Cyclobutenes - American Chemical Society

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Cyclobutenes: At a Crossroad between Diastereoselective Syntheses of Dienes and Unique Palladium-Catalyzed Asymmetric Allylic Substitutions Antonio Misale, Supaporn Niyomchon, and Nuno Maulide* University of Vienna, Institute of Organic Chemistry, Währinger Straße 38, 1090 Vienna, Austria CONSPECTUS: The rich chemistry of cyclobutanes is underpinned by a large body of synthetic literature devoted to their synthesis and decoration. This is motivated by the widespread representation of cyclobutane moieties in biologically active natural products and manmade molecules. Surprisingly, this vast array of knowledge finds no parallel in the chemistry of cyclobutenes, their unsaturated analogues. In particular, a dearth of methods to synthesize enantioenriched cyclobutenes is apparent upon cursory investigation of the literature. As a leading example, the photocycloaddition of maleic anhydride to acetylene or dichloroethylene, probably a benchmark of cyclobutene synthesis, delivers a meso cyclic anhydride which can be further converted to a cyclobutene product by enantioselective desymmetrization by ring opening. Nonetheless, such an approach delivers products with a rather inflexible substitution pattern around the four-membered ring. The lack of general approaches has motivated our group and others to develop novel routes to cyclobutene scaffolds, leading to the development of a strategy that combines photochemistry and catalysis. Indeed, we have coupled the simple and efficient photochemical isomerization of 2-pyrone into a strained bicyclo[2.2.0] lactone with palladium-catalyzed allylic alkylation as a simple and versatile access to functionalized cyclobutenes. Several nucleophiles can be added to the activated, strained intermediate, including malonate anions and azlactones. The products are mono- and bicyclic building blocks richly decorated with functional groups. Importantly, they are formed with high levels of diastereoselectivity as expected by the tenets of palladium-catalyzed allylic alkylation, which posit that the oxidative addition and nucleophilic capture steps proceed with inversion of configuration, resulting in overall retention (inversion + inversion). However, the transposition of the methodology to an asymmetric version subsequently led to the surprising discovery of a family of highly enantioselective, diastereodivergent catalytic processes. Indeed, we observed a ligand-dependent stereochemical outcome for a range of palladium-catalyzed allylic alkylations affording either overall retention or overall inversion of configuration, and that with very high levels of enantio- and diastereoselectivity. The new family of diastereodivergent reactions enables the conversion of the aforementioned racemic bicyclo[2.2.0] lactone into each of 4 stereoisomeric products, at will. Although the mechanistic details at the origin of this unusual stereodivergence are not yet fully elucidated, it became clear through our studies that unique Pd-allyl complexes, residing preferentially as their σ-(monohapto)-bound isomers, are at the heart of the process. The cyclobutenes prepared can also engage in electrocyclic ring-opening reactions (often spontaneous depending on the substitution pattern) that link this chemistry with that of diene and polyene frameworks. Using the strategies laid out above, our group was then able to harness the high stereospecificity of electrocyclic reactions and design modular syntheses of several natural products and natural product fragments. We believe that the methods presented herein shall soon pave the way for the streamlined synthesis of more complex polyenic natural products. methodologies have attained suitable flexibility and scalability for the preparation of functionalized cyclobutenes.

I. INTRODUCTION All-carbon four-membered rings are incorporated in a large number of naturally occurring and/or biologically active substances (Figure 1).1 Due to the high synthetic value of such targets, a plethora of methodologies and strategies targeting their synthesis have been developed over the past decades.2,3 In particular, cyclobutanes and cyclobutanones, readily accessible through photochemical and thermally allowed [2 + 2] cycloadditions, have been the target of most synthetic applications. In contrast, to date, only a handful of synthetic © 2016 American Chemical Society

II. STRATEGIES FOR SYNTHESIS OF CYCLOBUTENES The preparation of cyclobutenes is a particularly interesting synthetic endeavor given the potential associated with their intrinsic ring strain. Although cyclobutenones are available Received: July 20, 2016 Published: October 31, 2016 2444

DOI: 10.1021/acs.accounts.6b00375 Acc. Chem. Res. 2016, 49, 2444−2458

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Accounts of Chemical Research

Figure 1. Natural products containing a cyclobutane/cyclobutene scaffold.

need for more flexible and stereoselective routes to substituted cyclobutenes.6 A recent breakthrough has been reported by Echavarren and Lopez-Carrillo, who explored intermolecular reactions of alkynes 2 with alkenes 3 in the presence of an electrophilic Au(I)-catalyst. The regioisomeric cyclopropyl gold(I) carbenes shown in Scheme 2 are plausible intermediates.7 Ogoshi and co-workers reported a nickel-catalyzed intermolecular [2 + 2] cycloaddition of conjugated enynes with electron-poor alkenes (Scheme 3).8 The reaction mechanism was ultimately elucidated by isolation of a key cyclic (η3butadienyl)nickel complex reaction intermediate. Further examples of metal-catalyzed alkyne/alkene [2 + 2] cycloadditions delivering cyclobutenes were reported by the groups of Hilt9 and Kakiuchi,10 employing Cobalt catalysis. Our interest in developing an approach toward cyclobutenes focused on the photoisomerization of 2-pyrone 14, reported by Corey and Streith11d to generate the strained bicyclic lactone 15 (Scheme 4).11 Compound 15 was known to be an unstable and potentially explosive substance which, perhaps unsurprisingly, remained overlooked as a potential starting material for further elaboration. Its low-temperature decarboxylation, however, remains to this day as one of the paths of choice

through ketene/alkyne cycloaddition reactions,4 their carbonylfree analogues are not easily accessible in a direct manner. The photocycloaddition of maleic anhydride to acetylene or dichloroethylene is probably a benchmark of cyclobutene synthesis (Scheme 1).5 In spite of the numerous advances Scheme 1. Photocycloaddition of Maleic Anhydride for the Synthesis of Cyclobutene Derivatives

reported in the desymmetrization of the adduct 1 and analogues thereof through nucleophilic ring opening reactions, the products necessarily bear two carboxylic acid derivatives directly connected to the four-membered ring. This highlights a

Scheme 2. Echavarren’s Au(I)-Catalyzed Synthesis of Cyclobutenes

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Accounts of Chemical Research Scheme 3. Ni-Catalyzed Intermolecular [2 + 2] Cycloaddition of Conjugated Enynes with Alkenes

acid 16a, as a single diastereomer (Scheme 5). A variety of active methylene compounds are competent nucleophiles in this reaction.13 The high atom-economy of this reaction sequence prompted us to target substructures where the cyclobutene moiety is part of amino acid derivatives, and employing azlactones as nucleophiles served this purpose (Scheme 6).13 In the event, a ring-opening/rearrangement sequence takes place during the workup to deliver azabicyclic products of unusual structure. Particularly striking was the high diastereoselectivity encountered in these transformations. Common to both reactions is the obtention of a cis 3,4-disubstituted cyclobutene product. This is in accord with the well-known tenets of TsujiTrost allylic alkylation which posit that both (a) the oxidative addition/formation of an allylpalladium(II) species and (b) the nucleophilic capture of the latter species by a soft nucleophile (such as the stabilized carbanions employed in Schemes 5 and 6) proceed with inversion of configuration (vide infra). This explains the obtention of cis-disubstituted products from the cis-

Scheme 4. Envisaged Strategy for the Synthesis of Functionalized Cyclobutenes

for the in situ preparation of the antiaromatic cyclobutadiene.12 We were lured by its appeal as a promising starting material for the synthesis of functionalized cyclobutenes (16). Early attempts were met with success. The photoisomerization of 14 proceeded quantitatively and preliminary experiments revealed that the strained allylic lactone moiety of 15 responded productively to palladium catalysis. After optimization, we found that treatment of 15 with sodium dimethylmalonate in the presence of 5 mol % Pd(PPh3)4 led to a nearly quantitative yield of the cis-cyclobutene carboxylic Scheme 5. Scope of the Catalytic Alkylation of Lactone 15

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Accounts of Chemical Research Scheme 6. Scope of the Catalytic Alkylation Using Azalactones; Ar = (4-NO2)−C6H4.

to the formation of (E,Z)- or (Z,E)-diene products; instead, a trans-3,4-disubstituted cyclobutene provides (E,E)- or (Z,Z)dienes upon electrocyclic ring opening (Scheme 7).17 We came across this type of reactivity serendipitously while exploring the allylic alkylation of lactone rac-15.18,19 As shown (Scheme 8), sodium phenolates led to (Z,E)-butadienoic acids such as 19 in high yields. Conversely, when trimethylsilyl azide was employed, an (E,E)-azidodiene 20 was obtained. The high stereoselectivity observed gave away the intermediacy of push− pull, unstable stereodefined cyclobutenes. In fact, variable amounts of fleeting (trans) azido-cyclobutene products 18 were detected by NMR analysis of the crude mixture. Although several literature reports repeatedly refer to “the scarce reactivity of push-pull dienes towards [4 + 2]cycloaddition”, we were pleased to realize an intramolecular [4 + 2] cycloaddition of ortho-allyl derivatives of 19 under thermal conditions (Scheme 9).18 The resulting products 22, obtained with moderate diastereoselectivity, comprise the core of natural products such as euglobal and 4-isocymobarbatol. Seeking access to dienes with even more useful functionality, we discovered (Scheme 10) that lactone rac-15 could be ring opened by dry lithium halide salts alone at room temperature, affording trans-configured products 23 and complementing the already known HCl-mediated ring-opening (vide infra). Thermolysis thereof, preceded by carboxylate derivatization at will, afforded halodiene carboxylate products 24 ripe for modular use in synthesis.20a

configured electrophilic partner 15. The high stereoselectivity for the formation of the third stereogenic center of the compounds depicted in Scheme 6 was not anticipated and configures a notable case of high preferred relative topicity.

III. APPLICATION OF CYCLOBUTENES TO THE SYNTHESIS OF POLYENE NATURAL PRODUCTS III.i. The 4π Electrocyclic Ring-Opening of Cyclobutenes

It is long known that cyclobutenes are primed to undergo 4πelectrocyclic ring opening reactions to yield butadiene derivatives.14 The stereoselectivity of this thermal conrotatory process, in accordance with the Woodward−Hoffmann rules, allows prediction of the diene geometry based on the stereochemistry of the cyclobutene starting materials.15,16 For instance (Scheme 7), a cis-3,4-disubstituted cyclobutene leads Scheme 7. Conrotatory Electrocyclic Ring Opening of cisand trans-3,4-Disubstituted Cyclobutenes

Scheme 8. Discovery of a Domino Allylic Alkylation/Electrocyclic Ring Opening of Lactone rac-15

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Accounts of Chemical Research Scheme 9. Intramolecular Diels−Alder Reaction to Form Tricyclic Core Structures 22

Scheme 10. Ring Opening of Lactone rac-15 by Lithium Halide Salts and Thermolysis of the Products Thereof

Scheme 11. Total Synthesis of Inthomycin C

cyclobutene cis-36 (vide infra for its preparation) delivered biscyclobutene 35. Thermal 4π-electrocyclic ring opening provided the southeastern part of macrolactin A (37) with full stereocontrol for the two diene moieties.21 It should be pointed out that on each coupling step involving racemic electrophile 15 or racemic acid 36, diastereomeric mixtures are generated (33 obtained as a mixture of 2 diastereomers; 35 as a mixture of 4 diastereomers). Nonetheless, upon electrocyclic ring opening this matter becomes inconsequential, as only the enantioenriched stereocenter originally entailed in 32 remains in compound 37. The simple assembly of this relatively complex scaffold in only 4 steps from iodide 32 bodes well for future synthetic endeavors.

A formal synthesis of inthomycin C was achieved using the above-reported approach (Scheme 11). Halogenative cleavage of substituted lactone rac-25 followed by Weinreb amide synthesis and 4π-electrocyclic ring opening afforded diene 27 as single isomer. Stille cross-coupling, reduction and organocatalytic Mukayama aldol reaction delivered known ester 30, a precursor to the natural product, in 23% overall yield.20 We more recently targeted macrolactin A, a member of a wide family of macrolide natural products. Our synthesis of the fully functionalized southeastern fragment of macrolactin A is depicted in Scheme 12.21 Copper-mediated addition of a functionalized zincate (derived from optically pure iodide 32) to rac-15 afforded the trans-disubstituted cyclobutene 33. Further esterification with concomitant removal of the TIPSprotecting group, followed by Mitsunobu esterification with the 2448


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Accounts of Chemical Research Scheme 12. Towards the synthesis of Macrolactin Aa

a

Note: 33 is obtained as a mixture of two diastereomers and 35 as a mixture of four diastereomers.

Scheme 13. Commonly Accepted Stereochemical Outcome for Palladium-Catalysed Asymmetric Allylic Alkylation Employing Either “Hard” (Nonstabilized) and “Soft” (Stabilized) Nucleophiles

IV.i. Use of Soft Nucleophiles

IV. ENANTIOSELECTIVE SYNTHESIS OF CYCLOBUTENES

While developing asymmetric allylic alkylation reactions of lactone 15 with “soft” nucleophiles, in 2011 we serendipitously encountered an unprecedented ligand-controlled phenomenon, whereby the racemic lactone 15 can be converted into any one out of four stereoisomeric products in high selectivities (Scheme 14).23 As shown, this remarkable catalytic process hinges on the use of either monodentate TADDOL-supported phosphoramidites24 or phosphinooxazolines25 as ligands and delivers products with overall retention or inversion of configuration at will. We coined the term diastereodivergent deracemization for this observation.23 Several other elegant diastereodivergent phenomena in asymmetric catalysis appeared in the literature subsequently.26

Palladium-catalyzed asymmetric allylic alkylation is a powerful synthetic tool22 able to effect quantitative conversion of chiral racemic substrates into single enantiomeric products through deracemization. The most widely accepted model predicts opposite stereochemical outcomes for stabilized/“soft“ nucleophiles and their non-stabilized/“hard” counterparts. As aforementioned (cf. Scheme 13), it is expected that the former mediate outer-sphere nucleophilic attack (with inversion on the electrophile) while the latter add to the metal center and deliver the allylic alkylation products upon reductive elimination (with retention on the electrophile). 2449


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Accounts of Chemical Research Scheme 14. Diastereodivergent Deracemization of Bicyclic Lactone (rac)-15

Scheme 15. From Bicyclic Lactone (rac)-15 to Cyclobutene Carboxylate Derivatives

aforementioned implies that ring strain is not a prerequisite for this process.27 The use of the diastereomeric chloride trans-42 led to surprising results (Scheme 17). The use of L2b (under similar conditions) led again to the cis-product. As we originally assumed that L2b mediated stereoretentive allylic alkylation by palladium catalysis, this was an unexpected outcome.27 When L3a was employed, the trans-cyclobutene 40a was obtained in modest yield as the major diastereomer (dr = 95:5) with reasonable enantioselectivity (Scheme 17). As no detectable epimerization of trans-42 to cis-41 or formation of lactone 15 was observed during control experiments, trans-42 appears to be the real substrate of the transformation. The observations above have as corollary (Scheme 18) that a mixture of racemic epimers of the chlorocarboxylic acid (i.e., a mixture of 41 and 42) can still be deracemized with high ligand-dependent stereoselectivity. We termed this (to the best of our knowledge unprecedented) phenomenon diastereodivergent de-epimerization, wherein a racemic mixture of diastereoisomers with n stereocenters can be converted into each and every one out of the 2n (4, for n = 2) possible stereoisomers of the product.27 In order to assess the influence of the internal carboxylate moiety in this ligand-dependent process, esters 44 and 45 were prepared.27 In the presence of L2a, the cis-esters-44 were transformed into cis-disubstituted cyclobutenes 46a−d in good

Our initial efforts to understand this process centered on two aspects: (a) the role played by internal coordination from the pendant carboxylate in the putative allyl-palladium intermediate and (b) the overall contribution of strain-release which is intrinsic to the bicyclic framework of lactone 15. A 4halocyclobut-2-ene carboxylic acid akin to those presented above (cf. Scheme 10) emerged as an ideal candidate for our studies (Scheme 15). Indeed, (a) it has no marked ring strain release associated with the departure of the leaving group, and (b) the said leaving group is not contained in the final product. The opportunity to manipulate the carboxylate moiety and study the reactivity of ester and amide derivatives was also welcome.27 An efficient synthesis of racemic cis-41 and trans-42 chloro carboxylic acid precursors was developed using HCl.27,11b This eventually proved important, as the trans-isomer 42 offered the possibility to probe an electrophile with opposite stereochemical arrangement to that of lactone 15. We first probed the cis-isomer 41. In the event (Scheme 16), phosphoramidites L2a and L2b were highly cis-selective, affording substituted cyclobutenes with excellent diastereoand enantioselectivity for stabilized nucleophiles such as malonates and azlactones. Conversely, the use of the bidentate phosphine-oxazoline L3a enabled the preparation of the transisomer with a high degree of efficiency (Scheme 16). The renewed observation of diastereodivergence for the reactions 2450


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Accounts of Chemical Research Scheme 16. Diastereodivergent Process on the cis-Chloro Carboxylic Acid Substrate 41

imino fragment may result in a more significant contribution of cyclometalated η1-allyl intermediates, in which the carboxylate moiety of cis-41 and trans-42 can act as an additional ligand. Without this internal chelation the reactivity of L3a would be shut down. Intrigued by the mechanistic complexity of this system, we have sought structural characterization of intermediates.30 One such venture is depicted in Scheme 21, where equimolar amounts of chlorocarboxylic acid cis-41, a Pd(0) source and chiral ligand L3a were admixed. Characterization of the product of this experiment, 48, provided two surprising observations:30a (1) 48 was a σ-bound, monohapto palladium(II) allyl complex and not the π-allyl species that we postulated before (cf. Scheme 20). In hindsight, this should not have been so surprising, given the high ringstrain that would be associated with forced planarization on the four-membered ring which must take place in hypothetical πallyl isomer structures. (2) The combination of a chiral racemic substrate such as 41 with an enantiopure Pd-L complex would be expected to yield two diastereomeric species. Remarkably, one of those two possible diastereoisomeric complexes is formed preferentially (dr > 7:1). This implies that deracemization of cis-41 takes place during the very rapid oxidative addition step (full conversion within minutes at −30 °C). Such a rapid deracemization is unusual in palladium(II) chemistry.30a Notably, when sodium diethyl (2-methyl)malonate was added to complex 48, the trans-product 40d was obtained with 96% ee (Scheme 21). This remarkable selectivity from trans-complex 48 is not yet entirely understood; possible explanations involve invariably the isomerization of 48 to its cis-counterpart prior to nucleophilic displacement (vide infra).

yields and selectivities (Scheme 19). Surprisingly, however, L3a was not a competent ligand for this transformation. Conversely, L2b smoothly mediated the conversion of trans-esters-45 into trans-cyclobutenes 47a−d (Scheme 19), whereas ligand L3a led only to trace amounts of racemic products. This contrast between the behavior of the free carboxylic acids (41 and 42) and their esters (44 and 45) is noteworthy. The reactions of esters cis-44 and trans-45 both proceed with overall retention of configuration, and are examples of DYKAT (Dynamic Kinetic Asymmetric Transformation).28 The peculiar behavior observed with L3a shows that the −COOH moiety is actually a mandatory feature for activation of the Pd-L3a complex. Another important observation is that the ee values of cis products (i.e., those generated by the use of L2b) are virtually the same for identical products (compare cis-products in Schemes 16 and 17). This suggests that the intermediate involved in the enantiodetermining step is the same in both cases, at least when L2b is employed. Such a situation corresponds to a scenario characteristic of DYKAT, which is further supported by monitoring of the ee value during the course of the reaction.29 As isomerization of intermediate π-allyl complexes is usually possible by direct nucleophilic displacement of palladium from a metal-allyl complex by a second palladium(0) center, we speculated in 2012 that ligand L2b seemed to have a preference for the anti-π-allyl isomer when the carboxylate is present due to Coulombic repulsion (Scheme 20).27 As a consequence, when the corresponding esters are employed this Coulombic interaction is absent. The role played by the free carboxylate in the case of ligand L3a is less clear. Since L3a is a bidentate nonsymmetrical P,N-ligand, the weaker σ-donation by the 2451


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Accounts of Chemical Research Scheme 17. Diastereodivergent Process on the trans-Chloro Carboxylic Acid Substrate 21

Scheme 18. Highly Selective Diastereodivergent De-Epimerization of a Complex Racemic Mixture

in the deracemization phenomena described above remains a speculative proposal and will animate further investigations.30b

Upon standing at room temperature, complex 48 transforms into a new species identified as the palladium (E,E)-diene complex 49, arising via thermal conrotatory 4π-electrocyclic ring opening of trans-48. Unambiguous proof of structure for these and related complexes was obtained through X-ray analysis of an amide derivative 51 (Scheme 22).30a Interestingly, the distance between the chloride and the N−H hydrogen is 2.427 Å, implying a hydrogen bond between the two atoms. Whether such an interaction plays an important role

IV.ii. Use of Hard Nucleophiles

The large body of work developed for AAA with “soft” nucleophiles cannot be easily transposed to their “hard” counterparts. Indeed, the use of main-group organometallics such as Grignard reagents or organolithium derivatives is plagued by β-hydride elimination as competing mechanistic pathway. As a consequence, only few reports describe the use of 2452


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Accounts of Chemical Research Scheme 19. Introducing an Ester Substituent: Switching off Diastereodivergence

Scheme 20. Speculative Rationale Proposed in 2012 for the Diastereodivergent Behavior

Scheme 21. Stoichiometric Experiments: Selected Results with Phosphinooxazoline Ligands

“hard” nucleophiles in the context of AAA, and we have recently become involved in this area. Inspired by the work of Morken and co-workers,31 we investigated the behavior of our system in the presence of nonstabilized nucleophiles and achieved the catalytic, asymmetric regioselective allylation of lactone 15 with allylboronate esters.32 As shown in Scheme 23, ligand L3b allowed us to obtain good yields and high enantioselectivities. The use of branched allylboronates, however, was plagued by low diastereoselectivity

(cf. 52b−d) and the enantioselectivity was affected by steric bulk (cf 52e,f). Further studies on nonstabilized nucleophiles involved the use of dialkylzinc reagents, which are well-known to divert the standard reactivity of Pd-allyl complexes converting them into nucleophilic allyl moieties. This type of “Umpolung” chemistry constitutes a very successful class of reactions in its own right, with the Marshall-Tamaru propargylation as a prime example.33 Interested in such chemistry, we explored “Umpolung”-type 2453


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Accounts of Chemical Research Scheme 22. X-ray Structure of η1-Pd-Cyclobutyl Amide Intermediate 29

This ligand effect is particularly surprising given the rather close structural relationship of L2a and L1a. We investigated the transformation in the absence of electrophiles (i.e., using the mild aqueous workup as an ultimate source for the electrophile H+). An extensive screening of ligands was conducted on acid rac-41 and selected examples are depicted in Scheme 25. Surprisingly, it appears that only the chiral phosphoramidites L1/L4, bearing a TADDOL/TARTROL-backbone, can promote the alkyl transfer reaction. With all other ligands, only the product of formal halide reduction, cyclobut-2-enoic acid 58, was observed.34 Further optimization was carried out employing the ligand L1a, allowing the obtention of ethylated product 57a in high diastereo- and enantioselectivity. As portrayed in Scheme 26, both primary and secondary dialkylzinc nucleophiles can be added to the cyclobutyl framework with moderate to excellent selectivities and yields. Importantly, this chemistry was not limited to cyclobutenyl electrophiles as we showed that chiral racemic 6-membered ring allylic halides and esters also undergo substitution by diethyl zinc and concomitant deracemization in high yields and selectivities.34 IV.iii. Other Transformations

Ring-opening metathesis (ROM)/cross-metathesis (CM) appears to be a valuable synthetic strategy for the ring cleavage of azlactone 60 delivering the diastereomerically pure pyrrolidinone 61 (Scheme 27), structurally related to kainic acid.23 Oxidative cleavage of the cyclobutene ring is also a useful synthetic operation. As shown in Scheme 28, 62 (obtained by asymmetric allylic alkylation with diethyl zinc, cf. Scheme 26) readily undergoes ozonolysis with reductive workup to deliver an intermediate diol. This is followed by oxidative lactonization to generate lactone 63, the N-benzyl amide of isopilocarpic acid, in 56% yield.34

reactions of the cis-chlorocyclobutene ester rac-53 (Scheme 24). When this allylic chloride was exposed to the conditions shown in the presence of ligand L2a and benzaldehyde derivative 54, the “umpoled” nucleophilic addition product 55 was obtained in good yield. Surprisingly, when TADDOLderived ligand L1a was employed under exactly the same conditions, we observed the ethylated cyclobutene 56 as the only reaction product (Scheme 24).34

Scheme 23. Catalytic Deracemization of Lactone 15 Using Allylpinacol Boronates

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Accounts of Chemical Research Scheme 24. Catalytic Reactivity of Allylic Chlorides in the Presence of Diethyl Zinc: Umpolung versus Alkylation

Scheme 25. Ligand Screening for the Ethyl Transfer Reaction

Scheme 26. Catalytic Asymmetric Alkylation of a Cyclobutenyl Electrophile

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Accounts of Chemical Research Scheme 27. ROM-CM Generates a Polysubstituted Pyrrolidinone Structurally Analogous to Kainic Acid

Scientist in the Neuroscience Medicinal Chemistry department at Janssen Research & Development. Supaporn Niyomchon was born in KamphaengPhet, Thailand, in 1983. During her M.Sc., she worked under the supervision of Prof. Minoru Isobe (National Tsing Hua University, Taiwan). In 2012, she moved for her Ph.D. to the Max-Planck-Institut für Kohlenforschung (Germany) to join the group of Prof. Dr. N. Maulide. In late 2013 she moved with the Maulide group to the University of Vienna (Austria) and her Ph.D., completed in 2016, focused on Pd-catalyzed synthesis, heterocycle synthesis, and carbonyl olefination reactions. She is currently a Postdoctoral fellow at the Institut Curie (Paris), working with Dr. Raphael Rodriguez.

Scheme 28. Synthesis of (3S,4S)-N-Benzyl-isopilocarpic Amide

Nuno Maulide was born in Lisbon, Portugal in 1979. He graduated in Chemistry from the Instituto Superior Técnico in 2003 and obtained a Master’s degree at the Ecole Polytechnique in 2004 and a Ph.D. from the Université catholique de Louvain in 2007. Following a Postdoctoral stay at Stanford University, he began his independent research career as a Max-Planck Group Leader at the Max-PlanckInstitut für Kohlenforschung (Germany) before resuming his current position as Full Professor for Organic Synthesis at the University of Vienna (Austria) and ERC StG and CoG grantee. His research interests are broadly defined around the area of highly reactive intermediates and rearrangements.

V. CONCLUSION In this Account, we have retraced our explorations into the chemistry of cyclobutenes. Starting out with a simple design aimed to the synthesis of substituted four-membered ring derivatives, we serendipitously unveiled a unique diastereodivergent phenomenon in asymmetric catalysis. This has spurred many other researchers to enter the field of diastereodivergent asymmetric catalysis,26c and fully understanding its mechanistic implications is something bound to keep research teams busy for the foreseeable future. In the process, we also discovered a novel asymmetric allylic alkylation using dialkylzinc reagents. At the same time, realizing that the cyclobutenes we accessed were ideal platforms for the synthesis of butadienes opened up an entirely new field of investigations. This has led us to concise and expeditious preparations of polyene arrays that lend themselves particularly well to natural product synthesis. In particular, the ways in which stereodefined cyclobutenes can now be prepared combined with the faithful translation of stereochemical information that conrotation offer a plethora of possibilities for further development.

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ACKNOWLEDGMENTS We gratefully acknowledge all the co-workers that have participated in this project from its inception. N.M. is particularly grateful to the Max-Planck Society and the MaxPlanck-Institut für Kohlenforschung (Mülheim, Germany) where significant parts of this research were carried out, and the University of Vienna. N.M. expresses his personal appreciation for all co-workers who have been curious enough not to discard unwanted products and who, through their perseverance and ingenuity, led this project from one serendipitous observation to another.

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REFERENCES

(1) Natural products containing cyclobutanes: (a) Dembitsky, V. M. Naturally occurring bioactive Cyclobutane-containing (CBC) alkaloids in fungi, fungal endophytes and plants. Phytomedicine 2014, 21, 1559− 1581. (2) Synthesis of cyclobutanes and their applications in catalysis: (a) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Cyclobutanes in catalysis. Angew. Chem., Int. Ed. 2011, 50, 7740−7752. (b) Secci, F.; Frongia, A.; Piras, P. P. Stereocontrolled Synthesis and Functionalization of Cyclobutanes and Cyclobutanones. Molecules 2013, 18, 15541−15572. (c) Bach, T.; Hehn, J. P. Photochemical Reactions as Key Steps in Natural Product Synthesis. Angew. Chem., Int. Ed. 2011, 50, 1000−1045. (d) Iriondo-Alberdi, J.; Greaney, M. F. Photocycloaddition in Natural Product Synthesis. Eur. J. Org. Chem. 2007, 2007, 4801−4815. (e) Xu, Y.; Conner, M. L.; Brown, M. K. Cyclobutane and Cyclobutene Synthesis: Catalytic Enantioselective [2 + 2] Cycloadditions. Angew. Chem., Int. Ed. 2015, 54, 11918− 11928. (3) Applications of cyclobutanes in organic synthesis: (a) Namyslo, J. C.; Kaufmann, D. E. The Application of Cyclobutane Derivatives in Organic Synthesis. Chem. Rev. 2003, 103, 1485−1537. (b) Luparia, M.; Audisio, D.; Maulide, N. Palladium-Catalysed Synthesis of Stereodefined Cyclobutenes. Synlett 2011, 2011, 735−740. (4) Selected examples of cyclobutenone synthesis: (a) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser, R. L. [2 + 2] Cycloaddition of ketenes with ynamides. A general method for the synthesis of 3-aminocyclobutenone derivatives. Tetrahedron 2006, 62, 3815−3822. (b) Hamura, T.; Ibusuki, Y.; Sato, K.; Matsumoto, T.;

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Funding

European Research Council (ERC StG FLATOUT 278872), Deutsche Forschungsgemeinschaft (Grants MA 4861/3−1, 4− 1 and 4−2). Notes

The authors declare no competing financial interest. Biographies Antonio Misale was born in Messina, Italy, in 1982. During his M.Sc., he worked under the supervision of Prof. C. Scolastico (Milan University) and Prof. A. Chimirri. In 2007, he moved to UCL (London) where he acquired a CR-UK Ph.D. fellowship to work under the supervision of Prof. D. Thurston and Dr. G. Zinzalla. After a period working as scientist for Xention, he joined the group of Prof. Dr. N. Maulide (first at the Max-Planck-Institut für Kohlenforschung, Germany and since late 2013 at the University of Vienna, Austria) where his research broadly focused on the development of Pd- and Aucatalyzed enantioselective transformations. Currently he works as a 2456


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3a. For an interesting review on biosynthetic and biomimetic electrocyclisation, see: (e) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Biosynthetic and Biomimetic Electrocyclizations. Chem. Rev. 2005, 105, 4757−4778. (16) Fukui, K.; Yonezawa, T.; Shingu, H. A Molecular Orbital Theory of Reactivity in Aromatic Hydrocarbons. J. Chem. Phys. 1952, 20, 722− 725. (17) For torquoselectivity preferences during conrotation, see: (a) Kirmse, W.; Rondan, N. G.; Houk, K. N. Stereoselective substituent effects on conrotatory electrocyclic reactions of cyclobutenes. J. Am. Chem. Soc. 1984, 106, 7989−7991. (b) Niwayama, S.; Houk, K. N. Competition between ester and formyl groups for control of torquoselectivity in cyclobutene electrocyclic reactions. Tetrahedron Lett. 1992, 33, 883−886. (c) Niwayama, S. Interplay of Theory and Experiment: Reversal of the Torquoselectivity of the Electrocyclic Ring Opening of 3-Acetylcyclobutene by a Lewis Acid. J. Org. Chem. 1996, 61, 640−646. (d) Dolbier, W. R., Jr.; Koroniak, H.; Houk, K. N.; Sheu, C. M. Electronic Control of Stereoselectivities of Electrocyclic Reactions of Cyclobutenes: A Triumph of Theory in the Prediction of Organic Reactions. Acc. Chem. Res. 1996, 29, 471−477. (18) (a) Souris, C.; Luparia, M.; Frébault, F.; Audisio, D.; Farès, C.; Goddard, R.; Maulide, N. An Atom-Economical and Stereoselective Domino Synthesis of Functionalised Dienes. Chem. - Eur. J. 2013, 19, 6566−6570. For examples of cycloadditions with push−pull dienes, see: (b) Baldwin, J. E.; Claridge, T. D. W.; Culshaw, A. J.; Heupel, F. A.; Lee, V.; Spring, D. R.; Whitehead, R. C. Studies on the Biomimetic Synthesis of the Manzamine Alkaloids. Chem. - Eur. J. 1999, 5, 3154− 3161. For examples of Diels−Alder reactions with push−pull dienes, see: (c) Yoshimatsu, M.; Hibino, M.; Ishida, M.; Tanabe, G.; Muraoka, O. A Novel Push−Pull Diels−Alder Diene: Reactions of 4-Alkoxy- or 4-Phenylsulfenyl-5-chalcogene-substituted 1-Phenylpenta-2,4-dien-1one with Electron-Deficient Dienophiles. Chem. Pharm. Bull. 2002, 50, 1520−1524. (d) Branchadell, V.; Sodupe, M.; Ortuno, R. M.; Oliva, A.; Gomez-Pardo, D.; Guingant, A.; d’Angelo, J. Diels-Alder cycloadditions of electron-rich, electron-deficient, and push-pull dienes with cyclic dienophiles: high-pressure-induced reactions and theoretical calculations. J. Org. Chem. 1991, 56, 4135−4141. (e) Dalencon, S.; Youcef, R. A.; Pipelier, M.; Maisonneuve, V.; Dubreuil, D.; Huet, F.; Legoupy, S. Asymmetric Synthesis of Cyclohexene Nucleoside Analogues. J. Org. Chem. 2011, 76, 8059−8063. (19) Souris, C.; Frébault, F.; Audisio, D.; Farès, C.; Maulide, N. Direct Domino Synthesis of Azido-Dienoic Acids: Potential Linker Units. Synlett 2013, 24, 1286−1290. (20) (a) Souris, C.; Frébault, F.; Patel, A.; Audisio, D.; Houk, K. N.; Maulide, N. Stereoselective Synthesis of Dienyl-Carboxylate Building Blocks: Formal Synthesis of Inthomycin C. Org. Lett. 2013, 15, 3242− 3245. For completion of the synthesis, see, e.g., (b) Senapati, B. K.; Gao, L.; Lee, S. I.; Hwang, G.-S.; Ryu, D. H. Highly Enantioselective Mukaiyama Aldol Reactions Catalyzed by a Chiral Oxazaborolidinium Ion: Total Synthesis of (−)-Inthomycin C. Org. Lett. 2010, 12, 5088− 5091. (c) Webb, M. R.; Donald, C.; Taylor, R. J. K. A general route to the Streptomyces-derived inthomycin family: the first synthesis of (+)-inthomycin B. Tetrahedron Lett. 2006, 47, 549−552. (21) Souris, C.; Misale, A.; Chen, Y.; Luparia, M.; Maulide, N. From Stereodefined Cyclobutenes to Dienes: Total Syntheses of Ieodomycin D and the Southern Fragment of Macrolactin A. Org. Lett. 2015, 17, 4486−4489. (22) (a) Trost, B. M.; Crawley, M. L. Asymmetric Transition-MetalCatalyzed Allylic Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921−2943. (b) Trost, B. M. Asymmetric Allylic Alkylation, an Enabling Methodology. J. Org. Chem. 2004, 69, 5813− 5837. (c) Lu, Z.; Ma, S. M. Metal-Catalyzed Enantioselective Allylation in Asymmetric Synthesis. Angew. Chem., Int. Ed. 2008, 47, 258−297. (d) Helmchen, G.; Kazmaier, U.; Förster, S. Catalytic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2010; pp 497−641. (23) Luparia, M.; Oliveira, M. T.; Audisio, D.; Frébault, F.; Maulide, N. Catalytic Asymmetric Diastereodivergent Deracemization. Angew. Chem., Int. Ed. 2011, 50, 12631−12635. 2457


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Accounts of Chemical Research

(29) According to the theoretical treatment of Faber (ref 28b), one of the experimental distinctions between DKR and DYKAT lies on the ee values of starting material (eeSM) throughout the catalytic process. In a DKR, eeSM must be equal to 0 throughout the reaction. Conversely, in a DYKAT, eeSM ≠ 0 as observed in this specific transformation. See refs 27 and 28b. (30) (a) Audisio, D.; Gopakumar, G.; Xie, L.-G.; Alves, L. G.; Wirtz, C.; Martins, A. M.; Thiel, W.; Farès, C.; Maulide, N. PalladiumCatalyzed Allylic Substitution at Four-Membered-Ring Systems: Formation of η1-Allyl Complexes and Electrocyclic Ring Opening. Angew. Chem., Int. Ed. 2013, 52, 6313−6316. For additional structural investigations on these systems, see: (b) Xie, L.-G.; Bagutski, V.; Audisio, D.; Wolf, L.; Schmidts, V.; Hofmann, K.; Wirtz, C.; Thiel, W.; Thiele, C. M.; Maulide, N. Dynamic behaviour of monohaptoallylpalladium species: internal coordination as a driving force in allylic alkylation chemistry. Chem. Sci. 2015, 6, 5734−5739. (31) See, for example: (a) Zhang, P.; Brozek, L. A.; Morken, J. P. PdCatalyzed Enantioselective Allyl−Allyl Cross-Coupling. J. Am. Chem. Soc. 2010, 132, 10686−10688. (b) Brozek, L. A.; Ardolino, M. J.; Morken, J. P. Diastereocontrol in Asymmetric Allyl−Allyl CrossCoupling: Stereocontrolled Reaction of Prochiral Allylboronates with Prochiral Allyl Chlorides. J. Am. Chem. Soc. 2011, 133, 16778−16781. (32) Niyomchon, S.; Audisio, D.; Luparia, M.; Maulide, N. Regioand Enantioselective Cyclobutene Allylations. Org. Lett. 2013, 15, 2318−2321. (33) Marshall, J. A. Chiral Allylic and Allenic Metal Reagents for Organic Synthesis. J. Org. Chem. 2007, 72, 8153−8166. (34) (a) Misale, A.; Niyomchon, S.; Luparia, M.; Maulide, N. Asymmetric Palladium-Catalyzed Allylic Alkylation Using Dialkylzinc Reagents: A Remarkable Ligand Effect. Angew. Chem., Int. Ed. 2014, 53, 7068−7073. For a recent foray into related chemistry, see: (b) Oost, R.; Misale, A.; Maulide, N. Enantioconvergent Fukuyama Cross-Coupling of Racemic Benzylic Secondary Organozinc Reagents. Angew. Chem., Int. Ed. 2016, 55, 4587−4590.

(24) (a) Teller, H.; Flugge, S.; Goddard, R.; Furstner, A. Enantioselective Gold Catalysis: Opportunities Provided by Monodentate Phosphoramidite Ligands with an Acyclic TADDOL Backbone. Angew. Chem., Int. Ed. 2010, 49, 1949−1953. (b) Lam, H. W. TADDOL-Derived Phosphonites, Phosphites, and Phosphoramidites in Asymmetric Catalysis. Synthesis 2011, 2011, 2011−2043. (c) Klimczyk, S.; Misale, A.; Huang, X.; Maulide, N. Dimeric TADDOL Phosphoramidites in Asymmetric Catalysis: Domino Deracemization and Cyclopropanation of Sulfonium Ylides. Angew. Chem., Int. Ed. 2015, 54, 10365−10369. For a recent example outside the sphere of cyclobutene chemistry, see: (d) Oost, R.; Misale, A.; Maulide, N. Enantioconvergent Fukuyama Cross-Coupling of Racemic Benzylic Organozinc Reagents. Angew. Chem., Int. Ed. 2016, 55, 4587− 4590. (25) (a) von Matt, P.; Pfaltz, A. Chiral Phosphinoaryldihydrooxazoles as Ligands in Asymmetric Catalysis: Pd-Catalyzed Allylic Substitution. Angew. Chem., Int. Ed. Engl. 1993, 32, 566−568. (b) Sprinz, J.; Helmchen, G. Phosphinoaryl- and phosphinoalkyloxazolines as new chiral ligands for enantioselective catalysis: Very high enantioselectivity in palladium catalyzed allylic substitutions. Tetrahedron Lett. 1993, 34, 1769−1772. (c) Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Asymmetric palladium catalysed allylic substitution using phosphorus containing oxazoline ligands. Tetrahedron Lett. 1993, 34, 3149−3150. (26) For early examples of diastereodivergent deracemizations, see: (a) Tian, X.; Cassani, C.; Liu, Y.; Moran, A.; Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. Diastereodivergent Asymmetric SulfaMichael Additions of α-Branched Enones using a Single Chiral Organic Catalyst. J. Am. Chem. Soc. 2011, 133, 17934−17941. (b) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Enantio- and Diastereodivergent Dual Catalysis: α-Allylation of Branched Aldehydes. Science 2013, 340, 1065−1068. For a brief overview of diastereodivergence in catalysis, see: (c) Oliveira, M. T.; Luparia, M.; Audisio, D.; Maulide, N. Dual Catalysis Becomes Diastereodivergent. Angew. Chem., Int. Ed. 2013, 52, 13149−13152. (d) Oliveira, M. T.; Audisio, D.; Niyomchon, S.; Maulide, N. Diastereodivergent Processes in Palladium-Catalyzed Allylic Alkylation. ChemCatChem 2013, 5, 1239−1247. For recent examples, see: (e) Shi, S.-L.; Wong, Z. L.; Buchwald, S. L. Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols. Nature 2016, 532, 353−356. (f) Adams, C. S.; Grigg, R. D.; Schomaker, J. M. Complete stereodivergence in the synthesis of 2-amino-1,3-diols from allenes. Chem. Sci. 2014, 5, 3046−3056. (g) Mechler, M.; Peters, R. Diastereodivergent Asymmetric 1,4-addition of Oxindoles to Nitroolefins by using Polyfunctional Nickel-Hydrogen-Bond-Azolium Catalysts. Angew. Chem., Int. Ed. 2015, 54, 10303−10307. (h) Verrier, C.; Melchiorre, P. Diastereodivergent organocatalysis for the asymmetric synthesis of chiral annulated furans. Chem. Sci. 2015, 6, 4242−4246. (i) Rana, N. K.; Huang, H.; Zhao, J. C.-G. Highly Diastereodivergent synthesis of tetrasubstituted cyclohexanes catalysed by modularly designed organocatalysts. Angew. Chem., Int. Ed. 2014, 53, 7619−7623. Li, X.; Lu, M.; Dong, Y.; Wu, W.; Qian, Q.; Ye, J.; Dixon, D. Diastereodivergent organocatalytic asymmetric vinylogous Michael reactions. Nat. Commun. 2014, 5, 4479. (27) (a) Audisio, D.; Luparia, M.; Oliveira, M. T.; Klütt, D.; Maulide, N. Diastereodivergent De-epimerization in Catalytic Asymmetric Allylic Alkylation. Angew. Chem., Int. Ed. 2012, 51, 7314−7317 For a prior report on HCl cleavage of lactone 15, cf. ref 11b.. (28) For the definition of the concept of features of DYKAT, see: (a) Faber, K. Non-Sequential Processes for the Transformation of a Racemate into a Single Stereoisomeric Product: Proposal for Stereochemical Classification. Chem. - Eur. J. 2001, 7, 5004−5010. (b) Steinreiber, J.; Faber, K.; Griengl, H. De-racemization of Enantiomers versus De-epimerization of DiastereomersClassification of Dynamic Kinetic Asymmetric Transformations (DYKAT). Chem. - Eur. J. 2008, 14, 8060−8072. (c) Pellissier, H. Recent developments in dynamic kinetic resolution. Tetrahedron 2011, 67, 3769−3802. 2458


Cyclobutenes - American Chemical Society

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