hz, t H). 1.72 (ddd,.7- 20,8, 11, Q, 8.7 Hz, H), 1.5 (td, 2- 1,8, 8,0 Hz, H, 1.43 (s,9H).

[0491] ,3C MR (101 MHz, Chloreform-d) 8 172.03, 155.15, 136.60. 127.41, 122.32, 122.28. 119.54, 18.81, 112.87, 111,48, 79.43, 3,80, 43.76, 1,56. 0.36, 30.9L 39.60, 33.70, 28.53, 27,51, 25,39. Rf =“ 0,29 (40% Aceloae / Hex)

[0492] HR S (ESI) calculated for [ -s-Na]*: 434.2414, found 434,2409.

[0493] Example 25

[0494]

[0121] Methyl-(2-(6-((terZ-butoxycarbonyl)amino)spiro[3.3]heptan-2-yl)acetyl)glycinate (27)

[0495]

[0496] Methyl (2-(6-((f r^biU»xyeaFb«nyl)aiis(ae)sphx>p, ]beplaH-2 yl)s<?etyl)glyc ste (27) was obtained from 6 (fis74»tfoxyearboayl)aminc>)spiro[3.3]heptaiie~2-tarboxylic acid 41 (51.1 mg, 0.200 mmcl, 1.00 equiv) using General Procedure A with the following modification: once the decarboxylation reaction was complete, glycine methyl ester hydrochloride (126 mg, 1.00 mmol, 500 equiv) and DBU (299 pL, 2.00 mmol, 10.0 equiv) were added sequentially to the reaction vial. The reaction was then completed according to the general procedure. The crude product was purified via flash column cluoinatograpliy yielding the title cotupomid as a clear oil (5.2,0 mg, 76%).

[0497] H NMR (600 MHz, Chforoform-ti) 35.91 (s, IH), 4.60 (s, IH), 4.01 (in, 3H), 3.7$ (s, 3H), 2.55 (h, J = 8,0 Hz, H). 2.47 (di, J = 12,3, 6.3 Hz, IH), 2.35 -2.20 (tn, 4H), 2,10 (ddd, 3 = 11.9, 7,8, 4.2 Hz. IH), 1.83 - 1.68 (m, 4H), 1.41 (s, 9H1.

[0498] 13C NMR (151 MHz, C:hforoform-d)6172.17, 170.69, 155.05. 79.33, 52.52,44.00,43.62,43.34.

[0499] 41.53, 1.22, 40.70.40.1, 33.69, 28.52, 27.45.

[0500] Rf- 0,36 (70% EtOAc / Hex)

[0501] HRMS (ESI) calculated for [MHSfoJ': 363.1891, found 363.1965.

[0502] Example 26

[0503]

[0122] Tert-butyl (6-(2-(methoxy(methyl)amino)-2-oxoethyl)spiro[3.3]heptan-2-yl)carbamate (28)

[0504]

[0505] Tert-butyl (0-(2-(methoxy(methyl)amteo)-2-ox4ethyI)splr«(3.3]heptaB-2-yi earba»iafe (28) was obtained from 6-((<w*tmtoxycathonyd)a iao)^iro[3.3jheptane«2-cartxjxyiic acid 41 (51.1 g, 0.200 mmch 1.00 eqaiv) using General Procedure A with the following modification: once the decarboxylation reaction was complete. N, O-dimefhyl hydroxylamine hydrochloride (97.5 mg, LOG mmol, 5.00 equlv) and DBU (209 L, 2.00 mmol, 10.0 eqniv) were added sequentially to the reaction vial, The reaction was then completed according to the general procedure. The exude product was purified via flash column chromatography yielding the title compound as a clear oil (50.2 mg, S0%).

[0506] *H MR (600 MHz, Chiwofo -d) & 4.59 (s, 1H). 4.01 - 3.96 (, IHj. 3.66 (s, 3H), 3.14 (s, 3H), 2.58 (hept, J - 7.9 Hz, 1H), 2.52 - 2.44 (, 3H), 2.32 - 2.22 (, 2H), 2.10 (ddd,. T - 11.3, 7.8, 4.1 HZ, 1H), 1.83 - 1.65 (m, 4H). 1.42 (s, 9H).

[0507] °€ N H (151 MHz. Chtoroform- ) o 173.74, 155.07, 79.28,01.30,44.02,43.75,41.58,40.80, 40.32, 38.84, 33.88, 32.09, 28,53, 26.75.

[0508] RE- 9.52 (70% EtOAc / Hex)

[0509] HRMS (ESI) calculated tor [MENa: 335.1942, found 335.1951.

[0510] Example 27

[0511]

[0123] rcrf-butyl-(6-(2-(4-(3-cyanopyridin-2-yl)piperazin-l-yl)-2-oxoethyl)spiro[3.3]heptan-2-yl)carbamate (29)

[0512]

[0513] Tert- butyl (6-(2-(4-(3-cyanopyridiB-2-yi)piperaaha-i-yt)~2-oxoe«feyi)spfi'o[3.3]hepetat-2- yl)cm‘bmaafe (29) was obtained from 6 (r^-^butoxycsrlx>ayl)am <>)spiK^3.3]hepmn.e’2- csitwxylic acid 41 (51.1 mg. 0.200 mmcl, LOO e uiv) using General Procedure A with the following modification: once the decarboxylation reaction was complete. 2-(piperazm-l- yi)n otinonitrile (108 mg, 1.00 mmoi, 5.00 equiv) ami DBU (149 uL, 1.00 mmol, 5.00 eqniv) were added sequentially to die reaction vial. The reaction was then completed according to the general procedure. A crude3H N R yield of §2 was obtained tor this reaction.JH WR (609 MHz, Cfttoroform- ) 5 8.36 (dd. J « 4.8. 1.9 Hz, 1H), 7.80 (dd, J « 7.6, 2.0 Hz, 1 H). 6.82 (dd, J “ 7.6, 4.8 Hz, 1H), 4.63 - 4.58 (m, Hi, 4.04 - 3.93 (m, 1 H), 3.77 - 3.56 (m. H), 2.59 (hept, J - 7.9 Hz, 1H), 2.46 (nt, 3H), 2.28 (ddd. 1 - 11.7, 7.9, 4.3 Hz, 2H), 2.12 (ddd, J - 11.8, 7.9, 4.2 Hz, I Hl, 1.84- 1.67 (, 4H), 1.41 (s, H).

[0514] °C NMR (151 MHz, Chloroform-d) S 170.90, 160.82, 155.06, 152.00, 143.89, 117.86, 114.99, 95.82, 79.30, 48.36. 48.20, 45.41, 44.0, 43.69, 4.1.5?, 41.26, 40.91, 40.42, 40.20, 33.87, 28.52, 2?.2O.

[0515] Rf * 0.32 (5% (MeOH w / 10% NHrOH) in DC )

[0516] HRMS (ESI) calculated for [M Naf: 462.2476, found 462.2475.

[0517] Example 28

[0518]

[0124] / V-((l / ?,2 / ?)-l-hydroxy-l-phenylpropaii-2-yl)-. V-methyl-3-propylhexanamide (30)

[0519]

[0520] obtained from valproic add (28.8 m 0209 mrnel, 1 00 eq iv) using General Procedure A with the fallowing modification: after the decarboxylation reaction was complete, (~ j^eodoephednne (165 tug, L00 mmol. 5.00 equiv) and DBU (149 pL, 1.00 mol, 5.00 eq tv) were added sequentially tn the reaction vial The reaction was then completed according io the general procedure, A crudeSH R yield of 62% was obtained for this reaction.

[0521] NMR (500 MHz, Chlo»'efor -d) 37.42 - 7.31 (nr, 4H), 7.27 (in, 1H), 4.65 - 4.53 (m, 1H), 4.46 (. 1H). 4.03 p,7= 7.1 Hz, 0.3 H), 2.91 (s, 0.7 / 3 H), 2.81 (s, 2.4 / 3 H), 2.42 - 2.26 (, 0.7 / 2 H), 2.2 — 2.13 (m, 1.6 / 2 H), 1.93 (h, 5.8 Hz, 1H). 1.69 (s, 1H), 1.39 - 1.19 (nt. 8H), 1.12 (d, J - 7.0 Hz, 3H). 0.98 (d, J - 6.8 Hz, 1 H). 0.89 (t, J~ 6.8 Hz, 6H).

[0522] U€ NMR (151 MHz. C&for»for t~d) § 175.69, 124.27, 142.70, 141.25, 128.8?. 128.57, 128.48, 127.72, 127.04. 126.47, 76,79, 75.72. 59.20, 58.53, 39.23, 38.77, 6.58, 36.47, 36.54, 36.32, 34.63, 34.46, 33.54.26.91, 19.96, 19.95, 19.90, 19.82, 15.51, 14.68, 14.57, 14.55.

[0523] Rf - 0.25 (20% Ace ne Hex)

[0524] HRMS (ESI) calculated for [W-Naf: 328.2247, found 328.2246.

[0525] Example 29

[0526]

[0125] Methyl-(57?)-5-((32?,87?,95,105,137?,145,177?)-3-hydroxy-10,13-dimethylhexadecahydro-l / fcyclopenta[a]phenanthren-17-yl)hexanoate (31)

[0527]

[0528] Methyl (SR) -5

[0529]

[0530] 3 -hydrox -10,13 dHuethyliiexsdeeahydro Iff eyciopeBta|4]phenan^re»-17 '-jijhexsm&ate (31) was obtained from lithocholic acid (73.3 g.

[0531] 0.200 nmol, 1.00 equiv) iag Oeaeral Procedure A. The crude product was purified via flush column chromatography yielding the title compound as a white solid (35.2 g. 44%).

[0532] rH NMR (500 MHz, Chloroform-d) 63.65 (s. 3H), 3.64 - 3.56 (at, 1H). 2.35 - 2.18 (tn, 2Hj.

[0533] 1.95 (dt J = 12., 3.1 Hz. 1H), 1.90 - 0.95 (m, 27H),0.9I (d, J~- 3. Hz, 6H), 0.63 (s. 3H).i3C NMR (151 MHz, Cltforefona-d) 6 174.50. 71.99. 56.62, 56.14, 51.57, 42.82, 42.23, 0.56, 40.30, 3.57. 35.97. 35.66, 35.53, 35.48, 34.76, 34.66, 30.67, 28.38, 27.33, 26.56, 24.34, 23.51, 21.72,20.94, 18.67, 12.14.

[0534] Rf » 0.17 (20% EtOAc / Hex)

[0535] SUMS (ESI) calculated for [M42cs]~: 288.1207, found 288.1208.

[0536] Example 30

[0537]

[0126] Methy I- (6, S’,115)- 1 l-(4-(benzyloxy )-4-oxobutyl)-6-(methoxycarbony l)-2,2-dimethyl-4, 9, 12-trioxo-3-oxa-5, 10, 13-triazapentadecan- 15-oate (32)

[0538]

[0539] Methyl («.9, H5>il-(4-(be»zyfoxy)-4-oxobuty'l)-6-(inethoxycarbo»yl)-2,2-dimethyl-4(9,i2-trtoxo-3-oxs-5,10 3-tHazape»tadeean~lS-oste (32^ was obtained fiwu (S)-4 (.i)-4-((?e??-butoxycarbonyl)ami»o 5-methox -5-oxopentaRamido)-5-( 2-inethoxy-2- xoefl»yl)amtao 5-oxopeatanoic acid S4 (92.3 mg, 0.200 mmol, 1.00 e uiv) using General Procedure A. A crude *H NMR yield of 42% was obtained for this re&ctfoa.

[0540] lH MR (600 MHz, C roform-d) 5 7.38 - 7.28 (m, 5H), 7.00 (s, 1H), 6.61 (s, 1H), 5.3S (s, 1H), 3.09 (s, 2H), 4.48 (s, 1 H), 4.28 (s, 1H), 4.00 (d, J - 5.6 Hz, 2H), 3.72 ($, 6H), 2.44 - 2.37 (m, 2H), 2.36 - 2.26 (m, 2H), 2.21 - 242 (m. 1H), 2.02 - 1.85 at, 2H), 1.78 - 1.64 (, 3H), 1.42 (s, 9H).

[0541] IJC hUR (151 MHZ, Chlor form-d) i> 173.26, 172.85. 172.26, 171.74. 170.09, 155.72, 135.88, 128.59, 128.28.128.24, 80.13, 66.35, 52.83.52.70, 52.48. 2.35, 1.15.33.57, 32.15, 31.31, 28.33, 28.31, 20.66.

[0542] Rf - 6.49 (70% EtOAcfflfex)

[0543] HRMS (ESI) calculated for [M+Na]*t 588.2528, found 588.2547, Example 31

[0544]

[0127] Benzyl-6-((3a. S’,4. S',6a / ?)-2-oxohexahydro-l / / -thieno[3,4-r / |iinidazol-4-yl)hexanoate (33)

[0545]

[0546] Benzyl 5-{(3aS<,4>5’,$a«)--2-ox«bexaftydro-lf?-tBi«ao[3,4-4]tmt4az01-4-yl)hex3®e»fe (33^ was obtained from biotin (48.9 mg, 0.200 mmol, 1.00 e uiv) using General Procedure A with the following modification: for the decarboxylation reaction, a 3:2 mixture of PhCF? (1.2 mL) and HFIP (0.8) was used. The reaction was then completed according to the general procedure. A crudeSH NMR yield of 30% was obtained for this reaction.

[0547] JH W ( 68 Hz, CMwoform-d) 57.39 ~ 7.30 (re, 5H), 5.62 - 5.44 (m, 1H), 5,11 (re, 3H), 4.48 (t, 1 - 6.5 Hz, 1H).4.28 ( d, J - 7.8, 4.7 Hz. 1 H), 3.13 (di, J - 9.1. 5.7 Hz. Hi), 2.90 (d. J - 12.9.4.7 Hz, 1H), 2.71 (d, J - 12.8 Hz, 1H).2,36 (t J « 7.4 Hz 2H), 1.66 (tdd, J « 17.4, 12.1, 7.0 Hz, 4H), 1.48 -• 131 (in, 4H).

[0548] nC MR (15.1 MHz, Chtoroterm-d) 8 173.73. 163.42, 136.18, 128.71, 1 836, 128.35, 66.31, 62.10. 60.20, 55.72, 40.71, 34.31, 29.13, 23.79, 23.56, 24.70.

[0549] Rf - 0.57 (5% (MeOH w / 10% NH«OH) in DCM)

[0550] H IS (ESI) calculated for

[0551]

[0552] 371.1400. found 371 1412.

[0553] Example 32

[0554]

[0128] Methyl 3-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl)propanoate (34)

[0555]

[0556] Methyl 3-(l-(4-c toroben2oyI)-5-methoxy-3-methyI-lH-l»doi-3-yi)propaB«ate (34) was obtained from indomethacin using General Procedure A with the following modifications: to 3. fiame-dried 1 dram vial were added a magnetic stir bar, indomethacin (71.6 mg, 0.200 mmol. 1.00 eqniv), O-aikeayl hydroxamate reagent 2 (129 mg, 0.300 mmol, 1.50 equiv). and (1- plwsphuryl)vinyl sulfonate 1 (223 reg, 0.600 mmol, 3.00 eqrev). The vial was moved into an srgcu-lille glovebox. To the vial were added PhCFs (1.0 tnL) and HFIP (1.0 reL). The vial was then sealed with a cap containing a PTFE septum. Teflon was wrapped around the cap. The vial was removed from the gksvebox and set to stir in a fumehcod at 50 C tor 16 hours. The reaction was then completed according io the general procedure. Hie crude product was purified via flash coltmtn cfirmnatography yielding the title compound as a yellow solid (58.9 utg, 75%>).

[0557] JH MR <609 MHZ, Chloroform-d) 57.69 - 7.61 (ni, 2H). 7.49 - 7.44 (m, 2H), 6.94 - 6.36 (.

[0558] 2H), 6.66 (dd, J = 9.0, 2.5 Hz, i H).3.84 (s. 3H), 3. 9 (s. 3H). 3,00 (t, J « 7,8 Hz, 2H), 2.62 (dd, J ~ 8.3, 7.2 Hz, 2H), 2.34 is. 3H).

[0559] I3€ NMR(151 Hz, Chloroform- d) S 173.47. 168.45, 156.0, 139.25, 134.70, 134.24, 131.25, 131.12, 130.73, 129.23, 118.11, 115.18. 111.37, 101.29, 55,91. 51.88. 34,04, 19.67, 13.36. Rf « 0.46 (20 EtOActHex)

[0560] HRMS (ESI) calculated for M -i-Hf: 386.1154, found 386.1167.

[0561] Example 33

[0562]

[0129] Benzyl 3-(4-isobutylphenyl)butanoate (35)

[0563]

[0564] Benzyl 3 (4-isohutyIpheuyl)butam>afe (35) was obtained from ibuprofen using General Procedure A with the following tnsxiihcatioiis: to a flame-dried 1 dram vial were added a magnetic stir bar, ibuprofen (41.3 mg, 0.200 mmol, 1,00 eqviv), G-alkenyl hydroxamaie reagent 2 (129 mg, 0.300 mmol, 1.50 equiv), and (l-phosphoryl)vinyl sulfonate 1 (223 mg.0.600 mol, 3.00 equiv). The vial was moved into an argon-filled glovebox. To the vial were added PhCFj (1.8 mL) and HFIP (0.2 mL). The vial was then sealed with a cap containing a PTFE septam. Teflon was wrapped around the cap. The vial was removed from the glovebox and set to stir in a fumehood at 50 " for 16 hours. The reaction was then completed according to the general procedure. The crude product was purified via flash column chromatography yielding the title compound as a yellow oil ( S.$ nig, 94%).

[0565] lH MR (609 MHz, Chlorofor -d) <s 7.38 - 7.24 (m, 5H), 7.14 - 7.03 (tn, 4H), 5.07 (s, 2H), 3.28 (h, J ~ 7.2 Hz, IH), 2.68 (dd, J « 15.0, 7.1 Hz, IH). 2.59 (dd, J ■« 15.0. 8.1 Hz, Hi), 2.45 (d, J - 7.2 Hz. 2H). 1.85 (d, 3 - 13.5, 6.8 Hz, IH), 1.29 (d, 3 - 7.0 Hz, 3H), 0.90 (d, J - 6.6 Hz, 6H).MCNMR(1S1 MHz, Chloroform-d) 8 172.48, 142.92, 139.85, 136.09, 129.34, 128.62, 128.29, 128.26, 126.56, 66.27, 5.17, 43.19, 36.29, 30.35, 22.55, 22.03.

[0566] Rf — 0.82 (20% EtOAc / Hex)

[0567] HRMS (ESI) calculated for [M-i af: $33.1825, found 333.1835.

[0568] Example 34

[0569]

[0130] Benzyl 2-((15',25,4a / ?,4b7?,75,9a7?,105,10a7?)-2-acetoxy-7-hydroxy-l-methyl-8-methylene-13-oxo-l,2,4b,5,6,7,8,9,10,10a-decahydro-4a,l-(epoxymethano)- 7,9amethanobenzo [a] azulen-10-yl)acetate (36)

[0570]

[0571] Benzyl 2-{(l. S',25) nR,41»I?,75',9ftR,106,i0aR)-2-ae<'toxy~7-hydroxy-l.sn<'feyi-8- ethylt'ne~ 13-0X8-1, 2,46,5,6,7, 8,9, 10,f0a~decahydro-4s,l-(epoxymethano)-7,9 a-methanobenzo[«]azulen- 10- l)acefof e (36) was obtained from gibberellin Ai-3-acetate (77.7 mg, 0.200 mmol, 1.00 eq v), which was prepared according to a published procedure, using General Procedure A with the following modification: for the decarboxylation reaction, a 3:2 mixture of PhCFs (1.2 ml.) and HPIP (0.8) was used. The reaction was then completed according to the general procedure. The crude product was purified via flash column cinematography yielding the title compound as an off-white foam (40.6 mg, 41%, >25:1 dr).

[0572] SH NMR (606 MHz, toroform-d) 57.39 - 7.30 (m, 5H). 6.36 (dd, J - 92, 0.8 Hz, IH), 5.82 (dd, J » 9.3, 3.8 Hz, IH), 539 - 5.28 m. IH), 5.20 (dd, J - 3 J, 1.7 Hz, IH), 5.17 - 5.09 (, 2H), 4.90 d, J - 2.1 Hz, IH), 2.60 - 2.49 (m, 3H), 2.49 - 2.3? (m, 2H), 2.09 (s, 3H). 2.07 - 1.97 (m, 2H), 1.95 - 1.78 (m, 3H), 1.77 -.61 (m, 2H). 1.39 - 1.3 (m, 2H), 1.28 (s, 3H).

[0573] 13C NMR (151 MHz, Chlor oform d) § 17734, 171.70, 169.97, 156.98, 135.67, 134.89, 129.07, 128.93, 128.86, 128.65, 107.14. 90.05, 78.05, 71.18, 66.80, 55.57, 52.61, 50.94, $.62, 45.57, 41.72, 40.86, 37.93, 36.39, 20.96, 17.10, 14.78.

[0574] Rf- 0.63 (70 EtOAc / Hex)

[0575] HUMS (ESI) calculated for [M-tbfof: 515.2041, found 515.2060.

[0576] Example 35

[0577]

[0131] yieth.vl-2-((. S. S’.9. S’.10 / ?.13 / ?.14. S’)-10.13-diniethyl-3-oxo- 2,3,6,7,8,9,10,ll,12,13,14,15,16,17-tetradecahydro-L / -cyclopenta[a]phenanthren-17-yl)acetate (37)

[0578]

[0579] Methyl 2 -((85', 9$', 10R,132?,149) 10, 13 ■dimetbyl-3 »x<u 23,6,7, 8,9, 16, 11,12,13,14,1$, 16, 17- tetradeeahydre-l^r-eycfopenta[«]pUeux»thren-17-y|)acetate (37) was obtained from (85,93;i0R,13<$'.1 6,173 10,13-dimefoyi-3-cx -,3,6,7,8?9,10,ll,i 33,14,i5,i,l?- tetradec hydr8-l -cyclopuiiEa[a']pheaantiireae-r7"C8rb<>xylic acid (63.3 mg, 0.200 s iol, 1.00 equiv) using General Procedure A. The crude product was purified via flash column chromatography yielding the title compound as a white solid and mix of inseparable diastereomers (40.8 mg, 59%, 7.4: 1 dr). Note: Diastereoselectivity was assigned using peak integrations from a quantitative!sC MR experiment. The d relaxation time was experimentally determined to be 10 seconds, which was used for the quantitative33C experiment Absolute st^eochemisfry could not be unambiguously assigned via *H-SH NOESY due to overlapping proton signals from both isomers. Therefore, foe major diastereomer was tentatively assigned in analogy to the observed selectivity for another decarboxylative C~C bond forming reaction. ■'

[0580] MR (Both diastereomers - 560 MHz, Cklerofo m-d) 85.71 (s, H), 3.64 (s, 3H), 2.46 2.29 (tn, 4H), 2.28 - 2.32 (m, I H), 2.15 (ddt. J 11.6, 6.1, 2.2 Hz, 1 H). 2.08 - 1.95 (m, 2H),.86 (ddt, J- 12.3, 5.7, 2.8 Hz. 1H), 1.75 - 1.63 {, 2H), 1.61 - 1.40 (, 4H), 1.25 - 1.19 (m, 3H), 1.17 (s, 3H), 1.11 - 0.99 (, 2H). 0.90 (m, 2H), 0,84 (s, 3H).

[0581] L,C NM (Major. Diastereomer - 151 MHz, Chloroform-d) 8 199.62, 174.28, 171.35, 23.93, 53.76. 51.58. 50.29, 44.27, 42.89, 38.74, 37.38, 36.04. 35.83, 34.07, 33.65, 32.99, 32.52. 28.38.

[0582] 25.68, 20.95, 20.40, 17.51.

[0583] Rf ~ 0.29 (40 Acetone / Hex)

[0584] HRMS (ESI) calculated for [M*NaF: 434.2414, found 434.2409.

[0585] Example 36

[0586]

[0132] Methyl 3-(4-(2-(4-chlorobenzainido)ethyl)phenoxy)-3-methylbutanoate (38)

[0587]

[0588] Methyl 3-(4- 2-(4-cMm'obenzamido)ethyI)phenoxy)-3-.methyIbutanoate (38) was obtained from bezafibrate (72.4 mg, 0.200 mmol. 1.00 equiv) using General Procedure A, The crude product was purified via flash cohmm chromatography yielding the title compound as a white solid (26.0 mg, 33%).

[0589] lH MR (600 MHz, C roform-d) t> 7.64 ~ ". S3 (in, 2H), 7.40 - 7.35 (m, 2H). 7.15 - 7.10 (m, 2H), 7.00 - 6.95 (m, 2H). 6.05 (s. 1H). 3.72 - 3.65 (. 5H), 2.89 (t, J - 6.9 Hz, H). 2.68 (&, 2H), 1.41 (s.6H).

[0590] i3C NMR 151 MHz, Cfeloroform-d) t> 171.29, 166.49. 153.33, 137.80, 134.32, 133.12, 129.46, 128.98, 128.36, 124.90, 78.89, 51.75, 6.52, 41.30, 35.03, 26.98.

[0591] Rf » 0.19 (2 % EtOAc Hex)

[0592] HRMS (ESI) calculated for [M-tNaf: 412.1286, found 12.1392.

[0593] Example 37

[0594]

[0133] Methyl-2-((4 / ?, 4a / ?, 6a / ?, 9,11 a / ?,llb / ?)-4, 9,11 b-trimethyl-8-oxotetradecahydro-6a,9-methanocyclohepta[«]naphthalen-4-yl)acetate (39)

[0595]

[0596] Methyl 3-((43?,4aR, a^,9<9,ilaR,ltl>fl! 4Allb-h'i etbyl-8-oxoteft'adecahydro-6a,9-meths: B«ryclohepta[rt]Kaphth«fou-4-yI)3<-etafe (3 )j was obtained ftom isosteviol (63.7 g, 0.200 mmol, 1.00 equiv) using Je xerai Procedure A. The crude product was purified via flash cohumi chromatography yielding the title compound as an ofl^white, crystalline solid (50.3 mg, 73%, >25:1 dr).

[0597] JH MR (500 Hz, Cblorefo -d) 53.63 (a, 3H). 2.65 (dd, J - 18.6, 3.8 Hz, 1 H).2.28 - 2.13 m, 2H), 1.75 (d, <7- 18.6 Hz, III), 1.67 - 1.15 (, 16HI, 1.04 (dd, J~ 11.9, 1.8 Hz, 1H), 0.95 (s, 3H), 0.93 (a. 3H), 0.88 (s, 3H), 0.83 id, J- 13.0, 12.5. 3.3 Hz, 1H).

[0598] •u€ NMR (151 MHz. OMorofonB^I >3222.75, 172.85, 55.58, 54.51, 53.88, 51.27, 48.86, 48.80, 48.54. 41.05, 39.48.38.97, 37.94, 3.73, 37,37, 37.08, 26.97, 20.37, 20.06, 19.96, 17.97, 15.46. Rf “ 6.28 (10% EtOAc / Hex)

[0599] HRM8 (ESI) calculated for

[0600]

[0601] 369.2400, found 369.2396.

[0602] Example 38

[0603]

[0134] (+)-Ambreinolide (40)

[0604]

[0605] (s-)- mbreinoh e (48)|was obtained frcra carboxylic acid SI using a modified General Procedure A as follows. To a flame-dried 1 dram vial were- added a magnetic sth' bar, SI (26.8 mg, 6.100 mmol, 1.00 equiv), O-alkeayl hydrox&mate reagent 2 (73.3 mg, 0.176 mmol, 1.70 equiv), and (1 - phosphotyi)vmyi sulfonate 1 (111 mg, 6.306 mmol, 3.00 equiv). The vial was moved into an argon-l lled glovebox. To the vial were added PhCFj (0.8 mL) and HFIP (0.2 mb). The vial was sealed with a cap containing a PTFE septum. Teflon was wrapped around the cap. The vial was removed from tire glovebox and set to stir in a fumehood at 90 ’’C for 1 hour.

[0606] After cooling to it, DBU (74.6 pL, 0.500 mol, 5.00 e ) was added. The reaction was then worked up according to the general procedure. The crude product was purified via flash column clitomafogntphy yielding the title compound as a while, crystalline solid (15.6 mg, 59%). Physical and spectral data were in accordance with literature data -9

[0607] JH NMR (500 MHz. Chforoform-d) 62.67 (ddd.,7- 18.8. 8.7, 2.9 Hz. 1H), 2.54 (dt, J- 18.5.

[0608] 8.9 Hz, IH), 202 (di,, J- 12.7, 3.3 Hz, 1H), 1.86 - 1 54 (m,6H), 1.54- 1.38 (m,3H), 1.38 (s, 3H), .1.39 (td, 13.2, 12.7. 3.3 Hz, IH), 1.17 (td,. / - 13.3, 4.2 Hz, IH),.1.04 - 9.91 (m,2H), 0.8 (s.

[0609] 3H), 0.84 (s, 3H), 0.81 (s, 3H}.

[0610] WC NMR (151. MH, €hl«r<»fo -d> 5 171.77, 83.94, 56.13, 53.73, 41.83, 41.36, 39.28, 37.38, 33.46, 33.31, 2 9.11, 23.01, 21.58. 19.77, 18.52,.15.94, 15.20.

[0611] Rf - 0.24 (20% EtOAc / Hex)

[0612] HRMS ESi calculated for [ -Wa 287.1982. found 287.1977.

[0613] Example 39

[0614]

[0135] 7er / -butyl-(6-(2-(benzyl(methyl)amino)-2-oxoethyl)spiro[3.3]heptan-2-yl)carbamate (S4)

[0615]

[0616] Tfo-Mutt l (6-(2-(heBz ’l(methyl)»infoo)~2-oxoefoyI)spiFc.3]hepfo8-2~ I)carbamate (S4) was obtained &o 6-((fei ii-la.u«xycarboii¥l)B.uiixv:.'>}$piro[3.3]li )taiie-' -e»iboxyii£ add 4.1 using General Procedure A on 1.80 mol ■scale. To a fiame-dried 50 uiL round bottom flask were added s magnetic stir bar, carboxylic acid 41 (460 mg, 1.80 mmol, 1.00 equiv), O-alkenyl hydroxamate 2 (1.16 g, 2. 0 mmol, i.50 equiv), and (l’pho$phofyl)viayi sulfonate 1 (1.34 g, 3.69 m ol. 2.00 equiv). The round bottom was then moved into an argon-filled glovebox. To the flask, were added PhCFj (16.2 m ) andHFIP (1.8 m ). The flask was sealed with a. septum and wrapped with teflon. The flask was removed from the glovebox and set to stir m a fomekood at 90:<C for 1 hour with an argon-filled balloon attached.

[0617] Alter cooling to rt, A’-beazybnethyianiine (1.16 niL, 9.80 mol. 5.98 equiv) was added via syringe, followed by DBU 1.34 L, 9.00 mmol, 5.09 equiv). The reaction was then stirred for 1 hour at rt. The reaction was concentrated sad pushed through a silica plug with EtOAc. The crude material was purified via flash column chromatography yielding the title compound as a viscous oil that slowly crystallized to a white solid over time (451 mg, 67%).

[0618] Note: The product exhibits amide cis-frans isomerism on the NMR timescale with several distinctSH and!iC signals for each isomer.

[0619] *H M» (6(01 Hflh, Chlorofonn-d) 57.36 (t. J « 7.5 Hz, IH), 7.31 (dd. J ■--■■■ 6.3, 6.8 Hz, 2H), 7.22 - 7.19 (m, IH), 7.14 (d, 7.5 Hz, IH), 4.58 (s, IH).4.56 (, 1.2 / 2 H), 4.50 (s, 0.8 / 2 H), 3.98 (s, IH), 2.91 (s. 1.3 / 3 H), 2.88 (s, 1.7 / 3 Hl, 2.63 (dh, 11.7, " 9 Hz. IH).2.46 (dq, 13". 7.0 Hz, 3H). 2.2S (dddd, 22.4, 11.6, 7. S, 4.0 Hz, 2H), 2.13 (dddt, J- 20.9, 11.9, 8.0. 3.7 Hz, IH), 1.85 - 1.61 (, 4H), t.42 (d, J 3.7 Hz, 9H).

[0620] J3C NMR f l.51 MHz, Chlorotonn-d) 5172.62. 172.23. 137.68, 136.85, 129.97, 128.70, 128.17.

[0621] 127.73, 127.43. 126.36, "9.30, 53.5", 53.39, 50.76, 44.07, 4.05, 43.76, 43.68, 41.59, 40.89, 40.44, 40.05. 34.95, 33.92, 33.87, 33.83, 28.54, 7.30, 27.22.

[0622] Rf ~ 0.12 (39% EiOAc / Hex) HRMS (ESI) calculated for [ -I-Naf: 395.2305. found 395.2302.

[0623] ; V.beB2yl-2-( -(3-(4- etlioxybea2yl)iiJ‘ekfo}spirc>[3.3]hepraH-2-yl)-A?- eliiyfoeetamKle (42) was obtained from Boc-deprotection and subsequent urea protection of S4. To a 1 dram ial was added S4 (74.5 mg, 0.200 mmol, 1.00 e uiv) and 0.5 mL DCM. The vial was then diluted with 4M HCi dioxane 1250 pl, 1.00 mmol, 5.00 equiv). The vial was set to stir for id hours at rt. Once complete, the vial was concentrated and rediasolved in 0.5 L DCM. NEb (55.8 tiL, 0.400 mmol, 2.00 equiv) was then, added and tire reaction stirred for 5 minutes at rt. Lastly, 4- methoxybeazyl isocyanate (42.8 pL, 0300 mmol, 1.50 equiv) was added dropwise. The reaction was monitored by TLC. Once complete, the reaction was then concentrated. The crude material was purified via flash column chromatography. The tide product was isolated as an opaque, viscous oil that slowly crystallized to a white solid over time (83.3 mg, 96%).

[0624] Note: The product exhibits amide cis-trans isomerism on the K timescale with several distinctSH and *-C signals for each isomer. Trace water can also cause substantial shifts inEH and; 5C signals between acquisitions.

[0625] 11 NMR (400 MHz, Ctiloroform-d) 8736 (dd, = 8.2, 67 Hz, IH),?.33 7.27 (m, 2H), 7.24 - 7.16 (m, 3H), 7.13 (d, J® 7.4 Hz, iH), 6.85 (dd, J- 8.6, 1.4- Hz, 2H), 4.58 (s, 1-1 / 2 H), 4.56 (s, C.9Z2 H), 4.48 - 435 (m, 2H), 4.28 (dd,. J~ 5.7, 2.7 Hz, 2H). 3.99 (dq, J « 14.5, 7.9 Hz, IH). 3.79 (s, 3H), 2.90 (s, 1 / 3 H), 2.8? (s, 1.6 / 3 H), 2.62 (dt, J~ 15.8, 7.9 Hz, IH), 2.54 ~ 2.40 (m, 3H), 2.27 (ddt, J 19.9. 11.4. 5.2 Hz, 2H), 2.19 - 2.06 (m, IH), 1.86 - 1.62 (m, 4H).

[0626] IS€ NMR (151 MHz, Chforofo -d) S 172.61, 172.22, 159.07. 157.23, 157.27, 137,64, 136.82, 131.35, 129.08. 129.01, 128.71. 128.16, 127.75, 127.45, 126.35, 114.18. 55.45, 53.40, 50.77, 44.18, 44.16, 43.89, 43.81, 41.61, 41.58, 40.99, 40.95, 40.59, 40.57, 40.42, 40.01, 34.97. 34.09, 34.04, 33.86, 27.30, 27.22.

[0627] Rf - 0.12 (70% EtOAc / Hex)

[0628] HRMS (ESI) calculated for [M-rNa]~ 458.241, found 458.2401.

[0629]

[0136] Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.

[0630]

[0137] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practicing the subject matter described herein. The present disclosure is in no way limited to just the methods and materials described.

[0631]

[0138] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs, and are consistent with: Singleton et al (1994) Dictionary of Microbiology' and Molecular Biology, 2nd Ed., J. Wiley & Sons, New York, NY; and Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immunobiology, 5th Ed., Garland Publishing, New York.

[0632]

[0139] Throughout this specification and the claims, the words "comprise." “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. It is understood that embodiments described herein include “consisting of and / or “consisting essentially of’ embodiments.

[0633]

[0140] As used herein, the term “about,” when referring to a value is meant to encompass variations of, in some embodiments ± 50%, in some embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ± 1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

[0634]

[0141] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of the range and any other stated or intervening value in that stated range, is encompassed. The upper and lower limits of these small ranges which may independently be included in the smaller rangers is also encompassed, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.

[0635]

[0142] Many modifications and other embodiments set forth herein will come to mind to one skilled in the art to which this subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. BIBLIOGRAPHY

[0636] (1) Y. Zabolotna, D. M. Volochnyuk, S. V. Ryabukhin, D. Horvath. K. S. Gavrilenko, G.

[0637] Marcou, Y. S. Moroz, O. Oksiuta, A. Vamek, A Close-up Look at the Chemical Space of Commercially Available Building Blocks for Medicinal Chemistry’. J. Chem. Inf. Model. 62, 2171-2185 (2022).

[0638] (2) F. Mao, W. Ni. X. Xu. H. Wang, J. Wang, M. Ji, J. Li, Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs. Molecules 21, 75 (2016).

[0639] (3) P. Ertl. T. Schuhmann, A Systematic Cheminformatics Analysis of Functional Groups Occurring in Natural Products. J. Nat. Prod. 82, 1258-1263 (2019).

[0640] (4) J. R. Dunetz, J. Magano, G. A. Weisenburger, Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Dev. 20, 140-177 (2016).

[0641] (5) G. Laudadio, M. D. Palkowitz. T. E.-H. Ewing, P. S. Baran, Decarboxylative CrossCoupling: A Radical Tool in Medicinal Chemistry. ACS Med. Chem. Lett. 13, 1413— 1420 (2022).

[0642] (6) D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W. Thomas, D. M. Wilson, A. Wood, Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383-394 (2018).

[0643] (7) K. Futatsugi, A. C. Smith, M. Tu, B. Raymer, K. Ahn, S. B. Coffey, M. S. Dowling, D. P. Fernando, J. A. Gutierrez, K. Huard, J. Jasti, A. S. Kalgutkar, J. D. Knafels, J. Pandit, K. D. Parris, S. Perez, J. A. Pfefferkom, D. A. Price, T. Ryder, A. Shavnya, I. A. Stock, A. S. Tsai, G. J. Tesz, B. A. Thuma, Y. Weng, H. M. Wisniewska, G. Xing, J. Zhou, T. V. Magee, Discovery' of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK.) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose. J. Med. Chem. 63, 13546-13560 (2020).

[0644] (8) T. S. Snowden, "One-Carbon Homologation and Homologation-Functionalization Reactions of Aldehydes.” In Homologation Reactions (Wiley -VCH GmbH, 2023), pp. 661-711.

[0645] (9) N. R. Candeias, H. M. T. Albuquerque, “Diazo-Mediated Homologation Reactions.” In Homologation Reactions (Wiley -VCH GmbH, 2023), pp. 1-77.

[0646] (10) F. Arndt, B. Eistert, Ein Verfahren zur Uberfuhrung von Carbonsauren in ihre hoheren Homologen bzw. deren Derivate. Berichte Dtsch. Chem. Ges. (A B Ser.) 68, 200-208 (1935).

[0647] (11) D. H. R. Barton, C. Ching-Yuh, J. Cs. Jaszberenyi. Homologation of carboxylic acids by improved methods based on radical chain chemistry’ of acyl derivatives of N- hydroxy-2-thiopyridone. Tetrahedron Lett. 33, 5013-5016 (1992).

[0648] (12) A. R. Katritzky, S. Zhang, A. H. M. Hussein, Y. Fang, P. J. Steel, One-Carbon Homologation of Carboxylic Acids via BtCH2TMS: A Safe Alternative to the Amdt-Eistert Reaction. J. Org. Chem. 66, 5606-5612 (2001).

[0649] (13) V. D. Pinho, B. Gutmann, C. O. Kappe, Continuous flow synthesis of 0-amino acids from a-amino acids via Amdt-Eistert homologation. RSC Adv. 4, 37419-37422 (2014).

[0650] (14) S. Bonciolini, A. Pulcinella, M. Leone, D. Schiroli, A. L. Ruiz, A. Sorato, M. A. J.

[0651] Dubois, R. Gopalakrishnan, G. Masson, N. D. Ca’. S. Protti, M. Fagnoni, E. Zysman- Colman, M. Johansson, T. Noel, Metal-free photocatalytic cross-electrophile coupling enables Cl homologation and alkylation of carboxylic acids with aldehydes. Nat. Commun. 15, 1509 (2024). (15) T. J. Fazekas, J. W. Alty, E. K. Neidhart, A. S. Miller, F. A. Leibfarth, E. J. Alexanian, Diversification of aliphatic C-H bonds in small molecules and polyolefins through radical chain transfer. Science 375, 545-550 (2022).

[0652] (16) C. G. Na, D. Ravelli, E. J. Alexanian, Direct Decarboxylative Functionalization of Carboxylic Acids via O-H Hydrogen Atom Transfer. J. Am. Chem. Soc. 142, 44-49 (2020).

[0653] (17) H.-M. Huang, P. Bellotti, J. Ma, T. Dalton, F. Glorius, Bifunctional reagents in organic synthesis. Nat. Rev. Chem. 5, 301-321 (2021).

[0654] (18) M. Sekine, A. Kume, T. Hata, Dialkyl acylphosphonates: a new acylating agent of alcohols. Tetrahedron Lett. 22, 3617-3620 (1981).

[0655] (19) M. Brunner, P. Saarenketo, T. Straub, K. Rissanen, A. M. P. Koskinen, Stereocontrolled a- Alkylation of Fully Protected L-Serine. Eur. J. Org. Chem. 2004, 3879-3883 (2004).

[0656] (20) M. Nagatomo. H. Nishiyama, H. Fujino, M. Inoue, Decarbonylative Radical Coupling of a-Aminoacyl Tellurides: Single-Step Preparation of y-Amino and a.|3- Diamino Acids and Rapid Synthesis of Gabapentin and Manzacidin A. Angew. Chem. Int. Ed. 54, 1537-1541 (2015).

[0657] (21) T. M. Faraggi, C. Rouget-Virbel, J. A. Rincon. M. Barberis. C. Mateos. S. Garcia- Cerrada, J. Agejas, O. de Frutos, D. W. C. MacMillan, Synthesis of Enantiopure Unnatural Amino Acids by Metallaphotoredox Catalysis. Org. Process Res. Dev. 25, 1966-1973 (2021).

[0658] (22) E. Juaristi, V. Soloshonok, Enantios elective Synthesis of / 3-Amino Acids. (Wiley, 2005).

[0659] (23) M. R. Bauer. P. D. Fruscia, S. C. C. Lucas, I. N. Michaelides, J. E. Nelson. R. I.

[0660] Storer, B. C. Whitehurst, Put a ring on it: application of small aliphatic rings in medicinal chemistry. RSC Med. Chem. 12.448-471 (2021).

[0661] (24) A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky, J. L. Gleason, Pseudoephedrine as a Practical Chiral Auxiliary for the Synthesis of Highly Enantiomerically Enriched Carboxylic Acids, Alcohols, Aldehydes, and Ketones. J. Am. Chem. Soc. 119, 6496-6511 (1997).

[0662] (25) J. R. Donald, W. P. Unsworth, “Ring Expansion Homologation: Synthetic Strategies and Reaction Design.’" In Homologation Reactions (Wiley-VCH GmbH. 2023), pp.

[0663] 713-726.

[0664] (26) E. Lederer, F. Marx, D. Mercier, G. Perot, Sur les constituants de 1’ambre gris II.

[0665] Ambreine et Coprostanone. Helvetica Chim. Acta 29, 1354-1365 (1946).

[0666] (27) 1. P. Wienecke, H. Gorls, H.-D. Arndt, Multigram-scale total synthesis of (±)- ambreinolide by a diastereoselective polyene cyclization. Bioorg. Med. Chem. I.eu. 'll, 128845 (2022).

[0667] (28) M. Liapis, V. Ragoussis, N. Ragoussis, Improved total synthesis of (±)-drimenin. J.

[0668] Chem. Soc.. Perkin Trans. 1 0, 815-817 (1985).

[0669] (29) V. Ragoussis, M. Liapis, N. Ragoussis, Synthesis and resolution of albicanic acid.

[0670] Simple access to optically active drimane sesquiterpenes. J. Chem. Soc., Perkin Trans. 1, 987-992 (1987).

[0671] (30) N. Fujiwara, M. Kinoshita, H. Akita, New total synthesis of (+)-ambrein.

[0672] Tetrahedron: Asymmetry 17, 3037-3045 (2006).

[0673] (31) A. Romero, A. Chandra, C. Evans, M. Shen, Preparation of (hetero)aryl urea compounds as NAMPT modulators. International Patent WO 2021 / 226276 A2, Nov.

[0674] 11, 2021.

[0675] (32) L. Li, Y. Yao, N. Fu, Free Carboxylic Acids: The Trend of Radical Decarboxylative Functionalization. Eur. J. Org. Chem. 26, e202300166 (2023). (33) S. B. Beil, T. Q. Chen, N. E. Intermaggio, D. W. C. MacMillan, Carboxylic Acids as Adaptive Functional Groups in Metallaphotoredox Catalysis. Acc. Chem. Res. 55, 3481-3494 (2022).

[0676] (34) J. D. Griffin, M. A. Zeller, D. A. Nicewicz, Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight. J. Am. Chem. Soc. 137, 11340-11348 (2015).

[0677] (35) N. P. Ramirez, J. C. Gonzalez-Gomez, Decarboxylative Giese-Type Reaction of Carboxylic Acids Promoted by Visible Light: A Sustainable and Photoredox-Neutral Protocol. Eur. J. Org. Chem. 2017, 2154-2163 (2017).

[0678] (36) A. A. Shah, M. J. Kelly, J. J. Perkins, Access to Unnatural a- Amino Acids via Visible- Light-Mediated Decarboxylative Conjugate Addition to Dehydroalanine. Org. Lett.

[0679] 22, 2196-2200 (2020).

[0680] (37) J. Lee, K.-C. Lim, X. Meng, S. Kim, Radical Alkylations of Alkyl Halides and Unactivated C-H Bonds Using Vinyl Tritiates. Sj / e / t 2010, 1647-1650 (2010).

Claims

1. THAT WHICH IS CLAIMED:

1. A compound having the structure:

4.

2. The compound of claim 1, wherein the compound is a solid.

3. A mixture comprising, the compound of claim 1 and a compound of Formula II:

9. 11.wherein,12.Rxis an optionally substituted linear or branched Ci-io alkyl or optionally substituted Ce-io aryl;13.Rla. Rlband Rlcare each independently selected from the group consisting of hydrogen, C2-C8 alkenyl, C2-C8 alkynyl, -C1-C3 alkyl-Ci-C3 alkoxy-, C3-8 carbocyclyl, Ce-io aryl, C3-8 heteroaryl, C2-8 heterocyclyl, -Ci- C3 alkyl-Cs-8 carbocyclyl, -C1-C3 alkyl-Ce-io aryl, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a,14.wherein, Q is O or is absent;15.R10ais hydrogen or C1-6 alkyl; and16.wherein, the carbocyclyl, aryl, heteroaryl, heterocyclyl and alkyl can each be independently optionally substituted;17.and, R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of C1-6 alkyl, halo-C 1-6 alkyl, halo, -CN, and -NO2.

4. The mixture of claim 3, further comprising a solvent.

5. The mixture of claim 3 or 4, further comprising a substrate.

6. The mixture of claim 3, wherein the substrate is a polymer or small molecule.

7. A method of preparing a homologated substrate, comprising:22.i. in the presence of compound 1 having the structure:

24. 26.and a substrate, contacting a compound of Formula II to form a mixture, wherein the mixture is at a temperature from about 25 °C to about 250 °C, wherein a nitrogencentered radical is prepared, and wherein:27.the substrate comprises a COOH group; and,28.the compound of Formula II has the following structure:

30. 32.wherein,33.Rxis an optionally substituted linear or branched Ci-io alkyl or optionally substituted Ce-io aryl;34.Rla. Rlband Rlcare each independently selected from the group consisting of hydrogen. C2-C8 alkenyl. C2-C8 alkynyl, -C1-C3 alkyl-Ci-Cs alkoxy-, C3-8 cycloalkyl, Ce-io aryl, C3-8 heteroaryl, C2-8 heterocyclyl, -Ci- C3 alkyl-Cs-8 cycloalkyd, -C1-C3 alkyl-Ce-io ary l, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a.35.wherein, Q is O or is absent;36.Ri°a-shydrogen or C1-6 alkyl; and37.wherein, the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl can each be independently optionally substituted;38.and.39.R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of C1-6 alkyl, halo-C 1-6 alkyl, halo, -CN, and -NO2;40.ii. allowing the substrate comprising a COOH group to contact the nitrogencentered radical to form a substrate radical;41.iii. allowing the substrate radical to contact compound 1, wherein, a COOH group on the substrate is functionalized to form an acyl phosphonate having a structure:

44.

8. The method of claim 7, further comprising contacting the homologated substrate with a nucleophile to convert the acyl phosphonate to49.

9. The method of claim 8, wherein Nuc is a residue of the nucleophile.

10. The method of claim 8, wherein the nucleophile is selected from the group consisting of water, alcohol, amine and thiol.

11. The method of claim 10, wherein the nucleophile is selected from the group consisting of56.

57.

12. The method of claim 7. wherein the compound of Formula II is present at 1.0 to 3.0 equiv of the compound of Formula I.

13. The method of claim 7, wherein the method is a one-pot synthesis.

14. The method of claim 7, wherein the mixture is at about 50 °C to about 150 °C.

15. The method of claim 7, wherein the substrate is a small molecule.

16. A homologated substrate prepared by the method of claim 7.

17. A method of functionalizing a substrate, comprising:63.i. in the presence of compound 1 having the structure:

65. 67.and a substrate, contacting a compound of Formula II to form a mixture, wherein the mixture is at a temperature from about 25 °C to about 250 °C, wherein a nitrogencentered radical is prepared, and wherein:68.the substrate comprises a C-H bond; and,69.the compound of Formula II has the following structure:

71. 73.wherein,74.Rxis an optionally substituted linear or branched Ci-io alkyl or optionally substituted Ce-io aryl;75.Rla. Rlband Rlcare each independently selected from the group consisting of hydrogen, C2-C8 alkenyl, C2-C8 alkynyl, -C1-C3 alkyl-Ci-C3 alkoxy-, C3-8 cycloalkyl, Ce-io aryl, C3-8 heteroary l, C2-8 heterocyclyl, -Ci- C3 alkyl-Cs-8 cycloalkyl, -C1-C3 alkyl-Ce-io aryl, -C1-C3 alkyl-Cs-8 heteroaryl, -C1-C3 alkyl-C2-8 heterocyclyl, linear or branched C1-6 alkyl, hydroxy-Ci-Ce-alkyl -CN, and -C(=O)-Q-R10a,76.wherein, Q is O or is absent;77.R10ais hydrogen or C1-6 alkyl; and78.wherein, the cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl can each be independently optionally substituted;79.and,80.R2is a Ce-io aryl, wherein the aryl can be optionally substituted one to five times with a substituent selected from the group consisting of C1-6 alkyl, halo-Ci-6 alkyl, halo, -CN, and -NO2;81.ii. allowing the substrate comprising a C-H bond to contact the nitrogencentered radical to form a substrate radical;82.iii. allowing the substrate radical to contact compound 1, wherein, a C-H bond in the substrate is functionalized to form a C-X bond, wherein X is:

84.

18. The method of claim 17, further comprising contacting the C-X bond with a nucleophile to prepare88.

19. The method of claim 18, wherein Nuc is a residue of the nucleophile.

20. The method of claim 18, wherein the nucleophile is selected from the group consisting of water, alcohol, amine and thiol.

21. The method of claim 20. wherein the nucleophile is selected from the group consisting of95.

22. The method of claim 17, wherein the compound of Formula II is present at 1.0 to 3.0 equiv of the compound of Formula I.

23. The method of claim 17, wherein the method is a one-pot synthesis.

24. The method of claim 17, wherein the mixture is at about 50 °C to about 150 °C.

25. The method of claim 17, wherein the substrate is a polymer or small molecule.

26. The method of claim 25, wherein the substrate is a small molecule.

27. A method of preparing a homologated substrate, comprising:103.i. forming a mixture comprising a compound of claim 1, a photoredox catalyst and a substrate; wherein, the substrate comprises a COOH group;104.ii. subjecting the mixture to light energy to form a radical:105.iii. allowing the substrate comprising a COOH group to contact the radical to form a substrate radical; and,106.iv. allowing the substrate radical to contact the compound of Formula I, wherein, a COOH group on the substrate is functionalized to form an acyl phosphonate having a structure:

108.

28. The method of claim 27. further comprising contacting the homologated substrate with a nucleophile to convert the acyl phosphonate to112.

113. Nuc 29. The method of claim 28, wherein Nuc is a residue of the nucleophile.

30. The method of claim 28, wherein the nucleophile is selected from the group consisting of water, alcohol, amine and thiol.

31. The method of claim 30, wherein the nucleophile is selected from the group consisting of117.

32. The method of claim 27, wherein the method is a one-pot synthesis.

33. The method of claim 27, wherein the substrate is a polymer or small molecule.

34. The method of claim 33, wherein the photoredox catalyst is an acridinium photoredox catalyst.

35. A homologated substrate prepared by the method of claim 27.

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