The Matteson homologation is found to be a versatile tool for the stereoselective synthesis of polyunsaturated alkyl boronic esters, which are excellent precursors for the construction of five- and six-membered carbocycles via ring-closing metathesis. The high diversity of the Matteson reaction allows for the
preparation of highly substituted cyclic boronic esters, which are also suitable for further homologations

Kazmaier, Uli

Kinsinger, Thorsten

Organic Chemistry Frontiers

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ORGANIC CHEMISTRYFRONTIERSRESEARCH ARTICLECite this: Org. Chem. Front., 2023,10, 2963Received 28th March 2023,Accepted 9th May 2023DOI: 10.1039/d3qo00457krsc.li/frontiers-organicStereoselective synthesis of five- and six-membered carbocycles via Mattesonhomologation/ring closing metathesis†Thorsten Kinsinger and Uli Kazmaier *The Matteson homologation is found to be a versatile tool for the stereoselective synthesis of polyun-saturated alkyl boronic esters, which are excellent precursors for the construction of five- and six-mem-bered carbocycles via ring-closing metathesis. The high diversity of the Matteson reaction allows for thepreparation of highly substituted cyclic boronic esters, which are also suitable for further homologations.IntroductionHighly substituted and functionalised carbocycles are wide-spread in a broad range of natural products, e.g. terpenoids,with interesting biological properties. Common structuralmotifs are substituted saturated or unsaturated cyclopentanesand -hexanes, as well as combinations of both (Fig. 1).1Therefore, straightforward and extremely flexible strategies forsynthesising these challenging structures are highly desirable.The ring-closing metathesis of functionalised and substituteddienes has been developed as a suitable approach, and manyexamples have been reported over the last few decades.2We recently reported the synthesis of allyl boronic esters3via Matteson homologation,4 which could provide suitablecandidates for ring-closing metathesis as long as a seconddouble bond could be incorporated during further homologa-tion steps.5 Donald Matteson described this interesting reac-tion initially in the early 1960s6 and developed it in the 1980s7as a valuable tool in organic synthesis.8Typically, a chiral alkyl boronic ester A is reacted withdeprotonated dichloromethane in the presence of zincchloride, generating an α-chloroboronic ester B in a highlystereoselective fashion (Scheme 1A). The addition of a suitablenucleophile onto the boron atom generates a boronatecomplex, which undergoes a 1,2-shift of the nucleophile to theα-position, replacing the chlorine in a SN2-fashion.5 Ongoinghomologation allows the highly stereoselective synthesis ofsubstituted and functionalised carbon chains. Commonnucleophiles are alkoxides9 or organometallic compounds,such as alkyl-lithium or -magnesium reagents.10 In addition,allyl zinc reagents are well-suited to introduce unsaturated sub-stituents,11 as well as vinyl organometallics.3,12In contrast to alkyl nucleophiles, which are generally notproblematic, vinyl nucleophiles tend to undergo various sidereactions, such as vinylboronic ester (C) formations(Scheme 1B).13 However, under optimised conditions, wherethe vinyl Grignard reagent is added in the presence of ZnCl2,these side reactions can be suppressed almost completely, andallyl boronic ester D is obtained in high yields (Scheme 1C).3We are now interested in such allylboronic esters beingfurther homologated and, in particular, if they allow the intro-duction of a second double bond, generating suitable sub-strates for ring-closing metatheses. Hoffmann and others14have used chiral allyl boronic esters intensively in carbonylallylations for polyketide syntheses. However, to our knowl-edge, few examples of Matteson homologations of allyl boronicesters have been reported, probably because of severalissues.13,15 For example, Brown et al. reported side reactions,such as allyl migration,16 and Hirschhäuser et al. obtainedlowdiastereoselectivity.17Results and discussionIn recent years, we have applied the Matteson homologationsuccessfully in several syntheses of natural products, in par-Fig. 1 Selected terpenoid marine natural products.†Electronic supplementary information (ESI) available: Experimental details,compound characterization, copies of 1H and 13C NMR spectra. See DOI: https://doi.org/10.1039/d3qo00457kInstitute of Organic Chemistry, Saarland University, P.O. Box 151150, 66041Saarbrücken, Germany. E-mail: u.kazmaier@mx.uni-saarland.deThis journal is © the Partner Organisations 2023 Org. Chem. Front., 2023, 10, 2963–2967 | 2963Open Access Article. Published on 16 May 2023. Downloaded on 7/5/2023 12:56:34 PM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article OnlineView Journal  | View Issueticular, peptides18 and peptide/polyketides conjugates.19Because of our additional interest in the class of terpenoids,we also investigated methylallylboronic ester 1, which was con-verted into the corresponding α-chloro boronic ester 2 underour previously optimised conditions (Scheme 2). To this end,dichloromethane was deprotonated with BuLi at −100 °C, andthe addition of 1, as well as two equivalents of ZnCl2, resultedin the formation of 2, which was not isolated. The nucleophile,either deprotonated p-methoxybenzylalcohol (at 0 °C) ormethyl Grignard reagent (at −78 °C), was added, and themixture was warmed to room temperature over 24 h. Underthese conditions, both desired products 3a and 3b could beobtained in high yields without forming side products.The next homologation step proceeded without any pro-blems, and we could obtain the two products 4a and 4b with aninverted substitution pattern. For the introduction of the seconddouble bond, we used vinyl magnesium bromide in the thirdhomologation step.3 In this case, the correspondingα-chloroboronic ester of the first step was isolated and reacted inthe presence of exactly one equiv. ZnCl2 with vinyl magnesiumbromide. Even with an excess of Grignard reagent, excellentyields of the desired allyl boronic esters 5a and 5b were obtainedwithout the formation of vinylboronic ester as the commonlyobserved side product. Ring-closing metathesis was performed at40 °C using second-generation Grubbs catalyst20 generating cyclo-hexene derivatives 6 containing three stereogenic centres and athreefold substituted double bond. Clearly, the substitutionpattern of the linear precursor had no significant influence onthe homologation or the cyclisation step.To also acquire access to fourfold substituted cyclohexenes,we started with the known α-chloroboronic ester 7,3,11 whichwas reacted with (Z)-1-propenyl magnesium bromide(Scheme 3). The Grignard reagent was freshly prepared frompure (Z)-1-bromopropene, but the desired boronic ester 8 wasobtained as a 9 : 1 (Z/E) mixture. During the formation of theGrignard reagent, partial (Z/E)-isomerisation occurred.However, in our case, this phenomenon was completely irrele-vant because the methyl substituent would be finally removedin the metathesis step. For this reason, the commercially avail-able E/Z mixture of 1-bromopropene can also be used as analternative to pure (Z)-1-bromopropene.Scheme 1 Matteson homologations.Scheme 2 Synthesis of threefold substituted cyclohexenes 6. Scheme 3 Synthesis of tetrafold substituted cyclohexene 12.Research Article Organic Chemistry Frontiers2964 | Org. Chem. Front., 2023, 10, 2963–2967 This journal is © the Partner Organisations 2023Open Access Article. Published on 16 May 2023. Downloaded on 7/5/2023 12:56:34 PM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article OnlineThe prolongation of the alkyl chain was performed asdescribed, but interestingly, the (Z/E)-ratio changed slightly inthe subsequent homologation step. This result was rather sur-prising since the reaction conditions should not cause an iso-merisation of the double bond.One explanation might be that the homologation of allyl-boronic ester 8 does not proceed in a SN2- but a SN′-fashion, atleast in part. While SN′ substitution did not change the substi-tution pattern in this case, it can influence the double-bondgeometry via allyl migration. Since the double bond configur-ation did not matter in our case, we proceeded with the follow-ing two homologation steps to boronic ester 11. Its ring-closing metathesis provided the highly substituted cyclohexene12 as a single stereoisomer in almost quantitative yield.The corresponding five-membered ring systems alsobecame available by simply reducing the number of homologa-tion steps (Scheme 4). The enantiomer of 9 (ent-9), obtainedfrom the boronic ester (S)-7 containing the enantiomeric chiralligand, was directly converted into the allylboronic ester 13,which was cyclised to cyclopentene 14 in comparable yield.Finally, we looked more closely at the isomerisation of thedouble bond in the homologation of allylboronic ester 8. Weassumed that at least a partial SN′ might occur during homolo-gation. In principle, this might also happen with boronic ester1 but, in this case, does not influence product formation.To investigate this option, we synthesised α-methylatedboronic ester 16 starting form known dichloroboronic ester 15(Scheme 5).14 This smart approach allowed the synthesis ofboth diastereomeric boronic esters simply by changing theorder of nucleophile introduction. We used vinylmagnesiumbromide in the first step and methylmagnesium bromide inthe second. Therefore, the configuration at the α-position wasthe opposite of that in the previous example (8), where themethyl group was incorporated first. However, unexpectedly, inthe next homologation step, the expected homologationproduct was not formed at all, but the derivative with a linearside chain and a terminal methyl group at the double bonddeveloped instead. In this case, the homologation proceededexclusively in a SN′ mode, giving rise to the trans-configuredproduct 17 exclusively. This SN′ reaction was already observedfor the formation of the corresponding α-chloroboronic esterintermediate, whereas the second step (nucleophile addition)proceeded in the expected way. Further homologation andring-closing metathesis provided the double-substituted cyclo-pentene 19, again in excellent yield.In all examples investigated, the resulting metathesis pro-ducts were also allylboronic esters. Therefore, we exemplarilyundertook a subsequent homologation step with 19 to ensurethe cyclic alkenes could be prolonged predictably.Furthermore, the accustomed high yield could be obtained,indicating that this protocol is well suited for synthesisingcomplex carbocyclic structures. More detailed investigationsconcerning the allyl migration during the homologation ofallylboronic esters are currently underway.ConclusionsIn conclusion, we showed that the high diversity of theMatteson homologation along with the functional group toler-ance of the ring-closing metathesis generates an effective toolfor the stereoselective synthesis of complex natural productsand related structures. No stereoisomers formed in any reac-tion step, except during allyl migration. However, this isomeri-sation is not reflected in the final products.Conflicts of interestThere are no conflicts to declare.AcknowledgementsFinancial support by the Saarland University and the DFG (Ka880/13-1 and Bruker Neo 500 - 447298507) is gratefullyacknowledged.Scheme 4 Synthesis of threefold substituted cyclopentene 14.Scheme 5 Synthesis of threefold substituted cyclopentene 19.Organic Chemistry Frontiers Research ArticleThis journal is © the Partner Organisations 2023 Org. Chem. Front., 2023, 10, 2963–2967 | 2965Open Access Article. Published on 16 May 2023. Downloaded on 7/5/2023 12:56:34 PM.  This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article OnlineReferences1 (a) Y.-P. Song, X.-H. Liu, Z.-Z. Shi, F.-P. Miao, S.-T. Fank andN.-Y. Ji, Bisabolane, cyclonerane, and harziane derivativesfrom the marine-alga-endophytic fungus Trichodermaasperellum cf44-2, Phytochemistry, 2018, 152, 45–52;(b) Y.-M. Zjou, G.-L. Ju, L. Xiao, X.-F. Zhang and F.-Y. Du,Cyclodepsipeptides and Sesquiterpenes from Marine-Derived Fungus Trichothecium roseum and TheirBiological Functions, Mar. Drugs, 2018, 16, 519;(c) Y.-P. Song, S.-T. Fang, F.-P. Miao, X.-L. Yin and N.-Y. Ji,Diterpenes and Sesquiterpenes from the Marine AlgicolousFungus Trichoderma harzianum X-5, J. Nat. Prod., 2018, 81,2553–2559.2 (a) L. Yet, Metal-Mediated Synthesis of Medium-SizedRings, Chem. Rev., 2000, 100, 2963–3008; (b) K. C. Nicolaou,P. G. Bulger and D. 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Stereoselective synthesis of five- and six-membered carbocycles via Matteson homologation/ring closing metathesis

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Stereoselective synthesis of five- and six-membered carbocycles via Matteson homologation/ring closing metathesis

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