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Title:
Facile access to diverse all-carbon quaternary center containing spirobicycles by exploring a tandem Castro–Stephens coupling/acyloxy shift/cyclization/semipinacol rearrangement sequence

Paper sections:
Introduction
<p>Spiro bicyclic scaffolds incorporating all-carbon quaternary stereocenters, as a big number of key structural moieties, broadly exist in bioactive natural products and pharmaceutical molecules, and oen play essential roles in their characteristic bioactivity. 1 Because of the highly steric repulsion caused by its four carbonic substituents, 2 however, the construction of this type of moiety is a long-standing challenging topic. 3 Taking the spirocyclo [4.5]decane skeleton as a typical example, a lot of bioactive natural products as well as synthetic intermediates contain this key unit (Fig. 1). 4 Therefore, in order to synthesize these target molecules and facilitate corresponding molecular function studies, how to efficiently construct this unit has become a crucial and difficult step. Although several strategies based on different intermolecular or intramolecular cycloaddition patterns of relatively complex substrates have been developed during the past decade, 5 it is still highly desirable to further explore alternative approaches for pursuing transformation efficiency, and product diversity as well as extensibility.</p>

Design plan
<p>Besides the above strategies, it is particularly noticeable that the semipinacol rearrangement reaction, which can generate Based on the mechanism analysis of the above four transformations, it is highly likely to achieve them in a tandem manner. Additionally, since a series of substituent combinations can be used from the two substrates, this strategy, once feasible, will not only exhibit better transformation efficiency and product complexity and diversity, but also further enrich the content of semipinacol rearrangement. Herein, we present such a novel sequence and its application in the construction of the tetracyclic ring system of waihoensene, a new example of complex bioactive molecule-directed synthetic methodology development.</p>

Optimization of reaction conditions
<p>Following the above assumption, we rst tested the feasibility of the designed tandem reaction using propargyl ester 1a and allylic bromide 2a as the model substrates. As the copper catalyst has been successfully applied in Castro-Stephens coupling and the 1,3-acyloxy shi process to form an allene group, 11 different copper catalysts were examined for promoting the expected reaction. 12 Although none of them afforded the desired nal product 5a, most could give the Castro-Stephens coupling product 3a, with a best yield of 68% using CuOAc. 12 Further screening of the base additive, solvent and reaction temperature showed that the use of Cs 2 CO 3 in DCE at 70 C could produce 3a in the best yield of 82% (Table 1, entry 1). Subsequently, the realization of the initial tandem reaction in a purication free manner was then investigated. Fortunately, aer a quick removal of the solid from the reaction mixture through Celite pad ltration following the Castro-Stephens coupling reaction, a rst attempt using the combination of 10 mol% AuPPh 3 Cl and AgOTf could promote the desired reaction to give the product 5a in 57% yield (Table 1, entry 7). Furthermore, the counterion effect 13 was also observed with this reaction, and the use of counterion NTf 2 À from AgNTf 2 exhibited the best result of 66% yield for 5a (Table 1, entry 8). Next, several different solvents were applied to this tandem reaction. Among them, benzene, THF and CH 3 CN could give the desired product in low yield (Table 1, entries 11-16). Other solvents were not compatible with this transformation. Finally, the use of CuOAc along with Cs 2 CO 3 and the combination of AuPPh 3 Cl and AgNTf 2 in DCE (Table 1, entry 8) was selected as the optimal reaction conditions.</p>

Substrate scope investigation
<p>With the optimal reaction conditions in hand (Table 1, entry 8), we began to explore the generality of this reaction, and the results are summarized in Tables 2 and 3. Among the substrates tested,   most of them could give the expected products in moderate to good yields. When R 1 and R 2 groups of propargyl ester formed a ring system (i.e., cyclohexyl and cyclopentyl), the reaction with bromide 2a (R 4 , R 5 , R 6 ¼ H) proceeded smoothly providing tricyclic products 5b and 5c in 53% and 55% yield, respectively. Moreover, with the R 1 as H, R 2 could be H, Ph, isopropyl, or methyl, and all reactions could give the desired products 5d to 5g in moderate to good yields, albeit with low diastereoselectivity for 5d to 5f. Additionally, the reaction was also compatible with substrate 2 with different R 4 /R 5 groups. In the case of substrate 2b with R 4 and R 5 being Me and H, respectively, the expected product 5h was obtained in 36% yield and 1/1 dr ratio. When both R 4 and R 5 were Me (2c), the desired product 5i was produced with good diastereoselectivity and yield. It should be noted that a series of natural product skeletons might be obtained by our protocol. For example, since the relative conguration of the two diastereoisomers of ketone 5e (ref. 14) (5e-1 and 5e-2) is consistent with natural products erythrodiene 4c,d and cedrol, 4g,h respectively, a new general synthetic strategy for these types of natural products might be developed based on propargyl ester with pivaloyl, and benzoyl was successful to give the corresponding products 5j and 5k in 53% and 50% yield, respectively. In order to prove the efficiency of this method in the rapid construction of product complexity, other four allylic bromides 2d-2g were applied to the reaction, which produced four spirocyclic products in good yields. Among them, products 5l and 5m conrmed the feasibility of adding additional substituents on the cyclobutanol moiety, while product 5n showed that the amine group is amenable to this reaction. It was noteworthy that substrate 2g with a 2,3-dihydro-1H-inden-2-ol motif could go through the reaction through a ve-membered ring to a six-membered ring expansion affording product 5o. In order to demonstrate the potential utility of such a reaction, the transformation between 1a and 2a was attempted on the gram scale giving 5a in a moderate yield of 43% (Scheme 2). Based on the above results, the application of this method in the construction of a functionalized cyclohexane skeleton with a phenyl-substituted quaternary carbon center, a common Table 2 Exploration of the generality of the tandem reaction of cyclic alkanes as migrating groups a a Unless specied, all reactions were conducted using 1 (0.5 mmol, 2.5 eq.), 2 (0.2 mmol, 1.0 eq.), CuOAc (30 mol%), Cs 2 CO 3 (50 mol%), AuPPh 3 Cl (10 mol%), and AgNTf 2 (10 mol%) in a reaction tube in DCE (2 mL) at indicated temperature. b 10 mmol of 1a (1.26 g) and 4 mmol of 2a (1.22 g) were used. c CHCl 3 was used as the solvent aer Castro-Stephens coupling. d AuCl 3 (10 mol%) in 2 mL HFB (hexauorobenzene) was used instead of the combination of AuPPh 3 Cl and AgNTf 2 aer Castro-Stephens coupling; the structure shows the relative conguration of the major isomer.</p><p>Table 3 Exploration of the generality of the tandem reaction of aromatic rings as migrating groups a a All reactions were conducted using 1a (0.5 mmol, 2.5 eq.), 6 (0.2 mmol, 1.0 eq.), CuOAc (30 mol%), Cs 2 CO 3 (50 mol%), AuPPh 3 Cl (10 mol%), and AgNTf 2 (10 mol%) in a reaction tube in DCE (2 mL) at indicated temperature.</p><p>Scheme 2 New synthetic strategy design toward corresponding sesquiterpenes.</p><p>moiety in a variety of natural products like limaspermidine 15a and strychnine, 15b was further investigated. Accordingly, a series of allylic bromides with an aryl substituted tertiary alcohol moiety were applied to this reaction with substrate 1a. All of the tested substrates afforded the expected products, and the regioselectivity of this reaction during the migration step agrees well with the common semipinacol rearrangement pattern, i.e., aryl groups and aryl groups with an electron-donating substituent are more preferred than alkyl groups and aryl groups with an electron-withdrawing substituent, respectively. For example, substrates 6a-6f all gave the aryl group migrated products, and substrate 6i led to ketone 7i as the sole product. Besides, the steric hindrance effect of the substituent on the aromatic ring has also been clearly observed. When the substituent on the phenyl ring was chloro, product 7c with the substituent at the para-position was obtained in higher yield than the one with it at the meta-position (7e).</p>

Synthetic application
<p>In order to demonstrate the efficiency of this method in constructing a highly complex structural skeleton, a quick assembly of the key tetracyclic skeleton of waihoensene, 16 a unique diterpene molecule isolated from the New Zealand podocarp, featuring fused and strained tetracyclic rings and four consecutive congested all-carbon quaternary centers, was attempted using this reaction as the key step (Scheme 3). Due to the great difficulty in constructing such a tetracyclic framework with vicinal quaternary carbon centers, only one synthetic strategy toward waihoensene has been reported in 2017 using a tandem cycloaddition reaction of an allene substrate prepared in 12 steps as the key step. 17 Herein, based on the method we developed, starting from prop-2-yn-1-yl acetate 1g and 2h synthesized from the known reagent 8 in 6 steps, a facile access to a tricyclic skeleton was accomplished affording 5p in 40% yield and a dr ratio of 3.2/1 using hexauorobenzene as the solvent. 18 The relative conguration of 5p and its diastereoisomer 5q was conrmed by the X-ray structure analysis of their derivatives. 14 Next, the TBDPS protecting group of 5p was removed with TBAF followed by IBX oxidation providing dicarbonyl compound 12. A K 2 CO 3 -induced tandem hydrolysis/ intramolecular aldol cyclization/elimination reaction would give compound 13. Thus a quick construction of the tetracyclic skeleton core of waihoensene with vicinal all-carbon centers was realized through the use of this key methodology. Additionally, an unprecedented [3.2.2] bridged motif 14 could be obtained through a different cyclization model in the presence of HCl.</p>

Conclusions
<p>In summary, targeting a highly functionalized spirocyclo [4.5]  decane skeleton, a purication free tandem Castro-Stephens coupling/1,3-acyloxy shi/cyclization/semipinacol rearrangement reaction of propargyl esters with allylic bromide has been successfully developed. This method not only features a highly efficient chemical conversion into complex spirobicyclic compounds from simple readily available substrates, but also exhibits a wide substrate scope. Especially, compared with our previous work on semipinacol rearrangement related synthetic methodology, some characteristic functional groups that are necessary for the corresponding bioactive natural products, such as isopropyl 4g,h and geminal methyl groups, 4a can be readily installed. Moreover, the generation of a vinyl ester moiety by this transformation provides an important hinge for subsequent transformation enabling a quick construction of the key 6/5/5/5-fused tetracyclic skeleton of waihoensene. Further application of this method for the total synthesis of related bioactive natural products is ongoing in the same lab.</p>

Conflicts of interest
<p>The authors declare no competing interests. catalyzed arylative dearomatization of phenols. Au-Containing all-carbon 1,3-dipoles: generation and [3+2] cycloaddition reactions, J. Am. Chem. Soc., 2011, 133, 9282-9285.  6 (a)</p>
Efficient combination of two or more reactions into a practically useful purification free sequence is of great significance for the achievement of structural complexity and diversity, and an important approach for the development of new synthetic strategies that are industrially step-economic and environmentally friendly.In this work, a facile and efficient method for the construction of highly functionalized spirocyclo[4.5] decane derivatives containing a synthetically challenging quaternary carbon center has been successfully developed through the realization of a tandem Castro-Stephens coupling/1,3-acyloxy shift/cyclization/ semipinacol rearrangement sequence. Thus a series of multi-substituted spirocyclo[4.5]decane and functionalized cyclohexane skeletons with a phenyl-substituted quaternary carbon center have been constructed using this method as illustrated by 24 examples in moderate to good yields. The major advantages of this method over the known strategies are better transformation efficiency (four consecutive transformations in one tandem reaction), product complexity and diversity. As a support of its potential application, a quick construction of the key tetracyclic diterpene skeleton of waihoensene has been achieved.