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Total Synthesis of Resiniferatoxin Enabled by RadicalMediated Three-Component Coupling and 7-endo Cyclization Satoshi Hashimoto, Shun-ichiro Katoh, Takehiro Kato, Daisuke Urabe, and Masayuki Inoue J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10177 • Publication Date (Web): 17 Oct 2017 Downloaded from http://pubs.acs.org on October 18, 2017

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Journal of the American Chemical Society

Total Synthesis of Resiniferatoxin Enabled by Radical‐Mediated Three‐Component Coupling and 7‐endo Cyclization Satoshi Hashimoto, Shun‐ichiro Katoh, Takehiro Kato, Daisuke Urabe,† and Masayuki Inoue* Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo‐ku, Tokyo 113‐0033, Japan ABSTRACT: Resiniferatoxin (1) belongs to a daphnane diterpenoid family, and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans‐fused 5/7/6‐tricarbocycle (ABC‐ ring) of 1 presents a daunting challenge for chemical synthesis. Here we report the development of a novel radical‐based strategy for assembling 1 from three components: A‐ring 9, allyl stannane 18b, and C‐ring 17b. The 6‐membered 17b, pre‐ pared from D‐ribose derivative 19, was designed to possess the caged orthoester structure with ‐alkoxy selenide as a rad‐ ical precursor. Upon treatment of 17b with 18b, 9, and V‐40, the potently reactive ‐alkoxy bridgehead radical was gener‐ ated from 17b, and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10‐linkage between the A and C‐rings, and extended the C4‐chain on the A‐ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7‐membered B‐ring was cyclized in the presence of n‐Bu3SnH and V‐40 by utilizing the xanthate on the C‐ring as the radical precursor and the allylic dithiocarbonate as the terminator. The second radical reaction thus enabled not only the 7‐endo cyclization, but also construction of the C8‐stereocenter and the C6‐exo olefin. Tricycle 14 was elaborated into the targeted 1 by a series of highly optimized chemoselective reactions. The pre‐ sent total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multi‐step target‐oriented syn‐ thesis.

INTRODUCTION Euphorbiaceae is a large family of higher plants distrib‐ uted in tropical and temperate regions. These plants con‐ tain numerous bioactive natural products used tradition‐ ally as medicines for the treatment of edema, gonorrhea, migraine, and warts.1 To date, over 650 diterpenoids iso‐ lated from the plant family have been shown to possess various medically important properties (e.g., antitumor, cytotoxic, anti‐viral, anti‐inflammatory activities). These diterpenoids are classified into more than 20 sub‐ categories according to their skeletal types. In 1975, Hecker et al. isolated resiniferatoxin (1, Figure 1) as an irritant component from the latex of Euphorbia res‐ inifera.2 The structure elucidation in 1982 revealed that 1 belongs to a daphnane diterpenoid family.3 Compound 1 was shown to exhibit its biological activity by potently activating transient receptor potential vanilloid 1 (TRPV1).4 TRPV1 is an ion channel protein in the plasma membrane of sensory neurons that transduces multiple painful stimuli, including noxious heat, extracellular pH, and chemicals such as capsaicin from hot chili peppers.5,6 TRPV1 recently attracted a great deal of attention as a potential therapeutic target for treating chronic inflam‐ matory, neuropathic, and cancer pains. Since 1 has ex‐ ceedingly strong analgesic properties through the desen‐ sitization of nociceptive neurons, it holds great promise for alleviating multiple modalities of pain.7,8

Figure 1. Structures of Resiniferatoxin (1) and Related Diterpenoids.

As exemplified by 1, genkwanine D,9 and daphnetoxin,10 the daphnane diterpenoids are characterized by a trans‐ fused 5/7/6‐tricarbocycle (ABC‐ring), a C9,13,14‐ orthoester motif, and a C13‐isopropenyl group on the C‐ ring. While these three natural products differ in their oxidation and unsaturation levels at the AB‐ring, they share the C‐ring moiety except for the attached ortho‐ esters. On the other hand, phorbol11 and crotophorbo‐

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lone12 are a tigliane diterpenoid and its derivative, respec‐ tively, and possess the same AB‐ring substructure as 1, but differently substituted C‐rings. The distinct functional group patterns on the common tricyclic framework im‐ part diverse biological functions to these diterpenoids. For example, genkwanine D, daphnetoxin, and the acylat‐ ed phorbol display cytotoxic, anti‐HIV, and tumor‐ promoting activities, respectively. Daphnanes, tiglianes and their derivatives together have attracted a great deal of attention from the synthetic community due to their significant biological activities and architecturally complex structures. 13 , 14 The most sought‐after target among them to date is phorbol. In 1989, the Wender group accomplished a racemic total synthesis of phorbol,15 followed by the asymmetric version in 1997.16 Cha’s group disclosed their own solution to this problem in 2001,17 and Baran’s group described the ele‐ gant biosynthesis‐inspired total synthesis in 2016.18 In 2015, our group achieved a chemical synthesis of croto‐ phorbolone, a derivative of phorbol, by a radical cycliza‐ tion.19 Despite many attempts over 40 years from the iso‐ lation, the sole successful synthesis of daphnanes is the de novo construction of 1 by Wender and co‐workers in 1997.20 Scheme 1. Wender’s Total Synthesis of Resiniferatox‐ in (1).

Wender ingeniously synthesized 1 via intramolecular 1,3‐dipolar cycloaddition and zirconium‐mediated cycliza‐ tion to assemble the tricyclic ring system (Scheme 1). After preparation of 3 from penta‐1,4‐dien‐3‐ol (2), ox‐ idopyrylium ion 4, generated by treating 3 with DBU, re‐ acted with the terminal olefin to simultaneously form the B‐ and C‐rings of 5. Elongation of the carbon chains at the C4,10‐positions from 5 gave rise to 6, which was treat‐ ed with Cp2ZrBu2 to produce the crucial tricycle 7. Then, subsequent functional group transformations from 7 re‐ sulted in the total synthesis of 1 (44 total steps from 2). Radical‐based carbon‐carbon (C‐C) bond formation is in principle an ideal reaction for the total synthesis of dense‐ ly oxygenated natural products, because it exhibits high efficiency under neutral conditions without affecting po‐ lar functional groups.21,22 Our continued interest in de‐

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veloping radical coupling strategies motivated us to inte‐ grate powerful radical reactions for the synthesis of 1.23 We envisaged that achieving such a radical‐based assem‐ bly of this extremely complex diterpenoid would lead to a true methodological innovation in the field of synthetic organic chemistry. Herein, we detail the development of a novel route to resiniferatoxin (1). The complex 5/7/6‐ tricyclic structure of 1 was efficiently built by inter‐ and intramolecular radical reactions: a three‐component cou‐ pling reaction between A‐, C‐rings and a side‐chain, and following 7‐endo B‐ring cyclization.24 The new strategy and tactics developed here will have further applications to total syntheses of numerous daphnane and tigliane diterpenoids with identical ring substructures. RESULTS AND DISCUSSION Synthetic Plan for Resiniferatoxin. The intricate tricyclic structure of 1 possesses three double bonds (C1,6,15), and seven contiguous stereogenic centers, including three tetrasubstituted carbons (C4,9,13) (Scheme 2B). The 5‐membered A‐ and 6‐membered C‐ rings are linked directly at C9 and C10, and indirectly at C4 and C8 through the four‐carbon spacer (C5‐7,20), and these two‐rings and spacer together constitute the seven‐ membered B‐ring. We planned to employ radical‐based methodologies to form all three ring‐connecting bonds (C4‐5, C7‐8, and C9‐10) highlighted in color in Scheme 2. To simplify the overall synthetic scheme, we were particu‐ larly interested in utilizing the three‐component radical coupling reaction to realize single‐step formation of the C4‐5 and C9‐10 bonds. Such radical multi‐component couplings, however, have been underexplored in compari‐ son to their ionic counterparts.25 The feasibility of the idea was validated by our recent model study (Scheme 2A). 26 Specifically, 2,4,10‐ trioxadamantane orthoester 8, cyclopentenone 9, and allyl stannane 1027 underwent coupling by the intermedia‐ cy of 11 and 12, producing 13 with the new C4‐5 and C9‐10 linkages. ‐Alkoxy bridgehead radical 11, generated from ‐alkoxy selenide 8, was tied back by the cage structure.28 Consequently, the radical center was more exposed and thus more reactive, and the O‐substituted stereocenter was fixed. These features permitted the reaction to pro‐ ceed with stereospecific bond formation at the sterically hindered C9‐postion of 13.29 We decided to implement this powerful methodology in our synthetic scheme for resiniferatoxin (1) (Scheme 2B). Accordingly, 1 was retrosynthetically disassembled into ‐ alkoxy selenide (C‐ring) 17b, cyclopentenone (A‐ring) 9, and branched allyl stannane 18b. The three‐component reaction of these fragments would be significantly more challenging than the model reaction, because the C9‐ radical‐generating position is shielded by the proximal C8‐ and C11‐substituents, and the cyclohexane ring is locked into the twist‐boat conformation by the orthoester at the C9,13,14‐OHs. Nevertheless, the single‐step reac‐ tion would rapidly build up structurally complex inter‐ mediate 16b, which would be easily derivatized into 15,


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the substrate for the second radical reaction. Radical C7‐ 8 bond formation from 15 was expected to cyclize the B‐ ring with the C6‐exo olefin. The functional groups would then be adjusted and attached to transform 14 into the target 1. The pivotal intermediate 17b of this radical‐ based strategy was planned to be synthesized from D‐ ribose derivative 19. Scheme 2. (A) Model Study of the Three‐Component Radical Coupling Reaction. (B) Synthetic Plan for Resiniferatoxin (1).

cleavage of the resultant 1,2‐diol of 20 generated hemiace‐ tal 21, which was sequentially subjected to n‐BuLi and isopropenyl magnesium bromide to afford 22 in a C9‐ stereoselective manner. Diene 22 was in turn treated with the Hoveyda‐Grubbs second generation catalyst30,31 (A, 2 mol%) at 80 C in (CH2Cl)2, leading to 6‐membered ring 23. In this ring‐closing metathesis reaction, 1,4‐ benzoquinone effectively impeded the olefin isomeriza‐ tion of 22.32 The stereostructure of product 23 was con‐ firmed by X‐ray crystallographic analysis. Next, the C9,11,13‐stereocenters were installed by taking advantage of the convex/concave bias forged by the ace‐ tonide‐protected cis‐fused ring systems. Interestingly, Pd/C and H2 isomerized the allylic C9‐alcohol of 23 to the C9‐ketone of 24 via protonation of the C9‐enol interme‐ diate from the convex face.33 The reaction thus set the correct C11‐configuration, and differentiated the C9‐ and C13‐oxidation levels. The NOESY correlations of H8‐H11 and H11‐H13 corroborated the C8,11,13‐equatorially orient‐ ed chair conformation of 24. Then, the lithiated ethyl vinyl ether equatorially attacked the‐face of C9‐ketone 24, stereoselectively furnishing the carbon‐extended 25. After oxidation of the secondary C13‐hydroxy group of 25 to the C13‐ketone of 26 by TPAP catalysis,34 isopropenyl lithium was added from the ‐face to produce 27 with the requisite C13‐stereocenter. Hence, construction of the four stereogenic centers corresponding to the C‐ring of 1 was completed at this stage.

Stereoselective Synthesis of the C‐Ring. We prepared the three radical donors 38, 17a, and 17b from starting material 19 to illuminate the structural fac‐ tors for an efficient three‐component coupling reaction (Scheme 3). First, 6‐membered ring 23 was constructed from the commercially available D‐ribose derivative 19. Compound 19 was treated with n‐BuLi to deprotonate the acidic protons, and then with vinyl magnesium bromide to provide triol 20 as a single C13‐stereoisomer. Oxidative

The unusual orthoester‐attached ‐alkoxy selenide structure of 36 was prepared from 27. The acidic hydroly‐ sis of the acetonide and the enol ether transformed diol 27 to tetraol 28 with the methyl ketone at the C9‐position. Benzoylation of the secondary C8‐hydroxy group of 28 occurred site‐selectively over the C14‐hydroxy group by reflecting its subtle steric differences, leading to mono‐ benzoylated 29. The remaining three free hydroxy groups of 29 were simultaneously capped using trimethyl ortho‐ acetate in acidic media to generate the caged ortho ace‐ tate 30. The C9‐methyl ketone of 30 was in turn convert‐ ed to the phenyl selenide of 36 with the following four steps. Treatment of 30 with TMSOTf and Et3N afforded TMS‐enol ether 31. The electron‐rich C9’‐olefin of 31 was oxidized with m‐CPBA chemoselectively over the C15‐ olefin to provide ‐hydroxy ketone 32, which was oxida‐ tively cleaved with Pb(OAc)4 in one pot to furnish car‐ boxylic acid 33. Mesyl ester 34 was formed from 33 with MsCl and Et3N,35 and then transformed into Barton ester 35 using 2‐mercaptopyridine N‐oxide sodium salt (B) and DMAP.36 Upon photo‐irradiation of unstable 35 without isolation, the C9‐bridgehead radical was generated, and in situ‐captured by (SePh)2, resulting in the construction of ‐alkoxy selenide 36.37



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Scheme 3.a Stereoselective Synthesis of the C‐Ring.

aReagents and conditions: (a) n‐BuLi, vinylmagnesium bromide, THF, 80%; (b) NaIO , THF, H O, 0 C; (c) n‐BuLi, isopropenyl‐ 4 2

magnesium bromide, THF, 77% (2 steps); (d) A (2 mol%), 1,4‐benzoquinone, (CH2Cl)2, 80 C, 81%; (e) H2, Pd/C, EtOAc, hexane, 0 C, 71%; (f) t‐BuLi, ethyl vinyl ether, THF, 0 C, 91%; (g) TPAP, 4‐methylmorpholine N‐oxide, CH2Cl2, MS4A; (h) t‐BuLi, 2‐ bromopropene, TMEDA, THF, 54% (2 steps) (recovered 26: 24%); (i) Dowex 50W, THF, H2O, 90 C; (j) BzCl, pyridine, CH2Cl2, 0 C, 83% (2 steps); (k) MeC(OMe)3, (+)‐CSA, benzene, 85%; (l) TMSOTf, Et3N, CH2Cl2, 87%; (m) m‐CPBA, CH2Cl2, 0 C; TBAF, 0 C; Pb(OAc)4, K2CO3, toluene; (n) MsCl, Et3N, CH2Cl2, 0 C; (o) B, DMAP, toluene; h, (SePh)2 31% (3 steps); (p) K2CO3, MeOH, 0 C, 87%; (q) Ac2O, DMAP, pyridine, CH2Cl2, 87%; (r) DMSO, Ac2O, 35 C; (s) NaBH4, CeCl37H2O, MeOH, ‐78 C; (t) Ac2O, DMAP, pyridine, CH2Cl2, 84% (3 steps); (u) TMSOTf, 2,6‐lutidine, CH2Cl2, 0 C, 88% (3 steps).

The thus‐obtained 36 was utilized as the intermediate for synthesis of the three radical donors 38, 17a, and 17b, which differ only at the C8‐positions (‐OAc for 38, ‐ OAc for 17a, and ‐OTMS for 17b). Basic methanolysis of 36 afforded ‐alcohol 37, which was acetylated to obtain 38. On the other hand, the C8‐stereocenter of 37 was in‐ verted through oxidation with DMSO and Ac2O 38 and reduction of 39 with NaBH4 and CeCl37H2O,39 leading to ‐alcohol 40. Secondary alcohol 40 was protected as the acetate and TMS ether under standard conditions to pro‐ vide 17a and 17b, respectively. Overall, 38 and 17a/b were synthesized from 19, in 17 and 19 steps, respectively. Optimization of Three‐Component Radical Coupling Reactions. To attain an efficient three‐component radical coupling reaction, we separately screened the components (Scheme 4), and thus employed the three C‐rings (38, 17a, and 17b), the one A‐ring (9),40 and the two branched allyl stannane (18a and 18b).41 As shown below, the combina‐ tion of 17b, 9, and 18b delivered the coupling adduct in the highest yield.

When 38 was heated to 130 °C with 9 (5 equiv) and 18a (5 equiv) in the presence of V‐40 (0.5 equiv) in chloro‐ benzene, a sequential radical reaction underwent to give adduct 43. The obtained inseparable mixture of 43 and 9 was treated with K2CO3 in MeOH to produce pure 44, albeit in only 9% yield from 38. Although this basic treatment comprised the multiple reactions (elimination of the C1‐siloxy group, detachment of the C8O‐acetyl group, and oxy‐Michael addition of the C8‐OH to the enone), the low isolated yield of 44 clearly reflected the low efficiency of the coupling of 38. We postulated that the steric shielding effect of the equatorially disposed C8‐ acetoxy group lowered the reactivity of C9‐bridgehead radical 41. In fact, the C8‐epimeric 17a with the axial C8‐ acetoxy group was determined to be a better radical pre‐ cursor. After submitting 17a, 9, and 18a to the radical and basic conditions, enone 47 was obtained in 27% yield. No concomitant oxy‐Michael addition from 47 was likely to originate from the different spatial relationship between C1 and C8‐OH. To increase the trapping rate of the radi‐ cal, tri‐n‐butyl allyl stannane 18a was switched to tri‐ phenyl counterpart 18b. The modification indeed result‐ ed in the higher yielding generation of 47 (33%) after the two sequential reactions (17a→16a→47).


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Scheme 4. Optimization of Three‐Component Radical Coupling Reactions.

Figure 2. (A) The NMR Data of 16b. (B) The DFT‐ Optimized Structure of 16b (The TBDPS group was re‐ placed with the Me group. M06‐2x/6‐31g(d), 298 K, 1 atm).

Most importantly, changing the protective group of the C8‐OH from Ac (17a) to TMS (17b) doubled the yield of the coupling adduct. Namely, treatment of 17b with 9 (5 equiv), 18b (5 equiv), and V‐40 (0.4 equiv) at 130 °C deliv‐ ered 16b in 52% yield as a single isomer after purification. This dramatic improvement was likely due to the poten‐ tial disadvantage of the acetyl group of 45a compared with the silyl group of 45b. Neighboring group participa‐ tion of the acetyl C=O double bond of 45a to the C9‐ radical center would lead to undesired pathways, thus decreasing the overall efficiency.42 The structure of 16b was determined by detailed NMR experiments (Figure 2A). The coupling constants of H1‐H10 (J = 2.9 Hz) and H4‐H10 (J = 3.7 Hz) indicated pseudo axial orientations of the C1,4,10‐substituents, and the NOE correlations of H1‐H11, H4‐H8, and H5‐H10 prove the trans‐relationships of these three groups. The DFT‐optimized structure of 16b at the M06‐2x/6‐31g(d) level of theory (298 K, 1 atm)43 further supports the unique three‐dimensional (3D) shape of 16b (Figure 2B).

branched allyl chain, and introduction of the C4,10‐ stereocenters with stereochemical retention of the bridgehead tetrasubstituted C9‐carbon (Scheme 4). The chemo‐ and stereoselective two C‐C bond formations would be controlled by the intrinsic characters of the rad‐ ical species, and the 3D‐structures of the reactants. The nucleophilic ‐alkoxy bridgehead radical 45b generated via homolytic cleavage of the C‐Se bond of 17b first reacts with the electron‐deficient olefin of 9 from the opposite face of the bulky TBSO‐group to set the C10‐stereocenter of 46b. Then, electrophilic radical 46b adds to the elec‐ tron‐rich olefin of 18b in a trans‐manner to the large C‐ ring to introduce the C4‐stereocenter of 16b. Construction of the Tricyclic Framework by Radical 7‐endo Cyclization. Therefore, a radical three‐component coupling reaction of 9, 17b, and 18b intermolecularly linked the two hin‐ dered ring‐connecting bonds of 16b (C9‐10 and C4‐5), and markedly increased the complexity of the structure in a single step (Scheme 5). We envisaged that the remaining ring‐connecting C7‐8 bond would be constructed by an intramolecular radical reaction. Prior to this second radi‐ cal reaction, the A‐ring was functionalized. NaN(TMS)2‐induced elimination of the C1‐siloxy group transformed 16b to enone 48, which was treated with TBSOTf and Et3N to afford TBS‐enol ether 49. m‐CPBA‐ oxidation of 49 then provided tertiary C4‐alcohol 50 as the sole isomer, the C4‐configuration of which was un‐ ambiguously assigned by X‐ray crystallographic analysis of its derivative (see 67 of Scheme 9). Accordingly, the oxidation of 49 proceeded from the same face with the sterically cumbersome C‐ring structure upon establishing the desired C4‐stereogenic center.

It was remarkable that the three‐component reaction of 16b realized sequential attachment of the A‐ring and the



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Scheme 5.a Synthesis of the Tricyclic Framework by Employing the Two Radical Reactions.

aReagents and conditions: (a) 9 (5 equiv), 18b (5 equiv), V‐40 (0.4 equiv), chlorobenzene, 130 C, 52%; (b) NaN(TMS) , THF, 0 C, 2 77%; (c) TBSOTf, Et3N, CH2Cl2, 0 C; (d) m‐CPBA, NaHCO3, hexane, CH2Cl2, 0 C, 59% (2 steps); (e) DIBAL‐H, CH2Cl2, ‐93 C; (f) 2,2‐dimethoxytetrahydrofuran, (+)‐CSA, benzene, 50 C, 60% (dr = 5 : 3, 2 steps); (g) TBAF, THF; (h) NaH, CS2, MeI, THF, 90% (2 steps); (i) xylene, 110 C; n‐Bu3SnH, V‐40, 180 C (microwave), 71%.

To rationalize this counterintuitive stereochemical out‐ come, we performed DFT calculations of the transition states (M06‐2X/6‐31G(d), 298 K, 1 atm, Scheme 6). In facilitating the calculation, the C3O‐TBS, C7O‐TBDPS and C8O‐TMS, and C13‐C(CH2)CH3 of 49 were simplified into the C3O‐TMS, C7O‐Me, C8O‐Me, and C13‐H of 57, respectively, while m‐CPBA was replaced with peroxyben‐ zoic acid. The calculated activation energy of TS1 (‐face approach) is smaller than that of TS2 (‐face approach) by 2.61 kcal/mol (G), supporting the observed C4‐ stereoselectivity of 49. The higher energy of TS2 in com‐ parison to TS1 would be attributable to its higher tortion‐ al strain: the dihedral angle of C5‐C4‐C10‐C9 (38.9) of TS2 is smaller than that of TS1 (67.4).44 Since the steric interaction between the C5‐ and C9‐positions becomes larger in TS2, epoxidation occurs via TS1 to produce 58a selectively over 58b, and 58a is hydrolyzed to ‐alcohol 59a. The tricyclic framework 14 was constructed from 50 by the subsequent 5 steps (Scheme 5). DIBAL‐H‐reduction stereoselectively converted ‐hydroxy ketone 50 into syn‐ 1,2‐diol 51, which was protected as the oxacyclopentyli‐ dene orthoester using 2,2‐dimethoxy tetrahydrofuran and (+)‐CSA to produce 52. 45 After the TBDPS and TMS groups of 52 were removed with TBAF, the two hydroxy groups of 53 were simultaneously derivatized into the corresponding xanthates of 54 by treatment with NaH, CS2, and MeI.46 Before forming the 7‐membered ring, we

differentiated the radical‐generating propensity of the C7‐ and C8‐positions of bisxanthate 54. This was realized simply by heating 54 to 110 C in xylene, which promoted the [3,3]‐sigmatropic rearrangement of the allylic xan‐ thate of 54 into the less reactive dithiocarbonate of 15.47 Then, 15 was in situ‐heated to a higher temperature (180 C) under microwave irradiation in the presence of n‐ Bu3SnH and V‐40 to deliver tricycle 14 as the only isolable product in 71% yield. Under these conditions, the sec‐ ondary C8‐radical 55 was chemoselectively formed from 15 via C8‐O homolysis, and added to the less hindered C7‐ position rather than the C6‐position. The subsequently generated tertiary C6‐radical 56 in turn ejected the dithi‐ ocarbonate functionality via the C20‐S homolysis, thus terminating the radical reaction.48 Consequently, this SH2’ reaction realized 7‐endo cyclization of the B‐ring,49 at‐ tachment of the C6‐exo olefin, and introduction of the correct C8‐stereocenter. The lack of participation of the five oxygen‐based functionalities (C3,4,9,13,14), and the two olefins (C1,15) demonstrated the excellent chemose‐ lectivity of the radical reaction.


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Scheme 6. Rationale of the C4‐Stereoselectivity. (Values in parentheses are relative free energies: G, 298 K, 1 atm).

13

H 10 3

4

TBSO

9

O O

8

O

H 10

O

5

3

TMS

4

TMSO

7

13 9

O 5

8

H O O

the formation of 14 was preferred due to the less steric interactions of the corresponding transition state. Scheme 7. Rationale of the C8‐Stereoselectivity. (Val‐ ues in parentheses are relative free energies: G, 298 K, 1 atm).

O Me

7

49

TBDPSO

57 MeO peroxybenzoic acid

9 10 5 3

4

9 10 4

3

5

TS1 (0 kcal/mol) = 67.4°

(C5-C4-C10-C9)

H O O

H 4

O

TMSO O

4

O HO MeO

O

O Me 59a

O

TMSO O

O Me

Scheme 8.a Attempted B‐Ring Cyclizations. H O O

H O

4

O HO MeO

58b

MeO H O O

H

H O O

H 4

O Me 58a

MeO

TS2 (2.61 kcal/mol) (C5-C4-C10-C9) = 38.9°

O Me 59b

The perfect C8‐stereoselectivity of the cyclization indi‐ cated that the C7‐olefin of 55 approached the C‐ring only from the ‐face. To identify structural elements respon‐ sible for the phenomenon, the DFT calculation (UM06‐ 2X/6‐31g(d), 298 K, 1 atm) was performed using 60 (Scheme 7), in which the C13‐ and C20‐substituents of 55 were omitted, and the oxacyclopentylidene orthoester was replaced with acetonide. As a result, TS3 (‐face ap‐ proach), which leads to 61a, was calculated to be energet‐ ically favored by 2.69 kcal/mol (G) over TS4 (‐face ap‐ proach), which leads to 61b. The higher energy of TS4 is likely to come from the close contacts of the two atoms within the sum of the van der Waals radii [H‐H (2.20 Å) and H‐O (2.52 Å)]. Whereas both TS3 and TS4 have the three disfavored interactions indicated in the blue dotted lines, the atom distances of TS4 [H‐H (2.06 Å), H‐O (2.11, 2.27 Å)] are shorter than those of TS3 [H‐H (2.11 Å), H‐O (2.43, 2.49 Å)]. Thus, the calculation results clarified that

Scheme 8 illustrates the two selected negative data to show the difficulties associated with B‐ring construction. Substrate 62, which only differs from 54 in its C3,4‐ oxidation states and capped protective group, similarly underwent thermal rearrangement to afford dithiocar‐ bonate 63. Submission of 63 to radical conditions (n‐ Bu3SnH, V‐40, xylene, 180 C, microwave), however, led to



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only decomposition without providing 64, presumably because the electron‐rich C8‐radical intermolecularly added to the electron‐deficient carbonyl‐conjugated C1‐ olefin in the course of the reaction. On the other hand, ruthenium catalyst A promoted no ring‐closing metathe‐ sis between the two sterically hindered olefins of 65. These experiments accentuated the importance of the substrate design and reaction mode for achieving success‐ ful cyclization of the complex intermediate. Total Synthesis of Resiniferatoxin. The remaining key issues from 14 to 1 were modification of the carbon framework at C2,3,7,20, and decoration of the surrounding motifs (the ortho phenylacetate and homovanillate). These functional group transformations needed to be properly orchestrated, and judiciously opti‐ mized to achieve the total synthesis (Scheme 9). Before constructing the C3‐ketone and the ortho phe‐ nylacetate, pentaol 67 was prepared from 14. Full depro‐ tection turned out to be problematic due to the presence of the two acid‐sensitive allylic and tertiary hydroxy groups in 67. Importantly, the oxacyclopentylidene or‐ thoester of 14 allowed us to use relatively mild conditions for this particular reaction. Specifically, treatment of 14 with 1.5 M HCl in aqueous MeOH simultaneously de‐ tached the two orthoesters to furnish pentaol 67 after the addition of LiOH to the mixture to remove the partially remaining acetyl group. While orthoacetate 68 was re‐ covered as the minor compound, this was re‐subjected to the same conditions to obtain additional 67. The intricate 5/7/6‐tricyclic structure of 67 with 8 contiguous stereo‐ centers was clearly established by X‐ray crystallographic analysis. Next, the allylic C3‐hydroxy group of 67 was chemose‐ lectively oxidized over the secondary C14‐hydroxy group utilizing catalytic AZADO, CuCl, 2,2’‐bipyridyl, and DMAP under air to generate the C3‐ketone of 69.50 The ortho phenylacetate was introduced to the C9,13,14‐triol system of 69 to yield 70 by C14‐esterification with phenyl acetic acid by the action of activated ester C and DMAP at 0 °C, 51 and subsequent treatment with 2,4,6‐ trichlorobenzoic acid at 50 °C. The last remaining free C4‐alcohol of 70 was protected as the TMS ether with TMSOTf and 2,6‐lutidine, leading to 71. Then, C2‐functionalization and subsequent C7‐ hydroxylation transformed 71 into 77. After 1,4‐reduction of C3‐enone 71 to C3‐ketone 73, the C2‐position was methylated using LiN(TMS)2 and MeI to provide 74. N‐ methyl‐N‐(trimethylsilyl)trifluoroacetamide (D) 52 was applied to promote TMS‐enol ether formation from 74, and the resulting 75 was treated with NBS to afford C2‐ brominated 76. Although 76 has the three potential reac‐ tive sites (C5,7,16), allylic hydroxylation of 76 with SeO2 in t‐BuOH at 80 °C gave rise to ‐oriented C7‐alcohol 77 as the major product (77 : C5‐alcohol 78 = 5 : 1), while leav‐ ing the most kinetically protected C16‐position intact.53 Interestingly, the C5/7‐site‐selectivity of the allylic oxida‐ tion was significantly influenced by the A‐ring structure.

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SeO2‐induced allylic oxidation of 71 exclusively produced undesired C5‐hydroxylated compound 72. The unsaturat‐ ed A‐ring of 71 was assumed to affect the conformation and steric environment of the 7‐membered B‐ring, there‐ by changing the favorable pathway.54 The last four steps completed the total synthesis of 1. The reagent combination of Li2CO3 and LiBr transformed ‐bromo ketone 77 to ,‐unsaturated ketone 79 through the elimination of HBr. Allylic C7‐alcohol 79 was in turn treated with SOCl2 to induce the SN2’ substitution, pro‐ ducing allylic C20‐chloride 80 with the requisite C7‐ double bond. The introduced chloride of 80 underwent SN2 displacement upon treatment with cesium carbox‐ ylate E.55 Finally, TBAF‐promoted removal of the TMS group on the tertiary C4‐OH and TBS group on the phe‐ nolic OH, furnishing the targeted resiniferatoxin (1). All of the analytical data including 1H, 13C NMR, IR and []D value of the synthetic 1 were identical to those of the nat‐ ural counterpart. SUMMARY In summary, we developed a novel radical‐based syn‐ thetic strategy for the chemical construction of resinifera‐ toxin (41 total steps from 19 to 1). The synthetic route is highlighted by two powerful radical reactions. Design of the caged C‐ring structure 17b with the ‐alkoxy selenide enabled us to realize the three‐component coupling reac‐ tion with A‐ring 9 and 18b by the intermediacy of bridge‐ head radical 45b to produce 16b. After derivatization of 16b into bisxanthate 54, the selective [3,3]‐sigmatropic rearrangement of the allylic xanthate to the allylic dithio‐ carbonate, and the in situ radical reaction of 15 attained 7‐ endo cyclization to deliver 14 via the secondary radical formation and the dithiocarbonate expulsion. These in‐ ter‐ and intramolecular radical transformations thus an‐ nulated the 7‐membered B‐ring by stereoselectively link‐ ing the three hindered bonds (C4‐5, C7‐8, and C9‐10) that connect the A‐ and C‐rings without touching many po‐ tentially reactive functionalities. Other notable features of the successful synthesis include: 1) stereoselective preparation of 17b with five consecutive stereocenters by taking advantage of the 3D‐shape of the intermediates; 2) stereoselective introduction of the tertiary C4‐hydroxy group of 50 by exploiting the torsional strain‐controlled reaction; 3) C7‐site‐selective allylic oxidation of 76 with the properly functionalized A‐ring; and 4) construction of the allylic C20‐homovanillate by an SN2’‐reaction of 79 with SOCl2, followed by an SN2 reaction with cesium car‐ boxylate E. Because of their flexibility and robustness, the strategy and tactics developed here would be applicable to the synthesis of other biologically active daphnanes and tiglianes. Collectively, we hope that the present non‐ conventional route to 1 will enrich the science of radical chemistry, and offer new perspectives in the strategic de‐ sign of multi‐step target‐oriented synthesis beyond this work.


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Scheme 9.a Total Synthesis of Resiniferatoxin (1).

aReagents and conditions: (a) 1.5 M HCl in aqueous MeOH, 30 C; LiOH; 51% for 67 and 36% for 68 from 14; 57% for 67 from 68 (recovered 68: 28%); (b) AZADO, CuCl, 2,2’‐bipyridyl, DMAP, CH3CN, air, 0 C; 90%; (c) C, DMAP, toluene, THF, 0 C; 2,4,6‐ trichlorobenzoic acid, 50 C, 53% (recovered 69: 15%); (d) TMSOTf, 2,6‐lutidine, CH2Cl2, 74%; (e) SeO2, t‐BuOH, 80 C, 43% from 71; (f) LiBH(s‐Bu)3, THF, ‐78 C, 83%; (g) LiN(TMS)2, THF, 0 C; MeI, ‐20 C, 94%; (h) D, DMAP, DABCO, CH3CN, 110 C; (i) NBS, THF, 0 C; 88% (2 steps); (j) SeO2, t‐BuOH, 80 C, (77 : 78 = 5 : 1); (k) Li2CO3, LiBr, DMF, 150 C; (l) SOCl2, pyridine, Et2O, 25% (3 steps); (m) E, DMF; (n) TBAF, THF, 0 C, 92% (2 steps).

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org. Experimental procedures, and characterization data and NMR spectra of all newly synthesized compounds.

AUTHOR INFORMATION Corresponding Author *E‐mail: [email protected]‐tokyo.ac.jp

Present Address †Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu‐shi, Toyama 939‐0398, Japan

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This research was financially supported by Grant‐in‐Aids for Scientific Research (S) (JSPS, 17H06110) to M.I. and for Young Scientists (A) (JSPS, 16H06213) to D.U. Determination of X‐ ray crystallographic structures was financially supported by Nanotechnology Platform (MEXT, 12024046) of. Fellowships to S.H. and S.K. from JSPS are gratefully acknowledged.

REFERENCES

1. For recent reviews on daphnane diterpenoids, see: (a) Shi, Q.‐W.; Su, X.‐H.; Kiyota, H. Chem. Rev. 2008, 108, 4295. (b) Liao, S.‐G.; Chen, H.‐D.; Yue, J.‐M. Chem. Rev. 2009, 109, 1092. (c) Vasas, A.; Hohmann, J. Chem. Rev. 2014, 114, 8579. 2. Hergenhahn, M.; Adolf, W.; Hecker, E. Tetrahedron Lett. 1975, 16, 1595. 3. Adolf, W.; Sorg, B.; Hergenhahn, M.; Hecker, E. J. Nat. Prod. 1982, 45, 347. 4. Szallasi, A.; Blumberg, P. M. Neuroscience 1989, 30, 515. 5. For a review on TRPV1, see: Voets, T.; Talavera, K.; Owsian‐ ik, G.; Nilius, B. Nat. Chem. Biol. 2005, 1, 85. 6. (a) Liao, M.; Cao, E.; Julius, D.; Cheng, Y. Nature 2013, 504, 107. (b) Elokely, K.; Velisetty, P.; Delemotte, L.; Palovcak, E.; Klein, M. L.; Rohacs, T.; Carnevale, V. Proc. Natl. Acad. Sci. 2016, 113, E137. 7. (a) Brederson, J.‐D.; Kym, P. R.; Szallasi, A. Eur. J. Pharma‐ col. 2013, 716, 61. (b) Brown, D. C. Pharmaceuticals 2016, 9, 47. 8. For recent reviews on the roles of natural product struc‐ tures in drug discovery, see: (a) Harvey, A. L.; Edrada‐Ebel, R.; Quinn, R. J. Nat. Rev. Drug Discovery 2015, 14, 111. (b) Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2016, 79, 629. (c) Allred, T. K.; Manoni, F.; Harran, P. G. Chem. Rev. 2017, 117, 11994. 9. Zhan, Z.‐J.; Fan, C.‐Q.; Ding, J.; Yue, J.‐M. Bioorg. Med. Chem. 2005, 13, 645. 10. (a) Stout, G. H.; Balkenhol, W. J.; Poling, M.; Hickernell, G. L. J. Am. Chem. Soc. 1970, 92, 1070. (b) Vidal, V.; Potterat, O.; Louvel, S.; Hamy, F.; Mojarrab, M.; Sanglier, J.‐J.; Klimkait, T.; Hamburger, M. J. Nat. Prod. 2012, 75, 414.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 12

11. Hoppe, W.; Brandl, F.; Strell, I.; Röhrl, M.; Gassmann, I.; Hecker, E.; Bartsch, H.; Kreibich, G.; Szczepanski, Ch. v. Angew. Chem. Int. Ed. 1967, 6, 809. 12. Thielmann, H. W.; Hecker, E. Liebigs Ann. Chem. 1969, 728, 158. 13. For recent reviews on the total synthesis of terpenoids, see: (a) Maimone, T. J.; Baran, P. S. Nat. Chem. Biol. 2007, 3, 396. (b) Urabe, D.; Asaba, T.; Inoue, M. Chem. Rev. 2015, 115, 9207. (c) Brill, Z. G.; Condakes, M. L.; Ting, C. P.; Maimone, T. J. Chem. Rev. 2017, 117, 11753. 14. For synthetic studies of 1 and related daphnane and tig‐ liane diterpenoids, see: (a) Rigby, J. H.; Kierkus, P. Ch.; Head, D. Tetrahedron Lett. 1989, 30, 5073. (b) Harwood, L. M.; Ishikawa, T.; Phillips, H.; Watkin, D. J. Chem. Soc., Chem. Commun. 1991, 527. (c) Shigeno, K.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 4937. (d) Page, P. C. B.; Jennens, D. C. J. Chem. Soc., Perkin Trans. 1 1992, 2587. (e) Dauben, W. G.; Dinges, J.; Smith, T. C. J. Org. Chem. 1993, 58, 7635. (f) Paquette, L. A.; Sauer, D. R.; Edmondson, S. D.; Friedrich, D. Tetrahedron 1994, 50, 4071. (g) Sugita, K.; Neville, C. F.; Sodeoka, M.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1995, 36, 1067. (h) Lee, K.; Cha, J. K. Org. Lett. 1999, 1, 523. (i) Ovaska, T. V.; Reisman, S. E.; Flynn, M. A. Org. Lett. 2001, 3, 115. (j) Jackson, S. R.; Johnson, M. G.; Mikami, M.; Shiokawa, S.; Carreira, E. M. Angew. Chem. Int. Ed. 2001, 40, 2694. (k) Page, P. C. B.; Hayman, C. M.; McFarland, H. L.; Willock, D. J.; Galea, N. M. Synlett 2002, 583. (l) Wender, P. A.; Bi, F. C.; Buschmann, N.; Gosselin, F.; Kan, C.; Kee, J.‐M.; Ohmu‐ ra, H. Org. Lett. 2006, 8, 5373. (m) Wender, P. A.; D’Angelo, N.; Elitzin, V. I.; Ernst, M.; Jackson‐Ugueto, E. E.; Kowalski, J. A.; McKendry, S.; Rehfeuter, M.; Sun, R.; Voigtlaender, D. Org. Lett. 2007, 9, 1829. (n) Stewart, C.; McDonald, R.; West, F. G. Org. Lett. 2011, 13, 720. (o) Catino, A. J.; Sherlock, A.; Shieh, P.; Wzorek, J. S.; Evans, D. A. Org. Lett. 2013, 15, 3330. (p) Tong, G.; Liu, Z.; Li, P. Org. Lett. 2014, 16, 2288. (q) Hassan, A. H. E.; Lee, J. K.; Pae, A. N.; Min, S.‐J.; Cho, Y. S. Org. Lett. 2015, 17, 2672. (r) Li, Y.; Wei, M.; Dai, M. Tetrahedron 2017, 73, 4172. 15. (a) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954. (b) Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger Jr., J. D.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8957. (c) Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112, 4956. 16. Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897. 17. Lee, K.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 5590. 18. Kawamura, S.; Chu, H.; Felding, J.; Baran, P. S. Nature 2016, 532, 90. 19. (a) Asaba, T.; Katoh, Y.; Urabe, D.; Inoue, M. Angew. Chem. Int. Ed. 2015, 54, 14457. (b) Urabe, D.; Asaba, T.; Inoue, M. Bull. Chem. Soc. Jpn. 2016, 89, 1137. For a chemical conversion of phorbol to crotophorbolone, see: (c) Wender, P. A.; Kee, J.‐M.; Warrington, J. M. Science, 2008, 320, 649. 20. (a) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976. For a synthesis of daphnane congeners, see: (b) Wender, P. A.; Buschmann, N.; Cardin, N. B.; Jones, L. R.; Kan, C.; Kee, J.‐M.; Kowalski, J. A.; Longcore, K. E. Nat. Chem. 2011, 3, 615. 21. For recent reviews on radical reactions, see: (a) Rowlands, G. J. Tetrahedron 2009, 65, 8603. (b) Rowlands, G. J. Tetrahedron 2010, 66, 1593. (c) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692. 22. For selected recent examples of intermolecular radical ad‐ dition reactions in the total synthesis of terpenoids, see: (a) Schnermann, M. J.; Overman, L. E. Angew. Chem. Int. Ed. 2012, 51, 9576. (b) Sun, Y.; Li, R.; Zhang, W.; Li, A. Angew. Chem. Int. Ed. 2013, 52, 9201. (c) Wang, L.; Wang, H.; Li, Y.; Tang, P. Angew.

Chem. Int. Ed. 2015, 54, 5732. (d) Tao, D. J.; Slutskyy, Y.; Over‐ man, L. E. J. Am. Chem. Soc. 2016, 138, 2186. (e) Slutskyy, Y.; Jamison, C. R.; Lackner, G. L.; Müller, D. S.; Dieskau, A. P.; Un‐ tiedt, N. L.; Overman, L. E. J. Org. Chem. 2016, 81, 7029. (f) Slut‐ skyy, Y.; Jamison, C. R.; Zhao, P.; Lee, J.; Rhee, Y. H.; Overman, L. E. J. Am. Chem. Soc. 2017, 139, 7192. 23. Inoue, M. Acc. Chem. Res. 2017, 50, 460. 24. Murai, K.; Katoh, S.; Urabe, D.; Inoue, M. Chem. Sci. 2013, 4, 2364. This preliminary study describes the synthesis of a tri‐ cyclic carbon framework of 1 with the incorrect C10‐ stereochemistry. In the present study, we significantly short‐ ened the synthetic route to the C‐ring (‐7 steps), realized the construction of the tricycle with the correct C10‐stereochemistry, and accomplished the total synthesis of 1. 25. For recent reviews on multicomponent reactions, see: (a) Multicomponent Reactions, Zhu, J., Bienaymé, H. Eds.; Wiley‐ VCH, Weinheim, 2005. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulg‐ er, P. G. Angew. Chem. Int. Ed. 2006, 45, 7134. (c) Godineau, E.; Landais, Y. Chem. Eur. J. 2009, 15, 3044. (d) Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439. (e) Pellissier, H. Chem. Rev. 2013, 113, 442. 26. Urabe, D.; Yamaguchi, H.; Inoue, M. Org. Lett. 2011, 13, 4778. 27. Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829. 28. Walton, J. C. Chem. Soc. Rev. 1992, 21, 105. 29. ‐Alkoxy bridgehead radical reactions were utilized for the two‐ and three‐component coupling reactions in our labora‐ tory. (a) Urabe, D.; Nagatomo, M.; Hagiwara, K.; Masuda, K.; Inoue, M. Chem. Sci. 2013, 4, 1615. (b) Kamimura, D.; Urabe, D.; Nagatomo, M.; Inoue, M. Org. Lett. 2013, 15, 5122. (c) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; Urabe, D.; Inoue, M. J. Am. Chem. Soc. 2014. 136, 5916. (d) Nagatomo, M.; Hagiwara, K.; Masuda, K.; Koshimizu, M.; Kawamata, T.; Matsui, Y.; Urabe, D.; Inoue, M. Chem. Eur. J. 2016, 22, 222. (e) Kamimura, D.; Na‐ gatomo, M.; Urabe, D.; Inoue, M. Tetrahedron 2016, 72, 7839. 30. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168. 31. Metathesis in Natural Product Synthesis: Strategies, Sub‐ strates and Catalysts; Cossy, J., Arseniyadis, S., Meyer, C., Eds.; Wiley‐VCH: Weinheim, 2010. 32. Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 17160. 33. For recent examples of related reactions, see: (a) Constan‐ tino, M. G.; Beatriz, A.; da Silva, G. V. J.; Zukerman‐Schpector, J. Synth. Commun. 2001, 31, 3329. (b) Wang, Q.; Chen, C. Org. Lett. 2008, 10, 1223. 34. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Syn‐ thesis 1994, 639. 35. Nicolaou, K. C.; Baran, P. S.; Zhong, Y.‐L.; Choi, H.‐S.; Fong, K. C.; He, Y.; Yoon, W. H. Org. Lett. 1999, 1, 883. 36. Barton, D. H. R.; Bridon, D.; Zard, S. Z. Tetrahedron Lett. 1984, 25, 5777. 37. (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939. For reviews on Barton esters, see: (b) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413. (c) Saraiva, M. F.; Couri, M. R. C.; Hyaric, M. L.; de Almeida, M. V. Tetrahedron 2009, 65, 3563. 38. Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416. 39. Luche, J.‐L. J. Am. Chem. Soc. 1978, 100, 2226. 40. (a) Curran, T. T.; Hay, D. A.; Koegel, C. P.; Evans, J. C. Tet‐ rahedron 1997, 53, 1983. (b) Watson, T. J. N.; Curran, T. T.; Hay, D. A.; Shah, R. S.; Wenstrup, D. L.; Webster, M. E. Org. Process Res. Dev. 1998, 2, 357. 41. Weigand, S.; Brückner, R. Synthesis 1996, 475.

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Page 11 of 12

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42. (a) Giese, B.; Grӧninger, K. S.; Witzel, T.; Korth, H.‐G.; Sustmann, R. Angew. Chem. Int. Ed. 1987, 26, 233. (b) Korth, H.‐ G.; Sustmann, R.; Grӧninger, K. S.; Leisung, M.; Giese, B. J. Org. Chem. 1988, 53, 4364. 43. (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215. (b) Zhao, Y.; Truhlar, D. G. J. Phys. Chem. A 2008, 112, 1095. 44. (a) Cheong, P. H.‐Y.; Yun, H.; Danishefsky, S. J.; Houk, K. N. Org. Lett. 2006, 8, 1513. (b) Wang, H.; Houk, K. N. Chem. Sci. 2014, 5, 462. 45. Kennedy, R. M.; Abiko, A.; Takemasa, T.; Okumoto, H.; Masamune, S. Tetrahedron Lett. 1988, 29, 451. 46. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574. 47. (a) Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1972, 20, 2348. (b) Nakai, T.; Ari‐Izumi, A. Tetrahedron Lett. 1976, 17, 2335. 48. Ziegler, F. E.; Zheng, Z.‐L. Tetrahedron Lett. 1987, 28, 5973. 49. (a) Lee, E.; Lim, J. W.; Yoon, C. H.; Sung, Y.; Kim, Y. K.; Yun, M.; Kim, S. J. Am. Chem. Soc. 1997, 119, 8391. (b) Justicia, J.; Oller‐López, J. L.; Campaña, A. G.; Oltra, J. E.; Cuerva, J. M.; Buñuel, E.; Cárdenas, D. J. J. Am. Chem. Soc. 2005, 127, 14911. (c) Yokoe, H.; Mitsuhashi, C.; Matsuoka, Y.; Yoshimura, T.; Yoshida, M.; Shishido, K. J. Am. Chem. Soc. 2011, 133, 8854. 50. Sasano, Y.; Nagasawa, S.; Yamazaki, M.; Shibuya, M.; Park, J.; Iwabuchi, Y. Angew. Chem., Int. Ed. 2014, 53, 3236. 51. Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yama‐ guchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943. 52. Donike, M. J. Chromatogr. 1969, 42, 103. 53. (a) Sharpless, K. B.; Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154. (b) Arigoni, D.; Vasella, A.; Sharpless, K. B.; Jensen, H. P. J. Am. Chem. Soc. 1973, 95, 7917. 54. Rationale of the C5/7‐site‐selectivity was described in the Supporting Information. 55. (a) Kruizinga, W. H.; Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1981, 46, 4321. (b) Sanna, V.; Pintus, G.; Roggio, A. M.; Punzoni, S.; Posadino, A. M.; Arca, A.; Marceddu, S.; Bandiera, P.; Uzzau, S.; Sechi, M. J. Med. Chem. 2011, 54, 1321.

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