A Synthetic Entry to Polyfunctionalized Molecules through the [3+2

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A Synthetic Entry to Polyfunctionalized Molecules through the [3+2]-Cycloaddition of Thiocarbonyl Ylides Franz-Lucas Haut, Christoph Habiger, Klaus Speck, Klaus Wurst, Peter Mayer, Johannes Nepomuk Korber, Thomas Müller, and Thomas Magauer J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07729 • Publication Date (Web): 13 Aug 2019 Downloaded from pubs.acs.org on August 13, 2019

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Journal of the American Chemical Society

A Synthetic Entry to Polyfunctionalized Molecules through the [3+2]-Cycloaddition of Thiocarbonyl Ylides Franz-Lucas Haut,† Christoph Habiger,† Klaus Speck,‡ Klaus Wurst,§ Peter Mayer,‡ Johannes Nepomuk Korber,‡ Thomas Müller,† and Thomas Magauer*,† †Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80– 82, 6020 Innsbruck ‡ Department of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstrasse 5–13, 81377 Munich, Germany § Institute of General, Inorganic & Theoretical Chemistry, Leopold-Franzens-University Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria Supporting Information Placeholder ABSTRACT: Here we present a comprehensive study on the [3+2]-cycloaddition of thiocarbonyl ylides with a wide variety of alkenes and alkynes. The obtained dihydro- and tetrahydrothiophenes products serve as exceptionally versatile intermediates providing access to thiophenes, dienes, dendralenes, and vicquarternary carbon centers. The use of high-pressure conditions enables thermally unstable, sterically encumbered or moderately reactive substrates to undergo the cycloaddition under mild conditions, thereby increasing the yield by up to 58%. In addition, we showcased its utility by the formal syntheses of the pharmaceuticals NGB 4420 and tenilapine.

acceleration of the cycloaddition of 1a with 2 under high-pressure conditions.12 Indeed, reacting both components at 10 kbar at 23 °C afforded 3 in 68% yield.10 In contrast, for highly reactive substrates such as the strained cyclobutene 4,13 no significant difference in yields can be observed for either thermal (68% at 100 °C) or high-pressure activation (71% at 10 kbar, 23 °C). For both examples, a subsequent reductive desulfurization step14 revealed the vic-cis-dimethyl or -diethyl unit, respectively. Scheme 1. Application of the [3+2]-cycloaddition of thiocarbonyl ylides in organic synthesis.

Dicarbofunctionalizations of readily available feedstock alkenes or alkynes are powerful transformations to convert simple starting materials into polyfunctionalized molecules.1 Ideally, these transformations also allow for the late-stage functionalization of more complex substrates. The attractiveness of this approach lies in the potential to simultaneously form two vicinal carbon-carbon bonds in a highly regiospecific fashion in one synthetic operation.2 Although various elegant transition-metal catalyzed dicarbofunctionalization protocols have been developed for this purpose, the installation of quaternary carbon centers still poses a great synthetic challenge.3 In this context, pericyclic reactions such as the 1,3-dipolar cycloaddition represent a valuable alternative for their ability to rapidly create molecular complexity.4 Within the large family of 1,3-dipoles (nitrones, nitronates, azomethine ylides, carbonyl ylides, nitrile oxides, nitrile ylides and imines, diazoalkanes, azides and mesoionic systems), thiocarbonyl ylides have remained in a niche and their appearance in complex molecule synthesis is rare.5 Only recently, their use as a synthetic equivalent for the otherwise highly challenging installation of vicinal cis-dialkyl groups6 from α,β-unsaturated systems has revealed their potential in organic synthesis (Scheme 1). In a recent total synthesis of a family of tetracyclic meroterpenoids, we undertook extensive efforts to set two crucial stereocenters, one of which was quaternary.7 In this context, we found that the thermally promoted reaction (100 °C) between dipole precursor 1a8,9 and enone 2 only produced minute amounts of cycloadduct 3 (4% yield).10 Considering that pericyclic reactions typically have a negative activation and reaction volume,11 we envisioned

To further investigate the practicability and utility of this transformation we conducted a comparative study on the [3+2]cycloaddition of thiocarbonyl ylides under thermal and highpressure conditions investigating a broad panel of substrates. The synthetic potential of this transformation is in addition highlighted

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Scheme 2. Screening and substrate scope of the [3+2]-cycloaddition of thiocarbonyl ylides under thermal and high-pressure conditions.

A) Screening of reaction conditions for thermal and high-pressure mode of activation. B) Reaction scope. aUpper reaction: yield for thermal conditions [(Δ): 1a (2 equiv), DMPU, 80 °C, 1 h, 1 bar]; lower reaction: yield for high-pressure conditions [(HP): 1a (2 equiv), DMPU, 23 °C, 2 h, 5 kbar]. bThe reaction was performed at 14 kbar. cA solvent mixture of DMPU:CH2Cl2 (30:1) was used. dDouble addition product 10b was obtained as a mixture of two diastereomers (dr = 1:1).


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Journal of the American Chemical Society by providing an overview of highly valuable postfunctionalizations. At the outset, we subjected a solution of cyclohex-2-en-1one (6) and 1a to standard thermal conditions [1a (2 equiv), DMPU, 80 °C, 1 h, 1 bar] to obtain 7 in 40% yield (Scheme 2A). In comparison, carrying out the cycloaddition under high-pressure (5 kbar, 23 °C, DMPU) 7 was isolated in a yield of 85%. Higher or lower pressures led to either a small increase (entry 4, 14 kbar, 86%) or a significant lowering (entry 5, 1 kbar, 62%) of the reaction yield, respectively. While the use of DMPU consistently provided high yields for the cycloaddition product 7 (entry 5–7), other polar aprotic solvents such as MeCN, THF, DMF or DMSO were less effective to promote the reaction (entry 8–9). In general, higher temperatures were unfavorable as 1a undergoes an unproductive sila-Pummerer rearrangement to an unreactive thioacetal.15 Having established optimal reaction conditions, we started to investigate and compare different substrate classes in the [3+2]cycloaddition with 1a under thermal and high-pressure conditions (Scheme 2B). When applying high-pressure conditions to six- to nine-membered ring systems (7, 8b–d), significant higher yields were observed. Introduction of steric hindrance at the α-/γ-position (8e–h) or the use of deactivated substrates such as the chromone-derived 8i further revealed the benefit of high-pressure in comparison to thermal activation (up to 50% increase). In general, high to excellent diastereoselectivities were obtained for (+)-8k, (–)-8l, 8o and 8p. However, for the reaction of (R)-carvone with 1a to give (+)-8g we observed low selectivity for both modes of activation. Under high-pressure, acyclic (Z)-alkene gave the cycloadduct 8q as a single diastereomer in 71% yield. The application of thermal conditions provided 8q in a diminished yield of 33% and led to significant isomerization of the (Z)- to the corresponding (E)-alkene. From a mechanistic point of view, we suggest that the thermally induced cycloaddition in this case proceeds via a reversible, stepwise process.16 (E)-Alkenes containing electronwithdrawing substituents (–COR, –COOR, –CN, and –CHO) were shown to be ideally suited for the stereospecific cycloaddition with 1a, yielding 8r–u as single diastereomers in reproducible high yields. So far, only the presence of a nitro group gave a lower yield under high-pressure (8v, –19%). From the analysis of the crude reaction mixture, no other byproducts could be identified. A current limitation is displayed by β-disubstituted systems for which no cycloaddition products were obtained even under forcing conditions (14 kbar, 50 °C). Unexpectedly, electron-rich and electron-poor styrenes also reacted in moderate to good yields to give the 3-aryl substituted tetrahydrothiophenes (9a–e). Heteroaromatic compounds such as pyridine 9f and furan 9g were also well tolerated. However, for substituted styrenes (9h–i) lower yields were obtained and no reaction was observed in the case of aryl enol ethers. We next explored conjugated systems to study the inherent substrate regioselectivity. For γ-substituted conjugated dienes, the formal 1,4-addition pathway prevailed under thermal conditions to give 10a (21%). At high-pressure competing double addition occurred to provide a 3.4:1 mixture of 10a and 10b (53%), with 10a still representing the major product. For the formation of 10b, a consecutive 1,6-/1,4-addition process should be operative as 10a proved to be unreactive under the reaction conditions. As exemplified by 10c, exclusive 1,6-addition could be achieved by shifting the steric hindrance from the γ- to the β-position. Tropone selectively gave the higher-order [6+3]-cycloaddition product 11 (53%),17 which represents a masked polyketide building block. In contrast to the highly reactive alkenes (8r–u), the corresponding alkynes showed only low conversion to their cycloaddition products 12a–e under thermal conditions (8–45%). Nevertheless, the application of highpressure (14 kbar) enabled access to 12a–e in synthetically useful

yields (29–79%) provided that an electron withdrawing group (– COR, –COOR, –CN) was present. Otherwise and in contrast to styrenes, electron-rich alkynes are unreactive under the optimized reaction conditions. The synthetic utility and versatility of the obtained dihydro(DHT) and tetrahydrothiophenes (THT) was investigated in a series of postfunctionalizations (Scheme 3A). Reductive desulfurization of THT 8r was accompanied with partial epimerization to provide the trans-ketone 13 in 84% yield (dr = 5:1).14 Oxidation of 8r to its corresponding sulfoxide 14 (1.1 equiv m-CPBA) or sulfone 15 (2.2 equiv m-CPBA) proceeded in excellent yields. Additionally, S-methylation with Meerwein’s salt (Me3OBF4) and subsequent exposure to lithium carbonate led to ring-opening of the thiophene to deliver enone 16.18 Oxidation by using DDQ (130 °C)19 gave access to thiophene 17, which was also synthesized in excellent yield under mild conditions (DDQ, 23 °C)15a,20 starting from DHT 12a. Following the standard oxidation protocol, sulfolene 18 was obtained upon treatment with excess m-CPBA (92%). Exposure to elevated temperatures (110 °C) induced a retro-cheletropic reaction to give an intermediate diene that readily participated in the Diels–Alder cycloaddition with N-benzylmaleimide (19) producing 20 in good yield (80%).15b,21 Alkylation and elimination (Me3OBF4, Li2CO3) of 12a proceeded efficiently to give 21. This polyfunctionalized diene 21 was unreactive towards electron-poor or -rich dienophiles even at highpressure, but efficiently reacted in a Lewis-acid catalyzed, hetero Diels–Alder reaction with enol ether 22 to provide dihydropyran 23.22 Moreover, 21 was transformed into its corresponding [3]dendralene 24, a prominent substrate class for Diels–Alder cascades.23 Based on our findings that 1a reacts with alkynes at high-pressure to give a mixture of mono and double addition products (Scheme 2B, 12f and 12g), we speculated about its potential to access vic-quaternary carbon centers (Scheme 3B). For this purpose, dimethyl acetylendicarboxylate (25) was first selectively converted to dihydrothiophene 26 under thermal conditions in good yield (77%). For the second cycloaddition to occur with sulfoxide 1b, high-pressure (14 kbar) was essential as no cycloaddition product was observed under thermal conditions. With 27 in hand, we first reduced 27 to its corresponding diol followed by reductive desulfurization (Raney®-Nickel, 70 °C)14 to give meso-28. From there, enantiomerically pure products can be obtained by choosing from an array of desymmetrization methods.24 As depicted in Scheme 3C, we also applied our cycloaddition strategy for the formal synthesis of the pharmaceuticals NGB 4420 (32) and tenilapine (36). For this purpose, cyclohept-2en-1-one (29) was treated with 1b to give 30 as an inconsequential mixture of diastereomers. The use of high-pressure conditions (14 kbar) was not mandatory but provided significantly higher yields when compared to thermal conditions (+36%). Exposure of 30 to standard oxidation conditions (DDQ, 80 °C) gave tetrasubstituted thiophene 31 and thus shortens the known route to NGB 4420 (32) by one step.25 Next, we studied the reactivity between readily available dienone 33 and 1a. Surprisingly, only high-pressure (14 kbar, 4 equiv of 1a) afforded the desired double-adduct 34b (inconsequential mixture of two diastereomers).26 Treatment of 34b with DDQ (80 °C) accomplished the oxidation of eight C–H-bonds and simultaneously effected cleavage of the ketal to provide 35, a known intermediate along the synthesis to tenilapine (36).27 Again, our cycloaddition strategy displays a step-efficient alternative (three steps from 4-methoxyphenol) to key intermediate 35 in comparison to the literature (five steps).27a



Scheme 3. Postfunctionalizations, vic-quaternary carbon centers and formal synthesis of NGB 4420 and tenilapine.a

a

Reagents and conditions: a) Raney®-Nickel, EtOH, 80 °C, 3 h (84%, dr = 5:1); b) DDQ (2.5 equiv), PhCl, 130 °C, 2 h (63%); c) DDQ (1.1 equiv), CH2Cl2, 23 °C, 0.5 h (89%); d) m-CPBA (2.5 equiv), CH2Cl2, –78 °C to 23 °C, 1 h (92%); e) m-CPBA (1.1 equiv), CH2Cl2, – 78 °C to 0 °C, 1 h (99%, dr = 1.3:1); f) m-CPBA (2.2 equiv), CH2Cl2, –78 °C to 23 °C, 1 h (96%); g) Me3OBF4 (1.5 equiv), CHCl3, 23 °C, 6 h then Li2CO3 (3 equiv), MeOH, 23 °C, 15 h (71%); h) Me3OBF4 (1.5 equiv), CHCl3, 23 °C, 18 h then Li2CO3 (3 equiv), MeOH, 23 °C, 2 h (74%); i) N-benzylmaleimide (19, 2 equiv), PhMe, 110 °C, 12 h (80%); j) Eu(fod)3 (5 mol%), n-butyl vinyl ether (22, used as solvent), 60 °C, 16 h (75%); k) TBSOTf (2 equiv), Et3N (2.5 equiv), CH2Cl2, –78 °C to 23 °C, 4 h (43%); l) 1a (2 equiv), DMPU, 80 °C, 1 h (77%); m) 1b (4 equiv), DMPU, 23 °C, 2 h, 14 kbar (44% and 33% recovered 26); n) LiAlH4 (5 equiv), THF, 0 °C to 23 °C, 2 h; o) Raney®Nickel, THF, 70 °C, 2 h (42% over 2 steps); p) 1b (2 equiv), DMPU, 23 °C, 2 h, 14 kbar (62%); q) DDQ (2.5 equiv), PhCl, 80 °C, 2 h (60%); r) 1a (4 equiv), DMPU, 23 °C, 14 kbar (49% of 34a and 27% of 34b, dr = 1.3:1); s) DDQ (5 equiv), DCE, 80 °C, 1 h (26%). In summary, we have shown the synthetic potential of highpressure mediated thiocarbonyl ylide cycloaddition reactions and provided for the first time a comprehensive substrate scope. The potential of the cycloaddition products for organic synthesis was revealed by a series of powerful postfunctionalizations. The obtained products were utilized en route to highly functionalized thiophenes, dendralenes, meso-compounds or pharmaceuticals such as NGB 4420 and tenilapine. Despite intensive efforts, β-disubstituted substrates do not undergo the cycloaddition. A systematic variation of the substitution pattern of sulfoxide 1a as well as intramolecular variants of the reaction are currently ongoing and beyond the scope of this manuscript.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org. Experimental details and spectroscopic data (PDF) X-ray crystallographic data for (+)-8g, 8h, 8i, 8n, 8p, 8t, (–)-8z, 11, 12e and 20 (CIF)

AUTHOR INFORMATION Corresponding Author [email protected]


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Journal of the American Chemical Society Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported by the Austrian Science Fund FWF (P31023-NBL to T.M.), the Center for Molecular Biosciences CMBI and the Tyrolean Science Fund TWF (UNI-0404/2340 to F.-L.H.). We are grateful to Prof. Dirk Trauner (New York University) for providing unpublished data and helpful discussions. Furthermore, we thank Dr. Gabriele Prina Cerai and Robin Poller (University of Innsbruck) for assistance during the preparation of this manuscript.

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