The Joy and Challenge of Small Rings Metathesis**

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1 1,5-Enyne tathesis DI: /anie.200((will be filled in by the editorial staff)) The Joy and Challenge of Small ings tathesis** Karol Grela* Keywords: alkene metathesis enyne metathesis cycloisomerisation catalysis carbenes lefin metathesis (the term is derived from the Greek word μεταθεσιζ with the same pronunciation, which means transposition) is basically an alkylidene exchange between two reacting fragments, mediated by transition metals alkylidene complexes. [1] diene CM n enyne MP M/CM M/ Scheme 1. Selected types of olefin metathesis. ecent decades have seen a burgeoning of interest in olefin metathesis, as witnessed by a rapidly growing number of elegant applications. Using this tool, chemists can now efficiently synthesize an impressive range of molecules that only a decade ago required significantly longer and tedious routes. [1] Several types of olefin metathesis have been identified so far, among them ring-closing metathesis () and cross-metathesis (CM) being widely and successfully applied in the synthesis of biologically active complex compounds (Scheme 1). ing closing metathesis occurs when a diene undergoes intramolecular metathesis affording a cyclic olefin. Analogous intramolecular reaction of an enyne is sometimes called enyne cycloisomerisation or enyne. [2] ing-closing metathesis + C 2 =C 2 + C 2 =C 2 n reactions of dienes and enynes represent an attractive and powerful tool for formation of medium and large cycles ( 5 members). owever, it is generally acknowledged that small rings (three- and four-membered) and strained cannot be formed by. [] In such cases, the ring opening process can be far more thermodynamically favourable than ring closing. Indeed, various strained molecules, such as norbornene derivatives, are well known substrates for ring-opening metathesis polymerization (MP) reactions (Scheme 1). [4] P P P Gru-I ov-ii Figure 1. thenium catalysts commonly used in olefin metathesis. tathesis reactions involving the opening of a small ring. Cyclopropenes and cyclobutenes may be polymerised via ringopening in a similar fashion by the metathesis catalyst, although the examples of such transformations are less numerous than MP reactions of norbornenes. [4] The driving force in these reactions is the relief of the enormous - and 4-membered ring strain. Another possible transformation for highly strained cyclic olefins is M/CM transformation Michaut, Parrain and Santelli showed that the Grubbs ruthenium complex Gru-I efficiently catalyses ring-opening metathesis/cross-metathesis (M/CM) of cyclopropenone ketal 1a to afford 1,4-divinyl ketone ketal derivative 2 in good yields. [5] 1a [] Gru-I (1 mol%) C 6 6, T 15 min 86% []=C 2 2, E:Z = 95:5 10 examples 2-88% yield Scheme 2. M/CM of cyclopropenone ketal 1a. = trimethylsilyl [ ] Dr. Karol Grela Institute of rganic Chemistry Polish Academy of Sciences Kasprzaka 44/ , Warsaw, Poland Fax: klgrela@gmail.com [ ] K.G. thanks the Foundation for Polish Science for the "Mistrz" Professorship Kozmin and co-workers created a remarkably concise and efficient route to the protein kinase C activator, bistramide A (), based on opening of strained cyclopropenone ring as one of the key steps. [6a] The M/CM reaction of cyclopropene ketal 1b with alkene 4 led, after acidic hydrolysis, to divinyl ketone 5, a direct precursor of the key spiroketal domain of (+)-bistramide (Scheme ). 1

2 Bn Bn Bn (10 mol%) 4 6% C Scheme. Cyclopropenone ketal (1b) M/CM reaction in the enantioselective total synthesis of bistramide A (). The same elegant cascade of metathesis reactions involving opening of the strained cyclopropene 1b was used by Kozmin and coworkers in highly convergent syntheses of other spiroketal-containing natural products: spirofungin A (6) [6b] and routiennocin (7) [6c] (Scheme 4). 1b 1. (10 mol%) C 6 6, 60 o C 2. 1M 2 S 4, C 6%, 2 steps Bn C 2 Spirofungin A (6) C 2 Bn outiennocin (7) C 2 Bn Bn 5, E:Z = :2 1. 2, Pd() 2 /C 2. Dess-rtin 5%, 2 steps Bistramide A () 1b = In addition to cyclopropenes, some cyclobutenes have also been used in MP and similar processes. ne of the most impressive applications involving the ringopening event is seen in the recent total synthesis of (+)-asteriscanolide (10) by Limanto and Snapper, where the M/CM sequence followed by divinyl cyclobutane rearrangement was used to fashion the cyclooctane ring of the core structure of the natural product (Scheme 6). [8a] A similar M/CM reaction between substituted cyclobutene and gaseous ethylene was also used by Snaper in the preparation of series of isoprostane analogues [9b] and by arrity and co-workers in synthesis of (±)- sporochnol A. [9c] 74% C 2 =C 2 (1 atm) C 6 6, o C (+)-asteriscanolide (10) Scheme 6. M/CM of a cyclobutene in the enantioselective total synthesis of (+)-asteriscanolide (10). oveyda and co-workers reported on asymmetric ring opening/ring closing metathesis (AM/) of a disubstituted cyclobutene 11 promoted by the chiral Mo-alkylidene 12 (Scheme 7). [9] This tandem M/ reaction proceeds efficiently, with good enantioselectivity, providing rapid entry to optically enriched dihydrofurane 1. Scheme 4. M/CM of strained cyclopropene ketal 1b as a key step in enantioselective total syntheses of spirofungin A and routiennocin. An elegant asymmetric ring-opening/cross-metathesis (AM/CM) reaction of cyclopropenes catalysed by chiral ruthenium catalysts 8 has recently been described by oveyda et al. (Scheme 5). [7] 9 I 8 8 TF, 0 o C, 48 h Scheme 5. -catalysed asymmetric M/CM reaction of cyclopropene 9. 90% 9% ee 7 examples, ee 85-98% (meso), 22 o C 69%, 82% ee M [Mo] Scheme 7. An asymmetric M/ of meso cyclobutene 11 The icolaou group utilised similar sequence to open chiral cyclobutene-1,2-diol derivative 14 with achiral ruthenium catalyst. The ring-opening event, followed by resulted in smooth conversion of the strained cyclobutene 14 into the corresponding tetracyclic compound 15, with complete transfer of chirality (Scheme 8). [10] 1 Mo 12 2

3 14, 45 o C 80% Scheme 8. M/ of cyclobutene 14. A notable example of M/ reaction of alkyne-substituted cyclobutenes was reported by Mori and co-workers. In the enyne [2] variant of a M/ cascade, various isoquinolines, such as 16, were synthesized from cyclobutene derivatives (17) using the secondgeneration ruthenium carbene under ethylene atmosphere in good yields. (Scheme 9). [11] C 2 =C 2 C 2 2, 45 o C h, 60% Scheme 9. M/ of cyclobutene-yne 17. tathesis reactions involving the formation of a small ring. The above arbitrary selection of examples demonstrates that metathetical opening of strained three- and four-membered rings is very useful transformation, successfully used in numerous stereocontrolled total syntheses of natural and bioactive compounds as well as in preparation of polymers. At the same time, there are virtually no reports on the formation of three- and four-membered carbo- or heterocycles by metathesis reactions. n the contrary, it is generally considered that small cyclic products cannot be formed by. [1] In this regard, a new communication by Debleds and Campagne [12] on the preparation of vinyl-cyclobutenes via enyne is a real breakthrough. In this report, the authors have shown that Grubbs- and oveyda-type catalysts are able to promote enyne metathesis [2] on 1,5-enyne substrates 18 leading to functionalized cyclobutenes 19 (Scheme 10). In order to gain a closer view on this unprecedented transformation, the reaction of 1,5-enyne 18a was explored under various conditions (Scheme 10). In the presence of Gru-I catalyst, no cyclized product could be observed, whereas the use of more potent second generation [1] catalysts: and ov-ii led to the formation of the expected cyclobutene 19a in 20-5% yield. Importantly, the use of microwave irradiation [1] was found to be beneficial, leading to the formation of 19a in remarkable 58% yield. Unfortunately, all efforts to decrease the amount of ov-ii catalyst used were unsuccessful, leading to a substantial decrease in the yield. The reason, why at least 20 mol% of the catalyst is necessary to 17 Ts 8 examples, 9-8% yield Ts achieve the reasonable yield remains unclear. According to the authors, along with the expected cyclobutene 19b, only small amounts of the uncharacterised CM dimers (5%) and starting material 18a (10-15%) were identified in the crude reaction mixture. Interestingly, the formation of less strained cyclopentene 20, a product of an alternative cyclisation route, [14] was not observed. Campagne tested also the effect of ethylene (so called Mori's conditions for enyne reaction), [15] unfortunately the extensive byproduct formation was observed in this case. [16] Finally, the use of Pt 2 as the catalyst was probed, but no reaction was observed (Scheme 10). [17] cat. 1,5-enyne cat. (mol%) conditions Gru-I (20), C 2 2, 45 o C (20), C 2 2, 45 o C ov-ii (20), C 2 2, 45 o C ov-ii (20), C 2 2, µw, 70 o C ov-ii (10), C 2 2, µw, 70 o C Pt 2, toluene, 80 o C Scheme 10. 1,5-Enyne. µw = microwave irradiation. aving the optimised reaction conditions, Debleds and Campagne attempted to define the scope of this transformation. Various 1,5- enyne substrates were tested, providing cyclobutene products 19a-19l in yields up to 58%, as shown in Figure 2. It was concluded that while the cyclobutene ring can be decorated with various substituents (, ), only alkyl substituents are well-tolerated on the the alkynyl part ( ). A double cyclisation of a bis-enyne substrate was finally attempted, leading to the bis-cyclobutene 19l in a modest 19% yield (Figure 2). The moderate yields observed in these reactions were explained by the authors in part by not complete conversions (the unreacted starting material was present in the most of the reaction mixtures) and by the formation of some unidentified by-products. In addition, difficulties in the purification of the sensitive highly strained cyclobutenes can also be responsible for diminishing the yield. 19h, 2% Figure 2. Products of 1,5-enyne 19a, yield 0% 20-25% 5% 58% 20% 0% 19a, =, 58% 19b, =, 7% 19c, = F, 5% 19d, =, 57% 19e, =, 48% 19f, =, 5% These results open a convenient new entry to functionalized cyclobutenes, which are useful building blocks in organic synthesis. 19g, 52% 19a 20 19i, 0% 19j, 9% 19k, 8% 19l, 19%

4 The 1,-diene unit present in 19 can be further used in many transformations, such as Diels-Alder cycloaddition and others. Indeed, as it was shown by the authors, product 19a reacts with dienofile 21 at room temperature, to give the expected tricyclic compound 22 in respectable 80% yield and as a single diastereomer (Scheme 11). [12] 19a Scheme 11. Diels-Alder reaction of. 21 C 2 2, T 80% In conclusion, Debleds and Campagne have opened a novel field in the area of metathesis technology by demonstrating that strained fourmembered rings can be obtained by enyne reaction. At its current stage, the reaction suffers from rather mediocre yields and high catalysts loadings. The scope of substrates amenable for 1,5-enyne should be broadened as well. Although it seems that the reaction follows the established route of 1,n-enyne cycloisomerisations, [2] it would be important to provide some evidence as to the mechanism. It is reasonable to expected that further optimisation of the reaction conditions or the application of more potent catalysts will allow to increase the reaction efficiency and scope. The simplicity of the transformation in combination with the synthetic importance of the obtained products suggests that this method can find numerous applications. Definitely, the preliminary results reported by Debleds and Campagne are worth further investigations. eceived: ((wil be filled in by the editorial staff)) Published online on ((will be filled in by the editorial staff)) 22 Wiley & Sons: ew York, 1991; d) M.. Buchmeiser, Chem. ev. 2000, 100, [5] M. Michaut, J.-L. Parrain, M. Santelli, Chem. Commun. 1998, [6] a) A. V. Statsuk, D. Liu, S. A. Kozmin, J. Am. Chem. Soc. 2004, 126, 9546; b) J. Marjanovic, S. A. Kozmin, Angew. Chem. Int. Ed. 2007, 46, 9010; c) K. Matsumotoa, S. A. Kozmin, Adv. Synth. Catal. 2008, 50, 557. [7]. E. Giudici, A.. oveyda, J. Am. Chem. Soc. 2007, 129, 824. [8] a) J. Limanto, M. L. Snapper, J. Am. Chem. Soc. 2000, 122, b) T.. Schrader, M. L. Snapper, Tetrahedron Lett. 2000, 41, 9685; c) M. J. Bassindale, P. amley, J. P. A. arrity, Tetrahedron Lett. 2001, 42, [9] G. S. Weatherhead, J. G. Ford, E. J. Alexanian,.. Schrock, A.. oveyda, J. Am. Chem. Soc. 2000, 122, [10] K. C. icolaou, J. A. Vega, G. Vassilikogiannakis, Angew. Chem. Int. Ed. 2001, 40, [11] M. Mori,. Wakamatsu, K. Tonogaki,. Fujita, T. Kitamura, Y. Sato, J. rg. Chem. 2005, 70, [12]. Debleds, J.-M. Campagne, J. Am. Chem. Soc. 2008, 10, [1] For selected key references, see: a) Microwaves in rganic Synthesis (Ed.: A. Loupy), Wiley-VC, Weinheim, 2002; b) B. L. ayes, Microwave-Assisted rganic Synthesis (Eds.: P. Lidstrom, J. P. Tierney), Blackwell Publishing, xford, 2005; c) C.. Kappe, A. Stadler, Microwaves in rganic and dicinal Chemistry, Wiley-VC, Weinheim, 2005; d) Microwaves in rganic Synthesis 2nd ed. (Ed.: A. Loupy), Wiley-VC, Weinheim, 2006; e) Microwave thods in rganic Synthesis (Eds.: M. Larhed, K. lofsson), Springer, Berlin, [14] It was shown that metathesis of enynes containing an internal triple bond proceeds sometimes in a non-selective manner, leading to the formation of three products: a normal diene A, a byproduct B bearing an external double bond and a bicyclic product C, containing a cyclopropane unit. Compare: [ef. 2] and a) V. Sashuk, K. Grela J. Mol. Catal. A: Chem. 2006, 257, 59; b) T. Kitamura, Y. Sato, M. Mori, Adv. Synth. Catal. 2002, 44, 678. [1] For selected reviews on olefin metathesis, see: a) andbook of tathesis, (Ed.:.. Grubbs), Wiley VC: Weinheim, Germany, 200; b) P.. Deshmukh, S. Blechert, Dalton Trans. 2007, 2479; c) D. Astruc, ew J. Chem. 2005, 29, 42; d) A. Fürstner, Angew. Chem., Int. Ed. 2000, 9, 012; e) For an industrial perspective, see: A. M. Thayer, Chemical & Engineering ews 2007, 85, 7. [2] ecent reviews on enyne-metathesis: a) S. T. Diver, A. J. Giessert, Chem. ev. 2004, 104, 117; b) M. Mori, Ene-yne tathesis in andbook of tathesis, (Ed.:.. Grubbs), Wiley VC: Weinheim, Germany, 200, Vol. 2, pp 176; c) C. S. Poulsen,. Madsen, Synthesis 200, 1; c). Villar, M. Frings, C. Bolm, Chem. Soc. ev., 2007, 6, 55; d) M. Mori, Adv. Synth. Catal. 2007, 49, 121. [] For a short review on the preparation of cyclic strained molecules by olefin metathesis, see: S. K. Collins, J. rganomet. Chem. 2006, 691, [4] For a review on MP, see: [ef. 1a] and a) K. J. Ivin, J. C. Mol, lefin tathesis and tathesis Polymerization; Academic Press: London, c) G. dian, Principles of Polymerization, rd ed.; A B [] A B A B B A A B C [15] a) A. Kinoshita, M. Mori, Synlett, 2004, 1020; b) M. Mori,. Sakakibara, A. Kinoshita, J. rg. Chem. 1998, 6, [16] It is reasonable to assume, that the unwanted M/CM of a highly strained cyclobutene product 19, similar to that one shown in Scheme 6, could significantly be increased when the reaction is carried out under ethylene atmosphere. [17] It should be noted that metathetical cycloisomerication of 1,n-enynes represents only a small branch of the vast tree of transition metal catalysed bond reorganisation reactions of enynes. For selected key references, see: a) C. Aubert,. Buisine, M. Malacria, Chem. ev. 2002, 102, 81; b) M. ndez, A. M. Echavarren, Eur. J. rg. Chem. 2002, 15; c) G. C. Lloyd-Jones, rg. Biomol. Chem. 200, 1, 215; c) for recent examples of platinum-catalysed cycloisomerisation of enynes leading to the formation of cyclobutenes, see: F. Marion, J. Coulomb, C. Courillon, L. Fensterbank, M. Malacria, rg. Lett. 2004, 6, 1509; d) A. Fürstner, P. W. Davies, T. Gress, J. Am. Chem. Soc. 2005, 127,

5 Entry for the Table of Contents 1,5-Enyne tathesis Karol Grela* Page Page The Joy and Challenge of Small ings tathesis C 2 C 2 cat. C 2 M/CM C 2 cat. 1,5-enyne relief of ring strain creation of ring strain A molecular origami: metathetical opening of strained three- and four-membered rings is a well established transformation, successfully used in a number of total syntheses and in preparation of polymers. In the same time, it is generally considered that small cyclic products cannot be easily formed by. The recent report on preparation of substituted cyclobutenes via 1,5-enyne creates a notable example of a process where a strained four-membered ring is created by olefin metathesis methodology.