On the Structure of Intermediates in Enyne Gold(I)‐Catalyzed Cyclizations: Formation of trans‐Fused Bicyclo[5.1.0]octanes as a Case Study

Abstract The nature of cyclopropyl gold(I) carbene‐type intermediates has been reexamined as part of a mechanistic study on the formation of cis‐ or trans‐fused bicyclo[5.1.0]octanes in a gold(I)‐catalyzed cascade reaction. Benchmark of DFT methods together with QTAIM theory and NBO analysis confirms the formation of distinct intermediates with carbenic or carbocationic structures in the cycloisomerizations of enynes.


Introduction
Research in homogenous gold(I)c atalysis has provided unique tools for the construction of molecular complexity. [1] Thus, fundamental knowledge gathered in the study of 1,n-enyne cycloisomerizations [2] has led to many applications in total synthesis of complex natural products. [3] Although gold(I) carbenes have been proposed ask ey intermediates of many gold(I) catalyzed transformations, there is still some uncertainty regarding the structure of these species( carbenic or cationic character of CÀ Au bond), [4] especially considering their high reactivity,w hich makes their isolation very challenging. [5] In this context, our group recently reported the spectroscopic characterization of mesityl gold(I) carbenesi ns olution by NMR at low temperature, [6] which correspond to actual species presentu nder catalytic conditions.
As part of our program on the total synthesis of jatrophalactone (1) [7] (Scheme1), ac ytotoxic diterpene isolatedf rom the roots of Jatropha curcas,w eobserved the unexcepted formation of trans-fused bicyclo [5.1.0]octanes (5)b yag old(I)-catalyzed cyclization cascade.T od ate, no total synthesis of 1 has been reported. We envisioned that after the coordination of gold to the alkyne of dienyne 2,a6 -exo-dig cyclization would form cyclopropyl gold carbene A,w hich, after intramolecular nucleophilic attack of the OH moiety to the carbene, followed by OR elimination, would lead to the formation of intermediate B.P roduct 3 would finally be obtained by intramolecular cyclopropanation of the second alkene. In order to explore the feasibility of this transformation,s implerm odel substrate 4 was designed having ap henylr ing instead of the furan. However,t oo ur surprise, product 5 was obtainedi nt his reaction bearingarare trans-fused bicyclo [5.1.0] Although, the trans-bicyclo [5.1.0]-octane motif is present in some natural products, [8] such as cneorubin B ( 6), emmottene (7), and hemerocallal A( 8) ( Figure 1), the formation of this ring system is rather unusualb ecause it formally corresponds to the cyclopropanation of (E)-cycloheptene, which is unstable at room temperature. [9] This type of trans-fused bicyclo [5.1.0]octanes hado nly been obtainedb efore as minor byproducts in cyclization cascade reactions catalyzedb ygold(I). [10] Herein, we presenta ne xperimentala nd computational study on the selectivef ormation of cis-o rtrans-fused bicyclo [5.1.0]octanes by ag old(I)-catalyzed cascade.T his investigation also led us to reconsider the puzzling structure of the cyclopropyl gold(I) carbene-type intermediates. [11] In principle, upon coordination of gold(I)t ot he alkyne of the 1,6-enyne in Int1,t hree different possible structures could be generated, Int2-4.W hether or not structures Int2-4 are resonance forms or distinct stationaryp oints in the reactionc oordinate is still an open question and the different interpretations coexist in the current literature [4] (Scheme 2). Thus, we performed DFT calculations (including benchmark of functionals, QTAIM theory,and NBO analysis) in order to furtherdescribe the structure of intermediates Int2-4 and how they are interconnected.

Results and Discussion
Formation of trans-fusedbicyclo [5.1.0

]octanes
We examined the cyclization of dienynes 4a, 9 and 10,b earing OH or CO 2 Ha si ntramolecular nucleophiles, as models for the key cascade cyclization for the synthesis of jatrophalactone (see Scheme 1). Dienynes 4a, 9 and 10 reacted almosti nstan-taneously with [(JohnPhos)Au(MeCN)]SbF 6 as the catalyst at room temperature in CH 2 Cl 2 (Scheme 3). Surprisingly,( E)-configured enynes 9a and 10 a (ca. 1:1d iastereomeric mixture at the benzylic positions), afforded 11 as as ingled iastereomer in 45-50 %y ield, alongw ith 2-substitutedn aphthalene 12 (14 % yield). The presence of rare trans-fused bicyclo [5.1.0]octane, along with a trans-fused tetrahydronaphtho[1,2-c]furan unit, in compound 11 was confirmed by X-ray diffraction (Figure 2). Similarly,c arboxylica cid 4a yielded trans-fused cyclopropane 5a as as ingle diastereomer,a lbeit in lower yield. Again, naphthalene 12 was isolated in this reaction as am inor product. On the other hand, (Z)-configured dienynes 9b and 10 b gave an inseparable mixture of isomers 13 and 14 in moderate yield, together with traces of naphthalene (Z)-12 (Scheme 3).  Remarkably,w hen the two diastereomers of 9b and 10 b were separated by chromatography and exposed to gold(I)-catalysis, the same mixtureo f13 and 14 was obtained, although (Z)-12 was only formed from one of them.T he relative configuration of pentacyclicp roducts 13 and 14,w hich are clearly distinct from 11,was assigned by NOE NMRe xperiments. [12] To understand the effect of substituents and alkene configuration in the stereoselectivity of these transformations, other dienynes were prepared and submitted to the gold(I)-catalyzed cascade cyclization (Scheme 4). Therefore, simplers ubstrates 15 a,b and 16 missing the benzylic hydroxymethyl group gave products 17 a,b and 18 as single diastereomers in ca. 50 %y ield. All of these products feature a cis-fused bicyclo[5.1.0]octanes ystem as confirmed by X-ray diffraction analysis. The cascade reactions provedt ob es tereospecific with respect to the configurationo ft he alkene, as observed in many other gold(I)-catalyzed transformations. Additionally,p roducts 20 and 22 were obtained as single diastereomers by reaction of dienynes 19 a,b.D eprotection of TBS group of 20 and 22 gave rise to crystalline primary alcohols 21 and 23,w hose relative configurationwas confirmed by X-ray diffraction.
For those intermediates having the alcohol moietyinsyn-position with respectt ot he cyclopropyl( 9aa-Int2)a nd to the carbocationic center( 9ab-Int3), closureo ft he tetrahydrofuran ring was not observed. These intermediates could instead lead to the formation of naphthalene derivative side products 12 by loss of am olecule of formaldehyde in concomitance with a single cleavage rearrangement, connecting these intermediates (9aa-Int2 and 9ab-Int3)w ith 9aa-Int8 (Scheme 7). This mech-anistic possibility was not computationally explored,b ut it is supported by the products observed experimentally.
Similarly,c omputed pathways for diastereomer 9ba have very similare nergy barriers leading to 9ba-Int5.H owever,f or 9bb the predominantp athway by at least 7kcal mol À1 is the formation of cyclopropylg old(I) carbene 9bb-Int2 via 9bb-TS 1c-2, which would immediately give rise to 9bb-Int5 through 9bb-TS 2-5 .A gain,a si th appened for 9aa-Int2,t he formation of tetrahydrofuran product type Int5 was not observed from 9ba-Int2.W ea ssumed that this intermediate would also lead to the formation of corresponding (Z)-configured side product 12 (Scheme 7). Hence, 9bb would selectively lead to the formation of 9bb-Int5,i ng ood agreementw ith the experimentalr esults, since no side-product 12 waso btained for one of the diastereoisomers (presumably 9bb,a ccording to the presentedc alculations).
For both substrates 9a,b the two pairs 9aa-Int5 and 9ab-Int5,a nd 9ba-Int5 and 9bb-Int5 would lead to the formation of same intermediates 9a-Int6 and 9b-Int6 by elimination of the methoxy group (Scheme 8). Thise xplains why,w hen the reactionwas attempted separately (9ba and 9bb), both diastereomers delivered the same products, arising from common intermediate 9b-Int6.

Structure of cyclopropyl gold(I) carbene intermediates
In the previousm echanistic study (Scheme 6) we found that the initial cyclization can lead to the formation of cyclopropyl gold carbenes (Int2)a nd open carbocations (Int3), such as the pairs 9aa-Int2 and 9aa-Int3,w ith very distinct energies and geometries. Therefore, to rigorously settle this issue computationally and to determinet he dependenceo ft he structure of the most stable intermediates on the different substituents, we studied the first step in the cyclization of several 1,6-enynes.
Moreover,N PA charges of the carbons connected to the gold atom are also slightly different for each system. For 24-Int3 and 30-Int4,p ositive charges are clearly delocalized and, for that reason charges on the carbon-carbon double bond are more negative than for 24-Int2.
To further prove the structures of 25-Int2, 25-Int3, 30-Int4, we carriedo ut Quantum TheoryA tomsi nM olecules (QTAIM) [12,23] (Scheme 12). The bond criticalp oints (BCPs) and the ring critical points (RCPs) were located and analyzed using Laplacian maps. TwoR CP were located for intermediate 25-Int2,w hereas no RCP was observed between C8ÀC1 in the case of 25-Int3,and the Laplacian clearly indicates the absence of this bond. Finally,o nly one ring criticalp oint was observed in 30-Int4 as ac onsequence of its semi-opened ring system. Hence, QTAIM theory confirms that the molecular representation of these intermediates is accurate.

Conclusions
In summary,w eh ave uncovered an ew gold(I)-catalyzed cyclization cascade of substituted dienynes that can lead to selective formation of unexpected trans-fused cyclopropanes within a trans-bicyclo[5.1.0]octane framework, depending on the substrate geometry.D FT calculations and control experiments show that this specific selectivity is directed by the rigidity of the system. Likewise, computed pathways provide ar ational for the role played by the fused tetrahydrofuranr ing in the final cyclopropanation step. These new results expand the scope of these type of gold(I)-catalyzed cyclizations for the formation of highly complexc arbocyclic skeletons, in this case bearing trans-fused cyclopropanes. Our computational study included ar eevaluation of the nature of the key intermediates in cycloisomerizationso f enynes, providing evidence on the existence of three different types of cationici ntermediates depending on the substitution of the initial substrate. The QTAIM theory confirms that the molecular representation of the different types of intermediates is accurate. Moreover,t he metal carbenic or cationic character of thesei ntermediates was confirmed by NBO analysis.

Experimental
Full details of all synthesis, characterization and DFT calculations can be found in the Supporting Information.