Assembly of Complex 1,4‐Cycloheptadienes by (4+3) Cycloaddition of Rhodium(II) and Gold(I) Non‐Acceptor Carbenes

Abstract The formal (4+3) cycloaddition of 1,3‐dienes with Rh(II) and Au(I) non‐acceptor vinyl carbenes, generated from vinylcycloheptatrienes or alkoxyenynes, respectively, leads to 1,4‐cycloheptadienes featuring complex and diverse substitution patterns, including natural dyctiopterene C′ and a hydroxylated derivative of carota‐1,4‐diene. A complete mechanistic picture is presented, in which Au(I) and Rh(II) non‐acceptor vinyl carbenes were shown to undergo a vinylcyclopropanation/Cope rearrangement or a direct (4+3) cycloaddition that takes place in a non‐concerted manner.


Introduction
7-Membered carbocycles are important motifs present in avariety of natural products (Scheme 1, A). [1] However, they can be challenging to synthesize through traditional cyclization pathways. [1,2] Thes ynthesis of these medium-sized rings often relies on the use of cycloaddition strategies, [3] ring expansions, [4] ring-closing metathesis, [5] or cross-coupling reactions. [6] In particular, the divinylcyclopropane-cycloheptadiene Cope rearrangement has been established as aversatile alternative for the construction of 1,4-cycloheptadienes. [7] Them ain challenge of this approach is the stereoselective assembly of the key cis-divinylcyclopropane with the appropriate substitution pattern. In this regard, Davies and coworkers pioneered the reaction of 1,3-dienes with donoracceptor vinyl carbenes,generated from diazo compounds,to give cycloheptadienes after cyclopropanation and Cope rearrangement, through an overall formal (4 + 3) cycloaddition process (Scheme 1, B). [8] This strategy was successfully applied by several groups for the synthesis of 7-membered carbocycles, [9] but it displays the inherent problems associated to diazo compounds, [10] limiting the methodologies to the use of acceptor metal carbenes. [11] Different gold(I)-catalyzed (4 + 3) cycloadditions were developed over the years,mainly based on the reaction of 1,3-dienes with allenes [12] or vinyl carbenes generated from propargyl esters, [13] cyclopropenes [14] or by recombination of linear dienediynes. [15] In our pursuit to identify new sources of non-acceptor metal carbenes,wehave established both 7-vinyl-1,3,5-cycloheptatrienes (1)a nd 5alkoxy-1,6-enynes (6)a ss uitable precursors.T he former can undergo metal-catalyzed retro-Buchner reactions (releasing aromatic units), [16] and the latter can take part in ag old(I)catalyzed cycloisomerization/migration cascade sequence [17] generating non-acceptor vinyl carbene intermediates with diverse substitution patterns (Scheme 1, C). Here,w er eport the reactivity of these catalytically-generated intermediates with 1,3-dienes to give adiverse range of 1,4-cycloheptadienes through a( 4 + 3) formal cycloaddition process.W ea lso present ac omplete mechanistic picture in which two main pathways for the cycloaddition process were studied both experimentally and theoretically.O ur theoretical and experimental study shows that, depending on the substitution pattern of the substrates,adirect closing of ac ationic intermediate is sometimes favored rather than the Scheme 1. A. Examples of bioactive natural products containing 7membered carbocycles. B. Classical approach for the assembly of 1,4cycloheptadienes by diazo-carbene chemistry.C.This work:f ormal (4 + 3) cycloadditiono fdienes with non-acceptor vinyl carbenes generated from cycloheptatrienes or alkoxyenynes.
We investigated the reaction scope using complexes A and D (Scheme 4). Tetramethyl and pentamethyl cyclopentadiene afforded exclusively (4 + 3)-cycloaddition products 7b and 7c,r espectively,w ith both catalysts.I nterestingly,w hile the yield was slightly higher with phosphite complex D,JohnPhos catalyst A gave higher diastereoselectivity.I nc ontrast, 1,3cyclohexadiene only afforded cyclopropane product 8d. [26] Acyclicd ienes also reacted in moderate to good yields.F or 1,3-butadiene,g old(I) complex A was more selective for the    formation 7e than catalyst D,t hat essentially gave a1 :1 mixture of 7e and 8e.Introducing amethyl substituent at the 2-position (isoprene) led to adrop in selectivity,still giving 7f as the main product with both catalysts.E xchanging the methyl by aphenyl (8g), or adding asecond methyl group (8i) inverted the selectivity,g iving cylopropanes as major products.R eaction with an electronically biased 2-oxy-1,3-diene delivered 7hand 9 as a10:1mixture using catalyst A.Catalyst D afforded only (4 + 3) product 7hand bulkier complex B led to a1:1.4 ratio of 7hand 9,which is the product of formal (3 + 2) cycloaddition. Replacing the PNP migrating group by an acetate in the 1,6-enyne led to adrop of yield, but maintaining the same tendency in selectivity observed before,o btaining only 7h' '. [27] Finally,antracene was found to be agood reaction partner for the (4 + 3) cycloaddition, giving 7jin 68 %yield as as ingle isomer.T he PNP group in compound 7f was removed, delivering 7fa as ac rystalline solid in 30 %y ield over two steps.T his allowed the confirmation of the relative configuration of the (4 + 3) product by x-ray diffraction. [18] Compound 7fa is ah ydroxylated analogue of carota-1,4diene (7fb), an atural product isolated from Rosa rugosa leaves. [28] We studied the mechanism of the two systems by DFT calculations at 6-311G ++(d,p)(H, C, N, O, F, P) + LANL2TZ(Au, Rh)// B3LYP-D3/6-31G(d,p)(H, C, N, O, F, P) + LANL2DZ(Au, Rh) level of theory,taking into account the solvent effect (SMD = 1,2-dichloroethane or dichloromethane). Forthe first class of substrates,the process starts by the rhodium(II)-catalyzed retro-Buchner reaction of cycloheptatriene 1a (decarbenation) to give styryl carbene III releasing mesitylene (Scheme 5, A). [29] An activation barrier of 18.0 kcal mol À1 was calculated from I,which was identified as local minimum. After exchanging mesitylene for 1,3cyclohexadiene (IV), the most favorable pathway corresponds to as tepwise cyclopropanation, in which the formation of cis open intermediate Va is kinetically more favored than the trans by 2.6 kcal mol À1 ,w hich would account for ap erfect cis selectivity (80:1). [30] Ther esulting open intermediate Va can evolve through two pathways:a na lmost barrierless cyclopropanation (TS Va-VI )g iving Rh(II)-coordinated cis-divinylcyclopropane VI or ad irect (4 + 3) closing (TS Va-VII ), which affords Rh(II)-coordinated final product 3a (VII). Although both pathways are energetically feasible,the cyclopropanation TS is lower in energy (DDG°= 2.1 kcal mol À1 ). Ther esulting cyclopropane can further evolve through Cope rearrangement. Rh(II)-coordinated divinylcyclopropane VI is in downhill equilibrium with free divinylcyclopropane 3a' ' + I (1,3-cyclohexadiene h 2 -coordinated to Rh 2 TFA 4 ). This results in an activation barrier of 20.3 kcal mol À1 (larger,b ut rather similar than that for the retro-Buchner step) for the Rh(II)-coordinated Cope rearrangement (TS VI-VII ), which makes it the turnover-limiting step of the entire process.T he calculated energies are in agreement with the overall kinetic profile of the reaction (Scheme 5, B): following the reaction by 1 HNMR, we observed an accumulation of intermediate cyclopropane 3a' '.A lternatively,a fter decoordination from Rh(II), free cyclopropane 3a' ' can undergo at hermal Cope rearrangement (TS 3a' '-3 a ), with an only slightly higher energy barrier (DDG°= 1.2 kcal mol À1 ). In order to prove the existence of the catalyst-free pathway, we removed the Rh(II) catalyst after 1.5 ho fr eaction and then followed the evolution of the resulting mixture (Scheme 5, C). This showed ac lean thermal conversion of intermediate divinylcyclopropane 3a' ' into 1,4-cycloheptadiene 3a during 12 ha t3 08 8C. Thes uccessful removal of the Rh(II) catalyst was confirmed by the recovery of unreacted cycloheptatriene 1a.All in all, the entire mechanistic analysis is in agreement with the experimental observations,a nd explains why these vinyl Rh(II) carbenes generated from cycloheptatrienes lead cleanly to (4 + 3) cycloaddition products.
Ad ifferent scenario was found for the Au(I)-catalyzed transformation of enyne 6a(Scheme 6). Thefirst steps consist in an enyne cycloisomerization cascade involving a5-exo-dig cyclization, followed by a1 ,5-migration of the OR group to form vinyl carbene IX (Scheme 6, A). [31] This sequence contains the turnover limiting Step,w ith ao verall energy barrier of 6.1 kcal mol À1 from local minimum VIII.Next, the intermolecular trapping of intermediate IX by cyclopentadiene (2a)p roceeds stepwise (Scheme 6, B). [32] Thet wo possible orientations of cyclopentadiene approaching carbene IX afford diastereomeric allyl carbocations Xa and Xb through TS IX-Xa and TS IX-Xb ,respectively.T hese two TS differ in 2.6 kcal mol À1 ,w hich is consistent with the high diastereomeric ratio found experimentally in the final products.
Intermediates Xa and Xb can then evolve to deliver (2 + 1) or (4 + 3) cycloaddition products.S tarting from most populated intermediate Xb,t he formation of the cyclopropane ring in XIb through TS Xb-XIb is favored by 0.5 kcal mol À1 over the 7-membered ring-closing towards XIIb through TS Xb-XIIb .T his translates into a2 .5:1 calculated ratio of (2 + 1)/(4 + 3) cycloaddition products 8a and 7a after decomplexation, in excellent agreement with the experimental results for this same system using catalyst A (2:1 8a/7a ratio, Table 2). Although the gold(I)-catalyzed interconversion of 8a to 7a is energetically feasible and thermodynamically favored according to the calculated values (DG°= 14.7 kcal mol À1 , DG8 8 = À6.6 kcal mol À1 ), we did not observe such transformation to take place experimentally. [33] Finally,w e calculated the energy barriers of the thermal Cope rearrangement (Scheme 6, B). Divinylcyclopropane 8a would have to overcome 30.1 kcal mol À1 to rearrange into 7a,w hile 8a' ' can only be converted into 7a' ' (and not 7a' '' ',which has the relative configuration observed experimentally) by as tereospecific Cope rearrangement, also with ah igh-energy barrier of 34.3 kcal mol À1 .These results indicate that, in contrast to that observed with products 3 (Scheme 2), densely substituted (4 + 3) cycloaddition products 7,f ormed in the Au(I)catalyzed stepwise process,c annot be obtained by metalcatalyzed nor thermal Cope rearrangement of the corresponding divinylcyclopropanes.

Conclusion
To sum up,w eh ave developed two new approaches for the synthesis of aw ide variety of structurally complex 1,4cycloheptadienes.B oth reactions rely on the formal (4 + 3) cycloaddition of non-acceptor vinyl metal carbenes with 1,3dienes.The first approach involves the rhodium(II)-catalyzed decarbenation or retro-Buchner reaction of 7-vinyl cycloheptatrienes,r eleasing am olecule of mesitylene.I nt he second approach, these intermediates are generated from 5alkoxy-1,6-enynes by ag old(I)-catalyzed cyclization/migration cascade.W eshowed the potential of these two complementary methodologies in the rapid construction of molecular complexity,a nd in the total synthesis of natural compounds, such as dictyopterene C'.Furthermore,wepresent acomplete mechanistic picture for both reactions,b acked up by experiments and computations.W ef ound that both ac lassical vinylcyclopropanation/Cope rearrangement sequence or adirect formal (4 + 3) cycloaddition are feasible,a nd the preference for each pathway depends on the substitution pattern of the substrates and intermediates.