Branching Out: Rhodium-Catalyzed Allylation with Alkynes and

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Branching Out: Rhodium-Catalyzed Allylation with Alkynes and Allenes Philipp Koschker and Bernhard Breit* Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, 79104 Freiburg i. Brsg., Germany CONSPECTUS: We present a new and efficient strategy for the atom-economic transformation of both alkynes and allenes to allylic functionalized structures via a Rh-catalyzed isomerization/addition reaction which has been developed in our working group. Our methodology thus grants access to an important structural class valued in modern organic chemistry for both its versatility for further functionalization and the potential for asymmetric synthesis with the construction of a new stereogenic center. This new methodology, inspired by mechanistic investigations by Werner in the late 1980s and based on preliminary work by Yamamoto and Trost, offers an attractive alternative to other established methods for allylic functionalization such as allylic substitution or allylic oxidation. The main advantage of our methodology consists of the inherent atom economy in comparison to allylic oxidation or substitution, which both produce stoichiometric amounts of waste and, in case of the substitution reaction, require prefunctionalization of the starting material. Starting out with the discovery of a highly branched-selective coupling reaction of carboxylic acids with terminal alkynes using a Rh(I)/DPEphos complex as the catalyst system, over the past 5 years we were able to continuously expand upon this chemistry, introducing various (pro)nucleophiles for the selective C−O, C−S, C−N, and C−C functionalization of both alkynes and the double-bond isomeric allenes by choosing the appropriate rhodium/bidentate phosphine catalyst. Thus, valuable compounds such as branched allylic ethers, sulfones, amines, or γ,δ-unsaturated ketones were successfully synthesized in high yields and with a broad substrate scope. Beyond the branched selectivity inherent to rhodium, many of the presented methodologies display additional degrees of selectivity in regard to regio-, diastereo-, and enantioselective transformations, with one example even proceeding via a dynamic kinetic resolution. Many advances presented in this account were driven by detailed mechanistic investigations including DFT-calculations, ESI-MS and in situ IR experiments and enabled the application of our chemistry for target-oriented syntheses demonstrated by several examples shown herein. In general, this research topic has matured over the past years into a viable option when synthesizing chiral compounds, from small molecules such as quercus lactones to complex target structures such as Homolargazole or Clavosolide A. This demonstrates the importance and utility of these coupling reactions, especially considering the ease with which carbon−heteroatom bonds can be built stereoselectively, with many of the product classes displaying motifs common in modern APIs.

1. INTRODUCTION The transformation of simple and readily accessible starting materials to branched allylic derivatives is an important research topic in modern organic synthesis due to both the versatility of the allylic moiety for further functionalization and the potential for asymmetric synthesis with the construction of a new stereogenic center.1 Over the past decades, significant progress toward this goal has been achieved utilizing transition metal catalysis, in particular in regard to allylic substitution2 and allylic C−H oxidation3 chemistry (Scheme 1a). However, these methods suffer from drawbacks such as the required preinstallation of a leaving group or the use of stoichiometric amounts of oxidant, respectively. An alternative, atomeconomic pathway toward linear allylic products under Pdcatalysis, had been pioneered by Trost and Yamamoto in the late 1990s and early 2000s utilizing mostly terminal allenes or internal Me-substituted alkynes (Scheme 1b),4 with even one case for higher substituted internal alkynes.5 More examples using other metals have been reported over the following years.6,7 © XXXX American Chemical Society

More recently, our group has developed a new route toward the more valuable branched motif via a rhodium-catalyzed coupling of easily accessible alkynes or the double bond isomeric allenes with pronucleophiles (Scheme 1c). Inspiration for this new transformation came from the literature-known fact that alkynes bearing an α-C−H bond can be isomerized to the corresponding allenes, making them suitable precursors for allylic functionalization. In 1987, Werner et al. reported on the stoichiometric reaction of 2-butyne with a rhodium hydride complex, which was formed under Brønsted acidic conditions.8 The detection of a Rh π-allyl complex from this mixture led to the proposal of a transformation pathway involving the formation of the isomeric 1,2-butadiene complex as the detectable key intermediate (Scheme 2). The stoichiometric reaction indicated the possibility of using alkynes to form allylic intermediates, which is essential for catalysis. With the formation of the π-allyl complex a potential Received: May 25, 2016

A

DOI: 10.1021/acs.accounts.6b00252 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research Scheme 1a

Table 1. Rh-Catalyzed Allylation of Benzoic Acid with 1Octyne

ligand

yield (%)

B:AM-Z:M

DPPMP Xantphos DPPF DPEphos

90 68 70 80

0:94:3 (:AM-E) 0:0:100 65:32:3 94:0:6

partners and thus represented the first general branchedselective addition of carboxylic acids to alkynes in literature. Furthermore, transferring the successfully developed chemistry to an intramolecular variant enabled the synthesis of 14− 23-membered vinylic (macro)lactones (Table 2),12 which are

a

(a) Allylic substitution and allylic oxidation. (b) Pd-catalyzed allylation with alkynes and allenes. (c) Rh-catalyzed allylation with alkynes and allenes.

Scheme 2. Stoichiometric Reaction of 2-Butyne with a Rhodium-Complex and Brønsted Acid

Table 2. Examples of the Rh-Catalyzed Macrolactonization with ω-Alkynylic Acids

catalytic transformation enters a reaction pathway similar to the aforementioned allylic substitution. Thus, based on the work of the Evans group, where rhodium-catalyzed allylic substitution reactions have shown high levels of regioselectivity toward the branched allylic compounds,9 we imagined that rhodium might enable the nucleophilic addition to alkynes or their isomeric allene counterparts in order to obtain various branched allylic functionalized compounds.10

2. C−O BOND FORMATION VIA RHODIUM-CATALYZED ALLYLATION OF OXYGEN PRONUCLEOPHILES Based on this hypothesis, our investigations started out with the coupling of 1-octyne with benzoic acid using [Rh(COD)Cl]2 as the catalyst precursor. During a ligand screening, it was found that bidentate ligands catalyzed the desired reaction most efficiently, leading to high conversions (Table 1).11 The small bite-angle ligand DPPMP and the rigid large biteangle ligand Xantphos gave the anti-Markovnikov-selective (AM-Z) and Markovnikov-selective (M) addition toward the vinyl ester products, respectively. However, DPEphos with a medium bite-angle formed the branched allylic ester in 80% isolated yield and 94:6 branched selectivity, with the only observed byproduct being the Markovnikov ester. The reaction displayed high functional group tolerance for both coupling

generally regarded as challenging synthetic targets. As was to be expected, the yields drop significantly for medium-sized rings. The method utilizing similar conditions to the intermolecular coupling does not require any special reaction conditions such as high dilution via syringe pump addition in order to prevent the formation of dimers and higher oligomers. Several functionalized lactones were synthesized using this methodology and a slight substrate controlled diastereoselectivity of 1.5:1 to 2:1 was observed for chiral starting materials. Detailed DFT calculations for the Rh/DPEphos catalyst system and extensive experimental investigations including ESIMS and in situ IR measurements were undertaken.13 Thus, the initially proposed mechanism for the coupling of carboxylic acids with terminal alkynes was revised to a certain degree, now granting detailed insight into the way this coupling reaction proceeds mechanistically (Scheme 3). B


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therefore better selectivities and improved functional group compatibility. A similar allene coupling reaction using an achiral iridium catalyst had been reported by Krische, demonstrating the potential of this methodology.14 Indeed, by applying a rhodium/(R,R)-DIOP catalyst system, the coupling of terminal allenes with carboxylic acids furnished the corresponding branched allylic esters as the exclusive product, with good to excellent enantioselectivities of up to 96% ee and an even broader functional group tolerance when performing the reaction at temperatures as low as −3 °C (Table 3).15 It is noteworthy that also 1,1-disubstituted terminal allenes were tolerated, allowing for the asymmetric synthesis of the esters of tertiary alcohols.

Scheme 3. Mechanism for the Rh-Catalyzed Coupling of Carboxylic Acids with Terminal Alkynes

Table 3. Examples of the Asymmetric Allylation of Carboxylic Acids with Terminal Allenes

The rhodium precursor [Rh(COD)Cl]2 reacts with DPEphos to form the catalyst precursor [DPEphosRhCl]2 (A), which is in equilibrium with monomeric DPEphosRhCl (A′). Coordination of the terminal alkyne B generates the Rh complex C, which then forms intermediate D upon coordination of the carboxylic acid. An H-bonding between the terminal sp-hybridized carbon and the OH group of the acid facilitates the intramolecular protonation, leading to the Rh-vinyl species E. Unlike the proposed mechanism for palladium-catalyzed hydro-oxycarbonylations, the computed energies disfavor the process via hydrometalation of the alkyne. A subsequent reversible β-H elimination of E forms the allene rhodium-hydride intermediate F. Next, hydrometalation occurs to give the π-allyl rhodium species G, which is in equilibrium with the more stable σ-allyl complex H. This complex was identified as the turnover-determining intermediate and characterized by NMR spectroscopy and X-ray analysis. In the final step, reductive elimination of G via the transition state I furnishes the branched product J, reforming the catalyst. In agreement with the proposal by Werner, the mechanism shows the formation of a terminal allene coordinated to the Rh complex F as an essential step in the catalytic cycle. Both the intra- and intermolecular methodologies starting from terminal alkynes utilized an achiral ligand and therefore yielded racemic mixtures of the desired products. The search for a suitable chiral ligand for this transformation was rather difficult, since the catalyst system not only has to give good enantioselectivities for the addition step to the allene intermediate, but also be potent for the initial alkyne-allene isomerization. We speculated that a direct coupling reaction of carboxylic acids with terminal allenes should follow the same path and yield branched allylic esters. In this case, the catalyst only has to catalyze the addition, thus facilitating the search for a suitable ligand. Further expected advantages for this coupling were based on the increased reactivity of allenes in comparison to their alkyne counterparts, allowing for milder reaction conditions and

After the development of the enantioselective allene coupling, we turned our attention back to the asymmetric alkyne coupling. Based on the successfully applied chiral ligand (R,R)-DIOP, extensive ligand synthesis and screening were performed, resulting in the development of the enantioselective alkyne coupling under mild conditions at 20 °C, utilizing (R,R)Cp-DIOP as the ligand of choice (Table 4).16 The conditions for the asymmetric coupling displayed high functional group tolerance. With an average of 87% ee, this reaction represents the first literature-known example of an asymmetric hydro-oxycarbonylation of terminal alkynes with carboxylic acids, leading directly to attractive branched allylic esters. Furthermore, the reaction was scalable to be performed on a 5.0 mmol scale, yielding 1.0 g of the desired benzoic ester without significant influence on the selectivities. Very recently, we were also able to couple various alcohols enantioselectively with either terminal allenes or methylsubstituted alkynes (Table 5),17 which are substrates previously used by Yamamoto.4 This was made possible by the addition of a catalytic amount of a phosphoric acid ester. C


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product. It was suggested that the difficulty lies in the alkyne isomerization or the rhodium-allyl formation. The reduced acidity of other Nu-H substrates might hinder the intramolecular protonation step of the alkyne in the catalytic cycle for the carboxylic acid coupling (see Scheme 3). Therefore, inspired by this mechanistic analysis for the coupling of terminal alkynes with carboxylic acids, we proposed an acid-promoted process consisting of (1) the in situ formation of a rhodium-allyl intermediate in the presence of a carboxylic acid and (2) the attack of a pronucleophile on the rhodium-allyl intermediate (Scheme 4).

Table 4. Examples of the Asymmetric Allylation of Carboxylic Acids with Terminal Alkynes

Scheme 4. Proposed Rh-/Carboxylic Acid Catalyzed Allylation of Pronuclephiles with Terminal Alkynes

To prove this concept, sulfur-containing coupling partners were used as pronucleophiles due to the similarities between oxygen and sulfur. Initial reactions using highly nucleophilic sulfonyl anions via the in situ decomposition of the corresponding sulfonyl hydrazide, which had previously been used in literature for the addition to allenes,18 indicated that benzoic acid does indeed significantly increase the reaction yield from 10% to 58% (Table 6). In this case, the

Table 5. Examples of the Asymmetric Allylation of Alcohols with Terminal Allenes and Internal Alkynes

Table 6. Proof of Concept: Benzoic Acid as a Brønsted Acid Promoter

stoichiometric amount of benzoic acid serves as the proton source, while the nucleophilic attack of the sulfonyl anion is faster than the reductive elimination toward the carboxylic acid ester. After optimization of the reaction conditions, the scope for this coupling indicated that both aliphatic and aromatic substituted propargylic alkynes were compatible (Table 7).19 Several functional groups, including free hydroxyl, were well tolerated, granting access to a range of branched allylic sulfones. In order to further broaden the scope of sulfur nucleophiles, we focused on allenes as the more reactive coupling partner, where a simple addition step suffices in order to form the rhodium allyl complex. Similar to the coupling of carboxylic acids, allene coupling reactions allow for milder reaction conditions, which in turn lead to a wider range of pronucleophiles with concomitant increased chances of developing an asymmetric reaction. Indeed, both aromatic and aliphatic thiols could be coupled with terminal allenes enantioselectively using (R)-Difluorphos and (R)-3,4,5-MeO-MeOBIPHEP, respectively (Table 8).20 For aliphatic thiols, this gave access to very valuable branched allylic thioethers in high enantioselectivities. However, the aromatic thiols showed a tendency to isomerize to achiral

3. C−S BOND FORMATION VIA RHODIUM-CATALYZED ALLYLATION OF SULFUR PRONUCLEOPHILES The successful development of the C−O coupling chemistry inspired further investigations into the nature of pronucleophiles applicable for this reaction. Unfortunately, during our studies we found that the coupling of terminal alkynes with other pronucleophiles was much more difficult than was the case for carboxylic acids. Thus, intensive efforts on replacing carboxylic acids mostly led to no reaction or only traces of D


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products after their synthesis. Therefore, the aromatic thioethers were further oxidized in situ to the corresponding enantioenriched branched allylic sulfones, which are valuable building blocks for organic synthesis in their own regard. This chemistry could be successfully expanded to the less reactive internal 1,3-disubstituted allenes employing a modified rhodium catalyst (Table 9).21 The corresponding allylic sulfones were obtained in high Z-selectivity.

Table 7. Examples of the Allylation of Sulfonyl Hydrazides with Terminal Alkynes

Table 9. Examples of the Allylation of Thiols with Internal Allenes

Table 8. Examples of the Asymmetric Allylation of Thiols with Terminal Allenes

For unsymmetrically 1,3-disubstituted allenes in some cases good regioselectivities could be noted. Starting from racemic 1,3-disubstituted allenes and employing a chiral rhodium /(S,S)-Me-DuPhos catalyst the corresponding allylic sulfones could be accessed in high enantioselectivities and excellent Z/E selectivities (Table 10). Interestingly, this reaction proceeds as a dynamic kinetic resolution.

4. C−N BOND FORMATION VIA RHODIUM-CATALYZED ALLYLATION OF NITROGEN PRONUCLEOPHILES The coupling reaction utilizing N-pronucleophiles has been most thoroughly investigated due to the importance of nitrogen-containing building blocks and N-hetereocycles for modern drug research.22 Additionally, the increased nucleophilicity of nitrogen compared to oxygen promises the potential development of efficient methodologies. Our initial investigations focused on the C−N coupling toward simple allylic amines. By exchanging the achiral DPEphos used for the C−O coupling with the chiral ferrocene ligand Josiphos and additionally adding a polar-protic component such as EtOH to the solvent, we were able to successfully couple amines with allenes in high enantioselectivities (Table 11).23 Several functional groups on the allene coupling partner were well tolerated. However, while a wide variety of differently substituted aniline derivatives worked for this coupling, aliphatic amines were not reactive at all. More recently, a closely related substrate structure, aryl hydrazines, was successfully coupled at the N1 position, E


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Accounts of Chemical Research Table 10. Examples of the Asymmetric Allylation of Thiols with Internal Allenes

Table 12. Examples of the Asymmetric Allylation of Aryl Hydrazines with Terminal Allenes

Table 11. Examples of the Asymmetric Allylation of Anilines with Terminal Allenes

enantioselectivity of up to 98% ee (Table 13).26 For this methodology, using symmetrical imidazoles as substrates eliminates the potential issue of N1- vs N2-selectivity, thus leading to an exclusive coupling product. In regards to functional group tolerance, a wide variety of substituents on both the imidazole ring and the allene coupling partner was Table 13. Examples of the Asymmetric Allylation of Imidazoles with Terminal Allenes

utilizing a catalyst system based on the axial-chiral ligands (S)DTBM-Segphos or (S)-DTBM-BINAP (Table 12).24 The resulting allylic hydrazines were accessed in good yields, high N1-selectivity as well as enantioselectivities and lend themselves to the formation of enantioenriched indoles via a Fischer indole synthesis.25 Thus, a wide selection of functionalized indoles was made available in a one-pot two-step procedure. Since no direct coupling of indoles with allenes has been reported so far, this represents the first asymmetric route toward branched N-allylic indoles via Rh-catalyzed C−N coupling. Furthermore, we focused our attention on the direct synthesis of N-heterocyclic compounds. By applying either the same or a closely related ligand as for the synthesis of allylic anilines, the coupling of benzimidazoles and electron-poor imidazole derivatives was accomplished with high levels of F


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Accounts of Chemical Research tolerated, such as protected and free alcohols, esters, halides or protected amines. Again proving the efficiency of ferrocene-based ligands, the enantioselective allylation of pyrazoles was recently reported by our group (Table 14).27 However, this time by choosing the

Table 15. Examples of the Regio- and Enantioselective Allylation of Pyrazoles with Terminal Allenes

Table 14. Examples of the Regio- and Enantioselective Allylation of Pyrazoles with Terminal Allenes

appropriate catalyst system, we were able to apply unsymmetrical substrates with all products being formed in high N1selectivities of up to >99:1. This was also the first time that the addition of substoichiometric amounts of PPTS as an additional proton source led to improved results. The utility of this structural class will be shown further below with the synthesis of the commercial anticancer drug Ruxolitinib (see section 6). The coupling reaction with pyrazoles could be realized also for internal, methyl-substituted alkynes as reaction partners (Table 15).28 Such internal alkynes have also been used in 2015 by Dong for the C−N coupling with indolines.29 Using the chiral JoSPOphos ligand, a large variety of substituted pyrazoles and alkynes could be coupled in moderate to high enantioselectivities. However, this chemistry is so far limited to alkyne substrates where the alkyne functionality is in conjugation with an additional π-system. When moving to N-heterocyclic compounds containing more nitrogen such as benzotriazoles, our chemistry once again proved to be potent for the branched selective coupling (Table 16).30 This method improved upon the issue of regioselectivity mentioned in the context of the imidazole and pyrazole couplings even further by not only allowing for an N-selective coupling, but also accessing both N1 and N2 coupling products regiodivergently, depending on the ligand choice. Interestingly, this methodology represents the first N2-selective alkylation of benzotriazoles, to access the less aromatic N2-allylation products. Additionally, 1,1-disubstituted allenes could also be functionalized efficiently. Even tetrazoles are suitable substrates for the C−N coupling reaction. Again, disubstituted allenes can serve as substrates (Table 17).31 Utilizing another ferrocene ligand for the catalyst system gave the branched allylic products exclusively and in high enantioselectivities. Moving to 6-membered N-heterocycles, the use of a Rh/(R)DTBM-MeOBIPHEP catalyst also allowed for the coupling of 2-pyridones (Table 18).32 An interesting aspect of this

Table 16. Examples of the Regiodivergent Allylation of Benzotriazoles with Terminal Allenes

chemistry is the selectivity in regard to the two possible positions at which the coupling could occur, yielding either the C−N or the C−O coupling product. The actually observed products, which were obtained in good yields and high enantioselectivities, were the result of the C−N bond formation. G


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Accounts of Chemical Research Table 17. Examples of the Asymmetric Allylation of Tetrazoles with Terminal Allenes

Scheme 5. Proposed Mechanism for the Allylation of 2Pyridones with Terminal Allenes

Scheme 6. Synthesis of Primary Allylic Amines via Addition of Benzophenone Imine

Table 18. Examples of the Asymmetric Allylation of 2Pyridones with Terminal Allenes

Table 19. Examples of the Asymmetric Allylation of Benzophenone Imine with Terminal Allenes

The observed selectivity is a case of kinetic vs thermodynamic reaction control, which was demonstrated by the fact that after short reaction times the N/O selectivity is changed in favor of the C−O coupling product. This was further supported by DFT calculations, showing that the product of the C−N bond formation is indeed several kcal/mol more stable. Therefore, the catalytic cycle reflects the C−O product being formed quickly but reversibly, thus being converted to the more stable C−N product over longer reaction times (Scheme 5). Most recently, the initial challenge of successfully synthesizing primary allylic amines was overcome by our working group.33 Since the direct addition of ammonia to allenes was so far not possible, the alternative route via coupling of benzophenone imine as a synthesis equivalent was investigated (Scheme 6). Thus, a wide range of functionalized primary amines was synthesized in high yields and excellent enantioselectivities (Table 19). By changing the conditions of the second step of

the one-pot reaction, not only the free amines were accessible, but also different protected amines or amides could be received. These allylic amines could be easily transformed into valuable α- and β-amino acids, respectively.

5. C−C BOND FORMATION VIA RHODIUM-CATALYZED ALLYLATION OF CARBON PRONUCLEOPHILES Utilizing the allylation reaction for the formation of C−C bonds has been challenging so far.34 The problem appears to be the lack of C−H acidity, which is necessary in order to allow for the initial oxidative addition step in the catalytic cycle. H


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Instead of allenes, internal methyl-substituted alkynes could also be applied as initial substrates for this coupling reaction. Here a DIOP/rhodium catalyst was most reactive. (Table 21).36

Therefore, only a limited number of methodologies restricted to methylene active reagents have been developed so far. The first successfully applied substrate class for C−C bond formation was β-ketoacids. Applying a rhodium/dppf catalyst, the resulting γ,δ-unsaturated ketones could be isolated in good to excellent yields as the exclusive products (Table 20).35 These mild and neutral reaction conditions allowed for the preparation of a wide range of γ,δ-unsaturated ketones which are valuable synthetic building blocks.

Table 21. Examples of the Allylation of β-Ketoacids with Internal Alkynes

Table 20. Examples of the Decarboxylative Allylation of βKetoacids with Terminal Allenes

Under rather mild reaction conditions, a wide range of different branched allylated ketones could be isolated in good yields. Unfortunately, the enantioselectivity achieved in this case was still too low for a general asymmetric methodology. However, the fact that an enantiomeric excess could be observed serves as a proof of principle for the development of an enantioselective variant in the future. Simultaneously with our work, a rhodium/DPEphos catalyst was discovered to catalyze the same transformation. However, elevated temperatures were needed to achieve satisfying reactivity and yields.37 The first carbon−carbon bond formation using readily available terminal alkynes as coupling partners could be realized for 1,3-diketones. In this case, again a carboxylic acid cocatalyst was essential (Table 22).38 The role of the carboxylic acid is presumably again the formation of the intermediate rhodium allyl complex. Using an electron-poor carboxylic acid lowers its nucleophilicity and therefore ensures that the more potent carbon-nucleophile attacks the intermediate Rh allyl complex, leading exclusively to the desired product. The substrate scope in regard to both coupling partners, the 1,3-diketones and the alkyne, respectively, is relatively broad and excellent yields up to 99% were observed.

The proposed mechanism for this coupling is depicted in Scheme 7. The aforementioned problem of initiating the catalytic cycle is avoided by the carboxylic acid functionality serving as the proton source to form the Rh allyl complex B. A nucleophilic attack on this complex leads to the intermediate C. A rhodium-catalyzed decarboxylation releases the final product. Scheme 7. Mechanism for the Decarboxylative Allylation of β-Ketoacids with Terminal Allenes

6. SYNTHETIC APPLICATIONS The yardstick of new synthetic methodology is its application in target-oriented synthesis. New reactions offer new opportunities in synthesis. Thus, we embarked on several synthesis applications of the atom-economic addition of pronucleophiles to allenes and alkynes to evaluate their potential in organic synthesis. A simple three-step protecting group free synthesis of the naturally occurring quercus lactones could be achieved with the enantioselective coupling of terminal alkynes with cinnamic acid as the key step (Scheme 8).16 The remaining steps were a ring-closing metathesis followed by a diastereoselective cuprate addition. Both cognac and whisky lactone could be isolated in an overall yield of about 65% over three steps with 90−91% ee. These lactones, formed during the aging process of alcoholic I


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Accounts of Chemical Research Table 22. Examples of the Allylation of 1,3-Diketones with Terminal Alkynes

Scheme 9. Synthesis of Homolargazole Using the Asymmetric Hydro-Oxycarbonylation of Terminal Allenes

Scheme 10. Synthesis of Helicascolides Using the Asymmetric Hydro-Oxycarbonylation of Terminal Allenes Scheme 8. Synthesis of γ-Butyro Lactones Using the Asymmetric Hydro-Oxycarbonylation of Terminal Alkynes

formed initially can be separated and transformed separately to helicascolide A and B, respectively. After oxidation both those products lead to the same structure, helicascolide C. This intramolecular ring closure offers an attractive alternative to classic lactonization reactions, which usually proceed via the addition of an already installed alcohol functionality to an activated carboxylic acid. Additionally, the synthesis for the macrocyclic natural product Clavosolide A was also successfully completed recently, using an ω-allenylic carboxylic acid for a head-to-tail dimerization (Scheme 11).44 Again high diastereoselectivity was achieved and no protecting groups were necessary. Additional applications in total synthesis were developed for the C−N coupling reactions. One example is the five-step synthesis of (R)-ruxolitinib, which is an efficient JAK 1/2 kinase inhibitor and has shown antitumor activity.45 It contains a pyrazole ring and a defined stereocenter that can be built up asymmetrically via the allylation of pyrazoles (Scheme 12).27 This coupling is the first step of the synthesis, establishing the stereocenter with 90% ee early on, with a late-stage recrystallization leading to a significantly improved 98% ee. Using this synthetic route, 840 mg of pure Ruxolitinib were isolated. Another example of the Rh-catalyzed C−N coupling being the key step for the construction of natural products is shown

beverages in oak casks, are commonly used in the perfume and food additive industry.39 A more elaborate application for the C−O coupling is shown below with the synthesis of homolargazole (Scheme 9).40 Homolargazole is an analog to the marine natural product largazole, which has been isolated from cyanobacteria and has shown antitumor activity.41 The synthesis was completed with the longest linear sequence being 9 steps and with an overall yield of 13%. The allylation of N-protected (S)-valine with a terminal allene as the key step demonstrated complete catalyst control in regard to the absolute configuration of the newly installed stereocenter. By using either (R,R)- or (S,S)-DIOP and appropriate protecting groups, which are both commercially available, either of the two possible diastereomers was accessible with 12:1 or 20:1 dr, respectively. Very recently, an intramolecular coupling toward sixmembered lactones was utilized for natural product synthesis (Scheme 10).42 This synthesis of three different helicascolides43 is the first hydro-oxycarbonylation with our catalyst system to be highly diastereoselective. The two diastereomers which are J


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oxidation and methylation lead to the ester intermediate, which can be readily transferred to numerous amino heterocycles, many of which show biological activitiy.47

Scheme 11. Synthesis of Clavosolide A Using the Asymmetric Hydro-Oxycarbonylation of Terminal Allenes

7. SUMMARY In conclusion, over the last 5 years, we have developed a wide range of rhodium-catalyzed, branched-selective allylation reactions starting from either alkynes or the isomeric allenes, both terminal and internal. By choosing a suitable ligand for the catalytic system and applying appropriate reaction conditions, we were able to couple numerous pronucleophiles, allowing for C−O, C−S, C−N, and C−C bond formation. Many of these methodologies display additional degrees of selectivity. Particularly, many methods have been reported asymmetrically or show a high degree of regioselectivity when more than one nucleophilic functionality is present. So far, this development has led to significant advances in the field of TM-catalyzed allylation reactions, which had previously only been known to a limited degree.4 Nowadays, the growing maturity of this particular field of research makes hydrofunctionalizations of alkynes and allenes a worthy, atomeconomic alternative to previously established methods such as allylic substitution or oxidation reactions. This was also shown by several applications in target-oriented synthesis. Nevertheless, a large potential has not been touched so far, with many more pronucleophiles, internal alkyne and allene substrates and applications in total synthesis possible.

Scheme 12. Synthesis of Ruxolitinib Using the Asymmetric Coupling of Pyrazoles with Terminal Allenes

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Philipp Koschker studied chemistry in Freiburg, Germany, where he earned his Ph.D. in 2015 in the working group of Prof. Bernhard Breit. His research focus during his Ph.D. was the development of enantioselective C−O coupling reactions with both allenes and alkynes.

below with the formal synthesis of glucokinase activators in three steps from 4-cyclopentyl-1,2-butadiene and 4-methylsulfonyl-2-pyridone (Scheme 13).46 Again, the first step establishes the stereocenter with 94% ee and also leads to the product in almost quantitative yield. Subsequent Pinnick

Bernhard Breit studied chemistry at the University of Kaiserslautern, Germany, where he obtained his Ph.D. in 1993 with Prof. Regitz. After postdoctoral research with Prof. Trost at Stanford University he completed his habilitation in 1998 in Marburg with Prof. R. W. Hoffmann. In 1999, he was appointed as an Associated Professor at the University of Heidelberg. Since 2001, he has been a Full Professor of Organic Chemistry at the Albert-Ludwigs-University Freiburg. His research interests include the development of new concepts and methods for organic synthesis.

Scheme 13. Formal Synthesis of Glucokinase Activators Using the Coupling of 2-Pyridones with Terminal Allenes

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ACKNOWLEDGMENTS This work was supported by the DFG, the International Research Training Group “Catalysts and Catalytic Reactions for Organic Synthesis” (IRTG 1038), the Fonds der Chemischen Industrie, and the Krupp Foundation.

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REFERENCES

(1) Reviews on branched allylic derivatives: (a) Lumbroso, A.; Cooke, M. L.; Breit, B. Catalytic Asymmetric Synthesis of Allylic Alcohols and Derivatives and their Applications in Organic Synthesis. Angew. Chem., Int. Ed. 2013, 52, 1890−1932. (b) Hartwig, J. F.; Stanley, L. M. Mechanistically Driven Development of Iridium

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Branching Out: Rhodium-Catalyzed Allylation with Alkynes and

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