Electrochemical Borylation of Carboxylic Acids Lisa M. Barton†, Longrui Chen†, Donna Blackmond*†, and Phil S. Baran*†

†Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037 Supporting Information Placeholder ABSTRACT: A simple electrochemically mediated single electron transfer events electrochemically to method for the conversion of alkyl carboxylic acids to achieve borylation. (C) Summary of this work. their borylated congeners is presented. This protocol gaining traction, resulting in approved drugs such as features an undivided cell setup with inexpensive carbon- Velcade, Ninlaro, and Vabomere.2 It has been shown that based electrodes and exhibits a broad substrate scope and boronic acids can be rapidly installed from simple alkyl scalability in both flow and batch reactors. The use of this carboxylic acids through the intermediacy of redox-active method in challenging contexts is exemplified with a (RAEs) (Figure 1A).3 Our laboratory has shown that modular formal synthesis of jawsamycin, a natural both Ni3a and Cu3b can facilitate this reaction. Conversely, product harboring five cyclopropane rings. Li and Aggarwal both demonstrated photochemical variations of the same transformation.3c,d While these state-of-the-art approaches provide complementary access to alkyl boronic acids, each one poses certain Boronic acids are amongst the most malleable functional challenges. For example, the requirement of excess boron groups in organic chemistry as they can be converted into source and pyrophoric MeLi under Ni catalysis is not almost any other functionality.1 Aside from these versatile ideal. Although more cost-effective and operationally interconversions, their use in the pharmaceutical industry simple, Cu-catalyzed borylation conditions can be is challenging on scale due to the heterogeneity resulting Decarboxylative Borylation of Redox-Active Esters from the large excess of LiOH•H2O required. In addition A Chemical approaches: state of the art to its limited scope, Li’s protocol requires 4 equivalence of • [Ni]/L catalyzed • [Cu] catalyzed B2pin2 and an expensive Ir photocatalyst. The simplicity • Pyrophoric MeLi [ref 3a] [ref 3b] • Heterogeneous • Not process of Aggarwal’s approach is appealing in this regard and [Ni] [Cu] reaction amenable represents an important precedent for the current study.

Me O Me At the heart of each method described above, the O [Boron] source O Me underlying mechanism relies on a single electron transfer R1 N 1 (SET) event to promote decarboxylation and form an alkyl O Metal or hv R B Me 2 O R or PET R2 radical species. In parallel, the related borylation of aryl R3 O 3 R halides via a highly reactive aryl radical can also be • [Ir] catalyzed • Light promoted [hv] [PET] promoted by SET. While numerous methods have • No photocatalyst photoinduced electron demonstrated that light can trigger this mechanism transfer • Mild conditions [ref 3c] [ref 3d] 4 • Limited to 1º RAEs (Figure 1B), simple electrochemical cathodic reduction can elicit the same outcome.5 It was postulated that B Precedent for photo- and electrochemical borylation Bpin Bpin similar electrochemically-driven reactivity could be I hv translated to alkyl RAEs. This disclosure reports a mild, scalable, and operationally simple electrochemical B2(OR)4, base (+)Pt/Pt(–) additive B2pin2, Cs2CO3 decarboxylative borylation (Figure 1C) not reliant on R R [ref 4a–4h] R [ref 5a] transition metals or stoichiometric reductants. In C This work: electrochemical decarboxylative borylation addition to mechanistic studies of this interesting Me O Me transformation, applications to a variety of alkyl RAEs, O O Me comparison to known decarboxylative borylation 1 R N R1 B O [e-borylation] O Me methods, and a formal synthesis of the polycyclopropane R2 2 3 R natural product jawsamycin ((–)-FR-900848) are R O R3 [metal free] [scalable] [>30 examples] [1º, 2º, & 3º acids] presented. [inexpensive, abundant electrodes] [applications to synthesis] Initial experiments with RAE 1 were promising, delivering ca. 20% conversion to the borylated product. Figure 1. (A) Prior approaches to access alkyl boronic Extensive optimization of reaction conditions ultimately esters from activated acids. (B) Inspiration for initiating delivered 74% (64% isolated) yield of product 2 (Figure 1

2B). While the breadth of this experimentation can be scale. The presence of any water during found in the Supporting Information, outcomes from the transesterification caused large inconsistencies in the screening of electron equivalents, solvent, electrolyte, yields, leading to a ~20% loss in product. Therefore, current, electrode materials, and additives are showcased pinacol was thoroughly azeotroped with toluene prior to in Figure 2A. Experimentally, 1.8 F/mol of RAE were use. Finally, a slight excess of B2cat2 (1.5 equivalents) was needed to reach peak yields of 2; however, prolonged found to be necessary to achieve high yields. electrolysis resulted in erosion in yield due to observed product consumption (see SI). With optimized conditions in hand, the scope of this transformation was explored on a wide range of acids (Figure 3A), often in yields equivalent to or higher than Electrochemical Decarboxylative Borylation Optimization prior methods (comparative yields for Ni-,3a Cu-,3b hn-,3c,e Me and PET3d-based protocols are shown where reported). A [e-Borylation]: Optimization campaign Me O This method proved highly chemoselective towards O Me B borylation of RAEs, demonstrating a broad functional OA* O Me TsN [e-borylation] group tolerance including both aryl and alkyl halides (5– 1 TsN 2 7, 11, 16, 25), (31, 34), esters (8, 10, 27–29), 0 [F/mol] 45 0 [Solvent] 60 alkenes (14, 30, 32), alkynes (12), protected (2, 15, 17, 18), and amino acids (10). RAEs derived from 0 •1.0 •1.6 •0.8 •1.2 •1.8 natural products and drug molecules smoothly 0.4 •5.0 •2.0 •DCM •3.0 (4:1) (4:1) (9:1) •THF •DCM/DMF •4.0 •MeCN/DMFNMP Acetone/DMF underwent borylation, further highlighting the mildness •DCM/DMF•DMF (4:1) •DCM/DMA(9:1) •MeCN •THF/DMF (4:1) of this method. Finally, bicyclic motifs commonly 25 [Electrolyte] 60 0 [Current] 50 leveraged by medicinal chemists as phenyl bioisosteres8

6 4 were smoothly borylated using the developed conditions LiCl TBA• none LiBr 15 mA ClO 0 mA 5 mA 4 4 TBA•PF•TBABN•HCl (27–29). While this protocol proved successful on a range 3 4 NaCl LiBF 10 mA •Et EMIM•BF •30 mA•25 mA•20 mA •TBA•BF of substrates, there remained some limitations. In 30 [Electrode] 90 35 [Misc.] 80 particular, conformationally flexible tertiary, benzylic, and a-heteroatom RAEs were nonproductive under these (+)Ni (+)Zn/ foam/Ni reaction conditions (see SI). foam (–) •(+)RVC graphite(–) 2 2 (+)Ni /RVC(–) cat cat 2 •“Wet” pinacol 2 (+)S.S./ •1.0 Bequiv. •1.25B equiv.2 •Azeotroped pinacol foam/ •(+)graphite cat 2 graphite(–) graphite(–) /graphite(–) •TCNHPI B The protocol is highly scalable in an undivided cell, and •1.5–2.5 equiv. on smaller scales can be run using a commercial B Optimized conditions potentiostat. These conditions were easily translated to Me B2cat2 (1.5 equiv.) Me O LiBr (0.3 equiv.) larger scales in batch using Erlenmeyer flasks, homemade DCM/DMF (9:1) O Me electrodes, and a large DC power supply (vide infra, NHPI 2 B 0.241 mA/mm , 2 F/mol; O Me Scheme 1C). Furthermore, the reaction was conducted on (+)graphite/graphite(–) TsN 3 2 64% isolated 100 g scale in a flow system, affording comparable yields then pinacol, Et3N TsN (74% 1H NMR) to those obtained in batch (Figure 3B). Figure 2. (A) Graphical overview of electrochemical Following the exploration of this method’s utility, decarboxylative borylation optimization. Modifications preliminary studies were conducted to gain insight into listed as a function of yield. (B) Optimized reaction the reaction mechanism. Cyclic voltammograms (CVs) conditions. were performed to ascertain the identity of the species undergoing cathodic reduction (Figure 4A). Interestingly, Solvent had the most profound influence on the reaction, B2cat2 and the RAE independently exhibit reduction as a balance of conductivity, Lewis-basicity, and polarity potentials in DMF at –2.98 V and –1.57 V respectively was needed to achieve high yields. In particular, the (relative to Ag/AgCl). However, when a 3:2 ratio of B2cat2 addition of DMF (e = 37) was vital, as it can act as a Lewis- and RAE are premixed in DMF, a single reduction is 6 7 base with B2cat2 and undergo anodic oxidation making observed at –1.96 V. This shift provides evidence for the the overall reaction redox neutral, obviating the need for existence of complex 37, initially proposed to be the active a sacrificial anode. A combination of two inexpensive species under similar photochemical conditions.3c graphite electrodes gave yields close to those obtained using a sacrificial Zn anode. Temporal measurements of reaction progress (Figure 4B) reveal that the reaction exhibits zero-order kinetics in The choice of electrolyte also impacted the reaction, with [B2cat2] and in [RAE] at higher concentrations.9 The LiBr and LiBF4 facilitating the best outcomes. Optimum slower rate at lower [RAE] may to be due to its results were observed when the reaction remained strictly consumption in unproductive reactions (N–O cleavage anhydrous; therefore, LiBr was chosen as it is inexpensive leading to acid and decarboxylation/protodeborylation). and easily dried immediately prior to the reaction setup. Zero-order kinetics in both substrates suggests that the On the 0.1 mmol scale used for optimization, a current >15 RAE rapidly complexes with B2cat2 in solution to form mA was required for high yields, with the added benefit species 37 prior to electron transfer, with the subsequent that higher currents significantly shorten the reaction electron transfer at the cathode being rate-determining 2 time. An optimum current density of 0.241 mA/mm was (first-order).10 The observation of positive rate therefore identified, and holding this value constant was dependence on current, a feature that we have observed essential to achieving consistent yields when changing 2 in previous electrochemical reactions,11 supports the linear (39) to cyclic (40) borylated products, arising from proposal that the transfer of electrons at the cathode is 5-exo trig cyclization of the ensuing radical (rate constant rate limiting. = 1.0 × 105 s−1).12 Additionally, when RAE 41 (Figure 4C) underwent electrochemical borylation, only the The presence of an intermediate alkyl radical was inferred homoallylic boronic 14 was isolated (rate constant = by subjecting RAE 38 to the electrochemical borylation 1.3 × 108 s−1).12 conditions (Figure 4C). This resulted in an 8:1 ratio of

Electrochemical Decarboxylative Borylation A Evaluation of the scope of electrochemical borylation O Me O O Me DIC O B cat (1.5 equiv.), LiBr (0.3 equiv.) O R1 2 2 Me + HO N 1 OH DCM or R N DCM/DMF (9:1), 0.241 mA/mm2, 2 F/mol R1 B R2 O O Me R3 DCM/DMF (9:1) R2 (+)graphite/graphite(–); R2 O R3 O R3 [activation] then pinacol, Et3N [e-borylation]

Comparison to [Ni] = Baran (cat. [Ni], L1, [Cu] = Baran (cat. [Cu], [hν] = Aggarwal (B2cat2, DMAc, [PET] = Li (cat. [Ir], State of the Art B2pin2, MeLi, MgBr2•OEt2) B2pin2, LiOH•H2O, MgCl2) blue LEDs, then Pinacol, Et3N) B2pin2, 45 W CFL)

Primary Bpin Bpin Bpin Br Bpin Bpin MeO2C 9 R Br 6 7 8 4, R = H 5, R = Br [echem]: 65% [echem]: 52% [echem]: 61% [echem]: 67% [echem]: 53% [echem]: 52% [Ni]: 65% [hv]: 41% [Cu]: 72% [Ni]: 55% [hv]: 72% [Ni]: 65% [Ni]: 52% [Cu]: 70% [PET]: 71% [PET]: 54% [Cu]: 28% [PET]: 77% [Cu]: <10% [Cu]: 76% [PET]: 54%

BnO2C Bpin Cl Bpin Bpin Bpin Bpin Bpin BocHN Bpin NHBoc 10 11 12 13 14 15 [echem]: 65% [echem]: 42% [echem]: 60% [echem]: 20% [echem]: 65% [echem]: 60% [hv]: 59% [hv]: 41% [Cu]: 55%

Bpin R Secondary Bpin Bpin Bpin Tertiary Ph Bpin RN N O Me Bpin Boc Bpin 2, R = Ts 18 19 20 21 24, R = H 25, R = Cl F [echem]: 64% [echem]: 58% [echem]: 38% [echem]: 57% [echem]: 60%, dr 13:1 [echem]: 44% [echem]: 70% F [Cu]: 66% [Cu]: 62% [Cu]: 66% [Ni]: 67% [Ni]: 58%, dr > 15:1 [Cu]: 85% [Ni]: 59% 16 [hv]: 32% [Cu]: 59%, dr 10:1 [hv]: 91% [Cu]: 76% 17, R = Boc Bpin [echem]: 55% Bpin Bpin [Ni]: 53% [echem]: 56% 22 23 [Cu]: 75% [Cu]: 68% Me [hv]: 66% [echem]: 42% [echem]: 45% Bpin [hv]: 87% [hv]: 53% [Cu]: 65% OMe MeO C 26 2 X 27 Natural products / drugs O OH Me [echem]: 84% [Ni]: 59% [echem]: 60% Me [Cu]: <5% [Ni]: 53% 30 X Me O [hv]: 74% Bpin [echem]: 62% mycophenolic O Me H dehydrocholic Bpin 7 6 [hv]: 90% OMe acid acid Bpin oleic acid Me H 34, X = Bpin Me Me 32, X = Bpin, Me [echem]: 77%* [Ni]: 65% MeO2C O [echem]: 73%* H MeO2C 29 31 H [Ni]: 46% [Cu]: 69% 28 [echem]: 45% [echem]: 60% O [PET]: 67% Me Bpin [hv]: 29% [Cu]: 68% [echem]: 55% [Ni]: 45% pinonic acid [hv]: 46% 33, X = OH, 72% O 35, X = OH, 75% [hv]: 65% B Scale-up in flow O O B2cat2 (1.5 equiv.), LiBF4 (0.2 M) Bpin N O DCM/DMF (9:1), 1.8 A, 2.5 F/mol 36 O (+)graphite/graphite(–); 9 100 gram, 310 mmol then pinacol, Et3N 60% flow reactor

Figure 3. Scope and scale up of the electrochemical decarboxylative borylation. See Supporting Information for experimental procedures. Yields refer to isolated yields of products from corresponding RAE. *Refers to NMR yield of products that were directly oxidized to corresponding prior to isolation.

3

Taken together, this evidence supports the mechanistic can then react with another equivalent of 42, yielding the picture shown in Figure 4D. To begin, DMF complexes desired alkyl boronic ester 46. The liberated boron- with one equivalent of B2cat2 to form 42, which can centered radical 47 is most likely quenched, but in a coordinate with an RAE to form the ternary complex 37. minor pathway propagates a radical chain reaction by This species then undergoes single-electron reduction in attacking a second RAE leading to 48, whose the rate-limiting step at the cathode, yielding 43. Rapid fragmentation would complete the cycle (see SI for further fragmentation of 43 results in the liberation of 1 experimental investigation). This mechanistic picture equivalent of CO2, 44, and alkyl radical 45. This radical closely mirrors Aggarwal’s photochemical variant.3c

Mechanistic Investigation of Electrochemical Decarboxylative Borylation A Cyclic voltammetry • Complexation results D Proposed mechanism 50 in change in reduction potential 0 NMe2 Me A) Me2N µ -50 O B cat O Me 37 2 2 O B B O -100 O O O RAE O O O Current ( Current O B O NMe B B B2cat2/RAE O 2 O O -150 (3:2) R1 O B O 2 N O Me RAE -200 R O O -4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 3 R 37 42 1 Potential (V vs Ag/AgCl) N R O O R2 B Kinetic experiments – O R3 e – Order in Current Order in RAE e Solvent acts e– – as e source Me2N – Me e O

• 0.1 M RAE O O

[product] (M) [product] (M) B B • 19 mA • 0.15 M RAE CatB • 0.2 M RAE (standard) • 38 mA O O • 0.3 M RAE O • 76 mA (standard) Cathode • 0.4 M RAE O O

n 44 (t)(mA) time (min) N N R1

Anode O Order in B2cat2 ➢ First order in current R2 + O O 43 R3 ➢ Zero order in [B2cat2], [RAE] CO2 ➢ Slower order at lower [RAE] likely due to unproductive reactions CO2

[product] (M) ➢ Suggests complexation to + • 0.2 M B2cat2 • 0.3 M B2cat2 (standard) form 37 rapidly takes place 2 1 • 0.4 M B cat R R 44 2 2 prior to electron transfer R3 ➢ Radical chain pathway likely only O O time (min) B O minor route B Standard condtions: 1.2 mmol scale, 76 mA, 0.3 M B2cat2, 0.2 M RAE; varied parameters shown O 1 O NMe2 R C Radical clock experiments 45 Bpin Bpin N O 46 R2 O O O R3 O O Me + N O [e-borylation] 48 R1 Me R3 2 38 65% R minor NMe2 O 39 40 42 9 : 1 O O B O O major Bpin RAE O quenched N [e-borylation] 47 O 14 (radical 41 44% O recombination, [O]) Figure 4. (A–C) Experimental investigation of mechanism. (D) Proposed mechanistic picture.

The kinetic results suggest a rationale for the enhanced occurs off-cycle at the cathode, and it becomes difficult to efficiency of this electrochemical pathway with certain rationalize the positive order dependence on current. substrates. Generation of the free radical 45 from More likely is that the dominant route to product 46 lies decarboxylation of 43 serves as entry into the cycle shown in the continual generation of radical 45 via cathodic at the bottom of Figure 4D, which can theoretically reduction and the radical-chain cycle represents only a propagate by continuous regeneration of 45. However, in minor route. this scenario, the reaction at the cathode serves only to As a demonstration of the utility of this method, initiate this stand-alone cycle. For this scenario to hold, electrochemical borylation proved critical in accessing an induction period should be observed, as the slow step 4 large quantities of key intermediates for a unique modular Almost no product could be detected under Ni catalysis, strategy en route to the polycyclopropane natural product and only modest yields were observed when employing jawsamycin ((–)-FR-900848, 57, Scheme 1A).13 All either Cu or photochemical conditions. Even with the previous syntheses of this structurally fascinating natural original optimized electrochemical protocol, only ca. 13% product have commenced from olefins and relied on of the desired alkyl boronic ester was formed, with the asymmetric cyclopropanations to build the mass balance corresponding to either hydrolyzed acid or polycyclopropane backbone.14 In contrast, this strategy decarboxylated byproduct. However, by utilizing represents a complimentary approach, hinging on the electrodes with much higher surface areas (i.e. reticulated systematic coupling of chiral cyclopropane modules. This vitreous carbon, RVC) and activating the acid with the alternative retrosynthetic logic obviates the need for any more electron deficient tetrachloro N- asymmetric cyclopropanation step, as commercial hydroxyphthalimide derivative, workable yields of the building blocks such as 49 are easily desymmetrized to desired product 51 were obtained (43% by NMR, 35% the corresponding hemiester, giving two differentiated isolated). More importantly, this reaction was easily synthetic handles which can be readily diversified through scaled (Scheme 1C), and up to 40 mmols of RAE could be decarboxylative cross-coupling reactions.15 processed in a single pass using a homemade batch reactor, with isolated yields up to 40% of the desired At the outset, borylation of the chiral RAE 50 proved product 51. incredibly challenging using prior methods (Scheme 1B).

Utilizing Electrochemical Decarboxylative Borylation in the Synthesis of Jawsamycin A Formal synthesis of jawsamycin B Selected conditions for the borylation of 50 O MeO C CO A* CO Me 2 2 Conditions MeO2C a. A (10 mol%) 2 Bpin MeOH, 99% A* = NHPI c. [e-borylation] MeO2C O Bpin or TCNHPI b. TCNHPI, DIC see B and C 50 51 69% CO2A* [40 mmol scale] 51 entry selected reported conditions yield (%)a O 93% ee 40% 49 50 1 TCNHPI, NiCl2•6H2O, t-BuBipy,B2pin2, MeLi, MgBr2•Et2O, DMF <5 d. NaIO , 76% f. NaOH, 95% 4 2 NHPI, Cu(acac)2, B2pin2, LiOH•H2O, MgCl2, MTBE/DMF 17 MeO C e. Pd(OAc) , dppf 2 2 3 NHPI, B2cat2, DMAc, blue LEDs; then pinacol, Et3N 29 CO2Me g. TCNHPI, DIC, 71% NHPI, B cat , LiBr, DCM/DMF, graphite, 2 F/mol; h. K3PO4, THF, H2O 4 2 2 13 O then pinacol, Et3N 52 2 60% TCNHPI, B2cat2, LiBF4, DCM/DMF, RVC, 1.5 F/mol; 5 43 (35)b (+)RVC/RVC(–) then pinacol, Et3N B2cat2, LiBF4 (a) NMR yield (b) isolated yield 44% i. NaIO4, 96% C Scale-up of key boronic ester 51 Bpin MeO2C j. Pd(OAc)2 CO2Me CO2Me P(o-Tol)3, Cs2CO3 53 AgOAc, Diox, air, 54% 54

k. Ba(OH)2•8H2O, 47% (84% brsm) Me OH l. TCNHPI, DIC, 91% m. 55, n-BuLi, [Ni], 45% 56 n. LiAlH4, 83% 4 steps or 5 steps O Ref 14a Ref 14b HN ElectraSyn 2.0 batch reactor 4 × 1.35 mmol scale 40 mmol scale O 43% yield (35% isolated) 45% yield (40% isolated) jawsamycin N (–)-FR-900848 O H H Me 57 H N N Bpin Me N OH 55 S (prepared in 3 O OH NMe 2 A steps from acid)

Scheme 1. (A) Formal synthesis of jawsamycin. (B) Examination of decarboxylative borylation conditions. (C) Scale up of borylation. See Supporting Information for reagents and conditions. With sufficient quantities of 51 in hand, the boronic ester achieving reproducible results on scale (see SI for underwent oxidative cleavage to the corresponding acid, optimization summary). and the stage was set to explore Pd-catalyzed oxidative homocoupling. To the best of our knowledge, the homo- Next, to form the tetra-cyclopropane 54, this sequence of dimerization of cyclopropyl-boronic acids/esters has not borylation and homocoupling was repeated. Mono been reported before. Although multiple boronic esters saponification of dimer 52, followed by activation, and a second electrochemical borylation, afforded boronic ester were screened, only the acid was sufficiently active under 53. After oxidative cleavage to the however, these conditions. Performing the homocoupling under an atmosphere of oxygen to re-oxidize Pd and complete the we found that the original dimerization conditions resulted in no reaction; even on heating the reaction presumptive PdII/Pd0 catalytic cycle16 proved critical to 5 mixture to elevated temperatures, only protodeborylated the desired vinylated product was obtained, which product was observed. After extensive optimization (see contained all five of the cyclopropane fragments of SI), rigorous exclusion of water using a Cs2CO3/dioxane jawsamycin in place. A final reduction of the remaining system, as well as utilizing the phosphine ligand P(o-Tol)3 ester completed the formal synthesis, intercepting the began to result in product formation. The addition of same strategic intermediate 56 used in both prior AgOAc proved crucial here, ultimately corresponding to syntheses by Barrett and Falck.14a,b 54% of the desired tetramer 54. This dramatic improvement may arise from Ag serving dual roles by To summarize, a practical electrochemical aiding the initial transmetalation of cyclopropyl boronic decarboxylative borylation of alkyl redox-active esters has been developed. The scope and mechanism of this ester with Pd17 as well as functioning as an external transformation are similar to the photochemical variant oxidant.18 and can be conveniently scaled up in batch or flow (100 Mono saponification of the tetramer 54 and activation g). Finally, this newly developed method proved essential with TCNHPI set the stage for a final decarboxylative for the preparation of a key cyclopropane intermediate en alkenylation with cyclopropyl vinyl-Bpin 55 (prepared in route to the polycyclopropanated natural product 3 steps, see SI). Using a slight modification to previously jawsamycin. reported Ni-catalyzed Suzuki couplings of RAEs,15 45% of

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Table of Contents

Me [>30 examples] O Me O O [scalable] [metal free] B2cat2, LiBr Me 1 N 1 R DCM/DMF (9:1), 2 F/mol R B [1º, 2º, & 3º acids] O O Me O R2 (+)graphite/graphite(–); 2 3 O R R then pinacol/TEA R3 HN [e-borylation] O N Decarboxylative Homocoupling of O radical Vinylation B(OH)2 H retrosynthesis Me N OH of jawsamycin O OH

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