α,β‐Unsaturated Gold(I) Carbenes by Tandem Cyclization and 1,5‐Alkoxy Migration of 1,6‐Enynes: Mechanisms and Applications

Abstract 1,6‐Enynes bearing OR groups at the propargyl position generate α,β‐unsaturated gold(I)‐carbenes/ gold(I) stabilized allyl cations that can be trapped by alkenes to form cyclopropanes or 1,3‐diketones to give products of α‐alkylation. The best migrating group is p‐nitrophenyl ether, which leads to the corresponding products without racemization. Thus, an improved formal synthesis of (+)‐schisanwilsonene A has been accomplished. The different competitive reaction pathways have been delineated computationally.


Introduction
The study of gold(I)-catalyzed reactions of 1,n-enynes has led to the discovery of aw ealth of cyclization modes, including mechanistically intriguing skeletal rearrangements and nucleophilic addition reactions to cycloaddition processes. [1] In this context,w er ecently found that 1,6-enynes such as 1 bearing propargyl alcohols, ethers, or silyl ethers react with gold(I) catalysts through the usual type of highly delocalized cyclopropyl gold(I) intermediates 2, [2] which then undergo an ew type of 1,5-migrationoft he OR groupstog enerate species 3 [3] that we postulated as intermediate between a,b-unsaturated gold(I) carbenes and gold(I)-stabilized allyl cations. [2,4] In the presence of carbon nucleophiless uch as indole or furans,p roducts 4 [3] or trienes such as 5 [5] were obtained by Friedel-Crafts-type reactions (Scheme 1). Intermediates 3 can also react with electron-rich alkenes to form the corresponding cyclopropanes, [3] ar eactionw hich is also characteristico fg old(I) carbenes 2. [6][7][8] We demonstrated the potential of this tandem cyclization/1,5-OR migration/cyclopropanation to form products 6 that were key intermediates in the first total synthesis of the natural sesquiterpene (+ +)-schisanwilsonene A(7). [9] This type of gold(I)-catalyzed 1,5-migration has been found to compete [10] with 1,2-and 1,3-migrations of propargylic carboxylate groups. [10] Related processes have been found in the gold(I)-catalyzedr eactions of dienynes 8,w hich undergo cyclization/1,5-OR migration/intramolecular cyclopropanation through intermediates 9 to form stereoselectively hexahydroazulenes 10, [3] which were the key intermediates in our total synthesis of the sesquiterpernes (À)-epiglobulol( 11)a nd (À)-4b,7a-aromadendranediol (12)( Scheme2). [11] Alternatively, when the gold(I)-catalyzed reactionw as performed in the presence of allyl alcohol, this external nucleophile reacted to give 9',w hich underwent intramolecular cyclopropanation to give rise to the sesquiterpene (À)-4a,7a-aromadendranediol (13). [11] The proposed mechanism for these inter-and intramolecular reactions was based on the isolation of diversep roducts but not on ar igorous study of this intriguing process and its several possible competitive cycloisomerization pathways. Furthermore, although the chirality transfer in the intramolecular processes was satisfactory,p artial racemization was observed in the formation of intermediates 2 when RO = AcO, which led to (+ +)-schisanwilsoneneA( 7)w ith 9:1e .r.H ere we reportt hat 1,3-dicarbonyl compounds can also be used as the C-nucleophiles to trap the putative a,b-unsaturated gold(I)c arbenes 3 leadingt op roducts of formal alkylation.T his and additional studies on the intermolecular trapping of intermediates 3 with alkenes have allowed selecting p-nitrophenyl ether as the protecting group of choice in these reactions. This led us to develop an improved formals ynthesis of (+ +)-schisanwilsonene A ( 7) in which the key step proceeds with total retention of configuration. We have also found cases in which as keletal rearrangement takes place preferentially to form six-membered ring compounds. Ad etailed computational study has been performed to understand the mechanismsoft hese complex transformations.

Results and Discussion
Selection of the best OR migration group 1,3-Dicarbonyl compounds react as C-nucleophiles with 1,6enynes in the presence of gold(I) catalysts by formal attack at the alkene via opening of the cyclopropane of intermediates of type 2.
Scheme4.First-generation synthesis of (+ +)-schisanwilsoneneA(7)v ia cyclization/1,5-OR migration/cyclopropanation. [9] Chem. Eur We had reported that 1,6-enyne 20 a reacts with methanol in the presence of catalyst A to give stereoselectively adduct 21 in which the migration of the benzyloxy group has not taken place [15] (Scheme 7). Interestingly,a lcohol 20 b also reacted in the presence of catalyst A withoutm igration of the OH group to give 22,t he product of an endo-type single cleavage rearrangement. [16] This reaction was better performed in the presenceo f4 molecular sieves.S urprisingly,i nt he absence of molecular sieves, diene 23 was obtained as the major product of the reaction, whose structure was determined by X-ray diffraction. As peculative mechanism for the formation of this unexpected product could involve ar eactiono f22 with allyl cation 24 to form an ew allyl cation 25,f ollowedb ya romatization by proton loss and dehydration (Scheme 7).
Scheme7.Cyclizations of enynes 20 a, b and 22 with gold(I) catalyst A without OR migration and the proposed mechanism for the formation of 23. Table 3. Gold(I)-catalyzed reaction of 1,6-enynes 26 a-h to give endotype single-cleavage rearrangement products 27 a-h.  (Table 3, entries 6a nd 7). Somewhat surprisingly,t he reaction of the corresponding methyl ethersl ed only to decomposition.

Mechanistic discussion
We examined computationally the evolutiono fenynes Ia-c coordinated with AuL + (L = PMe 3 ). In all cases, in agreement with calculations, Ia-c reacted by 5-exo-dig pathways to form preferentially IIa-c (Schemes 8a nd 9), whichc orrespond to intermediates of type 2 in Scheme 1. [17] The alternative 6-endo-dig pathway leadingt oIIIa-c was less favorable in all cases. Whereasi nt he case of PNP-protected intermediate IIa,t he migration to form VIa proceeds in ad irect manner through TS 3a (Scheme 8), the migration of the OR group in complexes IIb and IIc proceeds via bicyclic intermediates IVb and IVc,w hich then lead to products of 1,5-migration VIb and VIc through very low barrier transition states TS 5b and TS 5c ,r espectively (Scheme9). The alternative evolution of IIa-c to products of single-cleavage rearrangement Va-c was found to be thermodynamically the most favorable pathway, [18] although kinetically the 1,5-migration is more favorable as TS 4a-c have highere nergies than TS 3a-c (Schemes 8a nd 9).
The calculated structure for minimum VIb shows very similar CÀCb ond lengths of 1.41 and 1.39 (Figure 2). The AuÀC bond length is 2.04 ,w hich might correspond to as ingle metal-carbon bond, and is similart ot hat found in well-characterized heteroatom-stabilized gold(I)c arbenes. [3,4] Overall, the calculated structure fits better with ag old(I)-stabilized allylic cation.
The observed reactivity trends when L = PMe 3 are reproduced in cases where the ligand on gold(I)i sc hanged to bulkier PPh 3 phosphine or the modelN HC ligand 1,3-dimethylimidazol-2-ylidene( Ta ble 4).   DFT calculations for the reaction of gold(I) complex Id led to much less clear-cut results (Scheme 10). Although the 5-exo-dig pathway leading to IId was againm ore favorable than the 6endo-dig cyclization to form IIId,t he 1,5-migration of IId through IVd to form VId was found to be the kinetically most favorable pathway, which is not what was observed experimentally for 20 b and 26 a-h.

Conclusions
In general, 1,6-enynes bearing OR groups at the propargyl position react through intermediates that can be formulated in as implified manner as a,b-unsaturated gold(I) carbenes,w hich react in general with alkenes to form cyclopropanes or 1,3-diketonest of orm products of a-alkylation. We have found that among the various migrating OR groups, p-nitrophenyl ether gives the best results. In addition, we have established that the gold(I)-catalyzed enyne cyclization/1,5-OR migration/cyclopropanation cascade takes place without racemization, which demonstrates that propargyl carbocations are not formed under the reaction conditions. This hasb een appliedf or the preparation of key intermediates for the synthesis of (+ +)-schisanwilsonene Aw ith higher enantiomeric purity.D FT calculations suggest that after the initial cyclization, the 1,5-OR migration proceeds stepwiset hrough ac yclic intermediate although the cleavageo ccurs through av ery low barrier. However,a dditional mechanistic work is still required to understand why in cases in which propargyl group does not migrate an endo-type single-cleavage rearrangement is the most favorable reaction pathway.