Application of Metathesis Protocols to the Stereocontrolled Synthesis of some Functionalized β‐Amino Esters and Azaheterocycles

In this account our aim was to give an insight into the application of metathesis protocols (ROM, RCM, RCEYM, CM, RRM) for the synthesis of various azaheterocyclic frameworks. Due to the high biological potential and importance in peptide chemistry and drug design of β‐amino acids our intention is to give a highlight on the synthetic procedures and transformation of these class of compounds with the above‐mentioned metathesis strategies with emphasis on selectivity, stereocontrol, substrate‐directing effect or functional group tolerance.


A Brief Overview to Olefin Metathesis
[62][63][64][65][66][67][68] The accepted mechanism for the olefin metathesis was proposed by Chauvin in 1971 (Scheme 2). [48]The process starts with a [2 + 2] cycloaddition between the metal alkylidene and an olefin, then the formed metallacyclobutane intermediate undergoes cycloreversion.The resulting new metal-alkylidene then repeat the previous process with another olefin.50][51][52][53] The properties of the metal alkylidene catalyst are very important.[52][53][54][55][56] Currently, two types of metathesis catalysts are commonly used, which have somewhat complementary properties.The molybdenum-based Schrock catalysts are highly active, but (like the majority of other metathesis catalysts) they are sensitive to moisture or air, and incompatible with many functional groups (however, they tolerate amines and phosphines which are incompatible with ruthenium-based catalysts). [50,51,53]In contrast, the ruthenium-based Grubbs and Hoveyda-Grubbs catalysts are easy to handle (because they are reasonably oxygen and moisture resistant), have good functional tolerance, and somewhat lower activity. [50,51,53]In addition, ruthenium-based catalysts are easily accessible, which contributed crucially to the current importance of olefin metathesis processes.Figure 5 shows structures of the most commonly used Ru-based catalysts. [53]][52][53]57] All of these transformations are stereocontrolled: the metathesis process only affects sp 2 carbons of olefin bonds, sp 3 carbons (including stereocenters) are untouched.Notably, although all metathesis reactions are reversible, the position of the equilibrium is highly affected by the reaction conditions and the stabilities of the olefins. [51,53]2][63]

Olefin Bond Functionalization via Cross-Metathesis
Cross-metathesis (metathesis reaction between two different olefins) is a commonly utilized method for the functionalization of C=C bonds. [50,53,56,64]Because subjecting the mixture of olefins A and B to metathesis should give three possible

P e r s o n a l A c c o u n t T H E C H E M I C A L R E C O R D
products (A + A homocoupling, B + B homocoupling, and A + B cross-coupling), careful planning is required to make cross-coupling the dominant outcome.In most cases, crossmetathesis mainly furnishes the thermodynamic product (usually, an E olefin). [53,64]Homocoupling of electron-deficient alkenes is slow, [56,89] but they still take part in cross-coupling, and their excess ensures that homocoupling of the divinylated substrates is suppressed (coupling partner/substrate encounters are more frequent than substrate/substrate encounters).
Divinylated β-lactams (�)-16, (�)-22, and (�)-26 (Scheme 3) were submitted to metathesis.The highest conversions were attained with HG-2 catalyst.In all cases, both terminal olefin functions underwent cross-metathesis, giving "decoupled" products with E geometry (Scheme 6). [30]he cross-metathesis of N-benzoylated amino esters (�)-32 and (�)-34.with methyl acrylate in refluxing anhydrous CH 2 Cl 2 yielded the expected "dimetathesized" products. [29]oubly N-Boc protected amino ester (�)-51 behaved similarly (Scheme 7). [33]Product (�)-50 was earlier prepared through Wittig reaction. [25]The Wittig pathway was not applied for the synthesis of transpentacins (trans-cyclopentane β-amino esters).Note that by applying the metathesis strategy the synthetic procedures could be shortened in comparison with the Wittig protocol as well as the usage of toxic reagents and high amounts of solvents could be reduced. [25]It should also be noted that purification of the metathesis products and elimination of the Ru-based catalyst residues were performed by extraction and gradient column chromatography protocols.
In the cases of the substrates depicted on Scheme 8-10, if the ester group and the vicinal vinyl group are cis to each other, coordination takes place more readily (because it gives more stable cis-annelated rings, not less-favored trans-annelated ones), and CM of this vinyl group is more suppressed.This is the reason for the regioselective CM of β-amino esters (�)-32 and (�)-42 (Scheme 11). [31]he second factor is hydrogen bonding interaction between the NÀ H hydrogen and the chlorine ligand of the catalyst, which facilitates transformation of the vinyl group which is closer to the NÀ H group.For example, CM of lactam (�)-16 provides one "monometathesized" product, but its N-Boc protected analogue (�)-20 provides two such products.Furthermore, cross-metathesis of β-amino ester (�)-32 is much less selective in hydrogen bond acceptor solvents (THF or 1,4-dioxane) which can disrupt substrate-catalyst hydrogen bonding formation (Scheme 11). [31]Finally, compared to its analogues (�)-32 and (�)-42, CM of doubly N-Boc protected ester (�)-51 is much less selective because hydrogen bonding is absent and steric hindrance is increased (see Scheme 12). [33]he third factor is steric hindrance.If the large Rucomplex cannot approach a vinyl group efficiently, transformation of that vinyl group will be hindered.Cross-metathesis of compound (�)-51 with a very large NBoc 2 group has low selectivity, while analogous reactions of compounds (�)-32 and (�)-42 (which contain a smaller NHCOPh group) are completely selective (Scheme 12). [33]heme 7. Synthesis of dialkenylated cispentacins and transpentacins.

Synthesis of some Azaheterocycles by Ring-Rearrangement Metathesis 2.1. A Brief Insight into the Ring-Rearrangement Metathesis
Ring-rearrangement metathesis (RRM) is a domino metathesis process.It starts with a ring-opening metathesis (ROM) step, which is immediately followed by either ring-closure metathesis (RCM) or ring-closing enyne metathesis (RCEYM).Scheme 13-14 depict the general mechanism of these processes. [57]he ROM/RCM process does not change the overall number of molecules (it transforms one molecule of substrate into one molecule of product), while the ROM/RCEYM process actually decrease it (one molecule of substrate and one molecule of ethylene is transformed into one molecule of product).59] Ring-rearrangement metathesis has a number of attractive features.Thus, it is capable of efficiently generating structural complexity in a single process.Furthermore, like all other metathesis processes, it preserves the configurations of the chiral centers.9]

Synthesis of some Azaheterocycles by Application of the Metathesis Protocol
37À 43] This subchapter will give some brief insight into the access of azaheterocycles vith ring-rearrangement metathesis.
North and co-authors described metathesis reactions of N,N'-diallylated and N,N'-dipropargylated derivatives of vicinal diaminocycloalkenes in the presence of G-1 and G-2 catalysts.In metathesis reactions of N,N'-diallylated sulfonamide 84, the dominant pathway was ring-closing metathesis.In fact, with G-1 catalyst, only RCM happened, while G-2 catalyst provided some RRM product 86 and lots of RCM product 85.N,N'-Dipropargylated sulfonamide 87 also disfavored RRM.In this case, CEYM was the dominant pathway, and the highest yield of RRM product 89 was achieved with G-2 catalyst.In contrast, transformation of N,N'-dipropargylated sulfonamide (�)-90 (prepared from commercially available (�)-trans-5-norbornene-2,3-dicarbonyl chloride) provided mainly the desired ROM/RCEYM/RCEYM product (�)-91 (accompanied with two ROM/RCEYM byproducts which were inseparable), and the transformation was the most efficient with G-1 catalyst.Scheme 15 depicts those reactions which provided the best yields for RRM products. [90]Peregrina and coworkers have elaborated an elegant process with ring-rearrangement metathesis for the conversion of 7azanorbornene systems into pyrrolizidine, indolizidine, and pyrrolo[1,2-a]azepine derivatives (Scheme 16). [93]Such frameworks are found in a wide range of biologically active natural products of particular interest. [38,94] ). [93]he same group extended the above approach for the synthesis of azaspiro The reaction tolerated various substitution patterns on the propargyl group and the arene ring, as well as functional groups, permitting access to a large variety of polycyclic lactams.These compounds are structurally similar to Erythrina alkaloids, a large family of natural products with interesting neurobiological activities.[96] Further examples for azaheterocycle synthesis via ring-rearrangement metathesis can be found in Ref. [58-59].

Synthesis of Azaheterocyclic β-Amino Acids by Application of the Ring-Opening/Cross-Metathesis Protocol
Azaheterocyclic β-amino acids are a special subclass of functionalized azaheterocycles.97À 99] This subchapter will discuss examples in which ring-rearrangement metathesis was utilized to obtain such compounds.
Guanti and co-workers described a synthetic route which used Ugi reaction of 7-oxanorbornene β-amino acids.Enantiopure amino acid (À )-112 was reacted with an aldehyde and an isocyanide in MeOH.The reaction was completely diastereoselective, furnishing compounds 113.Treatment of this with 10 mol% G-2 catalyst in CH 2 Cl 2 under ethylene or argon atmosphere afforded the azaheterocyclic β-amino esters 114 (Scheme 19).Product (+)-114 a was transformed further via transesterification and subsequent RCM to tricyclic derivative (+)-115 (Scheme 19). [97]gi reaction of the N-propargylated analogue of (À )-112 was not totally diastereoselective.However, major product (À )-116 was successfully isolated in pure form and subjected to metathesis.In the presence of G-1 catalysts and ethylene atmosphere only the expected ROM/RCEYM product (À )-117 was formed.However, when the reaction was performed with G2 catalyst, product (À )-117 was accompanied with CEYM/ROM/RCM product (À )-118 (Scheme 20). [97]heme 17. Synthesis of azaspiro[4.5]decanederivatives.In the cases of both kinds of tandem metathesis processes, more strained products form in lower yields.This is why closure of 6-membered rings was efficient, closure of 7membered rings was less efficient, and closure of 8-membered rings was inefficient.In fact, closure of the azacyclooctene ring only succeeded in the case of substrate (�)-124, while substrate (�)-130 provided only a ROM product. [98]cKendrick, Blechert, and coworkers reported RRM reactions on a number of oxanorbornene β-amino esters RRM of substrate (�)-135 proceeded smoothly with G-1 catalyst.RRM of (�)-137 and (�)-138 was more challenging, the key factors of success were utilization of G-2 catalyst (which is more reactive than G-1) and use of 0.5 mM substrate concentration.Norbornene β-amino ester (�)-142 was also prepared and subjected to metathesis.Under forcing conditions, the reaction was successful and provided the desired ROM/RCM product (�)-143 in 88 % yield. [99]This is in strong contrast with the behavior of the analogous methyl ester (�)-120, where olefin metathesis did not happen. [98]Further-more, according to our own experiences, RRM of (�)-142 proceeds well even under mild conditions (see Section 3.1.1,Scheme 26). [100]

P e r s o n a l A c c o u n t T H E C H E M I C A L R E C O R D
Base-promoted epimerization of diexo compound (�)-156 afforded exo-endo compound (�)-159.Then, both N-Boc protected β-amino esters were submitted to olefin metathesis, which gave the expected ROM/RCM products (�)-160 and (�)-161 (Scheme 28).With first generation catalysts, the yields were close to the RRM yields of the analogous Ntosylated compounds, but second generation catalysts were less efficient with N-Boc protected substrates.The best yield of product (�)-160 was accomplished with G-1 catalyst, while HG-1 catalyst was the best in the synthesis of (�)-161. [101]

Stereocontrolled Syntheses Across Ring-Rearrangement Metathesis of Oxanorbornene β-Amino Acid Derivatives
In view of the relevance of oxygen-containing cyclic β-amino acids the RRM-based stereocontrolled synthetic strategies were extended to oxanorbornene β-amino acid derivatives.

Transformation of other Cyclooctene β-Amino Acid Derivatives
β-Lactams (�)-227 and (�)-234 were also submitted to metathesis (Scheme 45).When N-allylated β-lactam (�)-227 was treated with metathesis catalysts in the presence of ethylene, only ring-opening metathesis occurred in low yield (the highest yield of product (�)-238, 25 %, was achieved by G-1 catalyst).Treatment of isolated ROM product (�)-238 with metathesis catalysts in the absence of ethylene resulted in fast and efficient ring-closing metathesis, providing the desired azaheterocycle (�)-239 in an excellent yield with all four catalysts.When N-propargylated β-lactam (�)-234 with metathesis catalysts in the presence of ethylene, ROM product (�)-240 and ROM/RCEYM product (�)-241 were formed.The After this, we planned to continue our work with the synthesis of β-amino lactones and β-amino lactams.Thus, N-Boc protected amino acid (�)-242 [23] was subjected to Oallylation (allyl bromide in the presence of DBU) or DCC-mediated amidation to prepare RRM substrates (�)-243 (an allyl ester) and (�)-245 (an N-allylated amide).ROM/RCM of these cyclooctene derivatives would yield an unsaturated lactone with an 8-membered or a 9-membered ring (the former is more plausible).Because the possible RRM products have comparable (or higher) ring strain to the substrates, it is not surprising that one-step ROM/RCM failed, and metathesis of these substrates in the presence of ethylene afforded only ROM products (Scheme 46).Second generation catalysts were more efficient than first generation ones, the best yields were 74 % for (�)-244 (G-2 catalyst) and 57 % for (�)-246 (HG-2 catalyst).Unfortunately, treatment the isolated ROM products with metathesis catalysts in the absence of ethylene failed to achieve RCM. [110]tathesis of ester (�)-247 in the presence of ethylene failed to achieve one-step ROM/RCEYM (probably because the RRM products would have similar ring strain as the substrate).ROM product (�)-248 and ROM/CEYM product (�)-249 were formed.Second generation catalysts were really inefficient in this transformation.In contrast, first generation catalysts were moderately efficient (48 % overall yield with both G-1 and HG-1).The best yields were of 23 % for (�)-248 (HG-1 catalyst) and 28 % for (�)-249 (G-1 catalyst).Both products resisted to ring closure attempts.In contrast, transformation of compound (�)-250 furnished directly the ROM/RCEYM product (�)-251.Second generation catalysts were highly inferior to first generation ones, the highest yield of the RRM product was accomplished with G-1 catalyst (39 %) (Scheme 47). [110]

Summary and Outlook
Olefin metathesis as a powerful tool to create C=C bond containing molecular entities has been effectively applied to create various unsaturated azaheterocyles and amino acid derivatives.Various types of metathesis protocols (ROM, RCM, CM, RCEYM, RRM) gave access to this class of compounds with stereocontrolled manner to synthesize βamino lactams/lactones and azaheterocyclic β-amino esters with multiple chiral centers.The key step was ring-rearrangement metathesis (RRM) of strained cycloalkene β-amino acid derivatives.The metathesis techniques were carried out with commercial Ru-based catalysts.The metathesis catalyst performance greatly depended on a number of factors: stereochemistry and skeleton of substrate, type of RRM, functional group directing effects, however it is difficult to make general conclusions.The metathesis transformations were dependent on the molecular architecture of the substrates and proceeded under stereocontrol with conservation of the configurations of the stereocenters: thus the structure of the starting compounds predetermined the structure of the formed products.The presence of one or more olefin bonds in the products may allow further C=C bond functionalizations of the structurally, and chemically diverse molecular entities.

List of Abbreviations
completed his Ph.D. in 2002 in the Department of Organic Chemistry at the Faculty of Sciences, Debrecen University (Debrecen, Hungary) under the supervision of Prof. Sándor Antus.In 2003, he joined the research group of Prof. Ferenc Fülöp at the Institute of Pharmaceutical Chemistry, University of Szeged (Szeged, Hungary), where he started working in chemistry of cyclic βamino acid chemistry.He followed postdoctoral research in the laboratories of Prof. Norbert De Kimpe at Ghent University (Ghent, Belgium), and Prof. Santos Fustero, University of Valencia.He is currently director of the Institute of Organic Chemistry, Research Center for Natural Sciences (Budapest).His scientific interest is directed towards the selective functionalization of cyclic amino acid derivatives and on the synthesis of highly functionalized fluorinated small molecular entities.Attila Márió Remete graduated as chemist in 2014 from University of Szeged, Faculty of Science and Informatics.He received his Ph.D. degree at the Institute of Pharmaceutical Chemistry, University of Szeged under the supervision of Prof. Dr. Loránd Kiss in 2019.Since 2020, he is a lecturer at the University of Szeged.His research interests include β-amino acid chemistry, fluorination strategies and selective functionalizations.Melinda Nonn graduated as chemist in 2007 from Babes-Bolyai University, Faculty of Chemistry and Chemical Engineering (Cluj-Napoca, Kolozsvár, Romania).She received her PhD degree at the Institute of Pharmaceutical Chemistry, University of Szeged (Hungary) under the supervision of Prof. Ferenc Fülöp in 2013.Since 2022 she has been working at the Institute of Materials and Environmental Chemistry, Research Center for Natural Sciences (Budapest).Currently she is also a János Bolyai Research Fellow.Her research interest includes synthesis of highly functionalized cyclic amino acid derivatives, development of asymmetric synthetic methods toward the preparation of this class of derivatives and organofluorine chemistry.Santos Fustero studied chemistry at the University of Zaragoza, where he obtained his bachelor's degree in 1972.He received his Ph.D. in organic chemistry in1975 from the same university under the supervision of Profs.Barluenga and Gotor.He carried out postdoctoral studies for two years at Prof. Lehmkuhl's group at the Max-Planck-Institut für Kohlenforschung in Mülheim/Ruhr, Germany.In 1983, he became an associate professor at the University of Oviedo, and in 1990, he was promoted to a full professor at the University of Valencia.His research interests include organofluorine and medicinal chemistry, organocatalysis, heterocyclic chemistry and new reaction methodologies.Anas Semghouli graduated as chemist in 2017 from At the Faculty of sciences, University of Mohammed V(Rabat-Morocco).He is currently finishing his PhD topic and working as a research assistant in the Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest.His research interests include βamino acid chemistry, metathesis strategies and selective functionalizations of small molecular entities.

Figure 2 .
Figure 2. Azaheterocyclic β-amino acid element containing molecules in natural products, bioactive compounds and drugs.

Figure 5 . 3 .
Figure 5. Structures of the most commonly used Ru-based catalysts and their abbreviations.
A L R E C O R D Chem.Rec.2023, 23, e202300279 (11 of 37) © 2023 The Authors.The Chemical Record published by The Chemical Society of Japan and Wiley-VCH GmbH