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

Abstract

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.

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Introduction

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 often 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.

Fig. 1 Representative important natural products bearing the spirocyclo[4.5]decane core.

Results

Design plan

Besides the above strategies, it is particularly noticeable that the semipinacol rearrangement reaction, which can generate a spirocyclic quaternary carbon center through functional group migration or skeleton reorganization, has been used by us⁶ and several other research groups⁷ for the syntheses of a variety of bioactive molecules containing spirocyclo[4.5]decane and related skeletons. Accordingly, the development of more efficient semipinacol rearrangement involved reaction patterns is always a main research program of our group, especially, through ingenious design and realization of sequential chemical transformations in step economy. Inspired by the special chemical properties of propargyl ester in acyloxy shift/cyclizations,⁸ we envisioned that a 1,3-acyloxy shift of the propargyl ester⁹ intermediate 3 generated by a Castro–Stephens coupling¹⁰ from propargyl ester 1 and allylic bromide 2 possessing a potential migration moiety might be viable to trigger a cyclization/semipinacol rearrangement of 4 affording multi-substituted spirocyclo[4.5]decane and related skeletons (Scheme 1). 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.

Scheme 1 Strategy design toward the spirocyclo[4.5]decane skeleton.

Discussion

Optimization of reaction conditions

Following the above assumption, we first 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 shift 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 final 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 Cs₂CO₃ 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 purification free manner was then investigated. Fortunately, after a quick removal of the solid from the reaction mixture through Celite pad filtration following the Castro–Stephens coupling reaction, a first attempt using the combination of 10 mol% AuPPh₃Cl and AgOTf could promote the desired reaction to give the product 5a in 57% yield (Table 1, entry 7). Furthermore, the counterion effect¹³ was also observed with this reaction, and the use of counterion NTf₂⁻ from AgNTf₂ 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 CH₃CN 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 Cs₂CO₃ and the combination of AuPPh₃Cl and AgNTf₂ in DCE (Table 1, entry 8) was selected as the optimal reaction conditions.

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Ag salt	Temp	Product	Yield
a Unless specified, all reactions were carried out using 1a (0.5 mmol, 2.5 eq.), 2a (0.2 mmol, 1.0 eq.), CuOAc (30 mol%), Cs2CO3 (50 mol%), AuPPh3Cl (10 mol%), and Ag salt (10 mol%) in a reaction tube in DCE (2 mL) at indicated temperature. b The solvent of Castro–Stephens coupling for 3a. c Temperature for the first coupling reaction. d Isolated yield of 3a. e The first coupling step was carried out at 70 °C. f Isolated yield of 5a in a purification free manner. g After filtration, the filtrate was concentrated and diluted with the indicated solvent (4 mL) for the subsequent operation.
1	DCE^b	—	70 °C^c	3a	82%^d
2	Benzene^b	—	rt^c	3a	40%^d
3	THF^b	—	rt^c	3a	47%^d
4	EtOH^b	—	rt^c	3a	55%^d
5	CH3CN^b	—	rt^c	3a	55%^d
6	DMF^b	—	rt^c	3a	54%^d
7	DCE	AgOTf	rt^e	5a	57%^f
8	DCE	AgNTf2	rt^e	5a	66%^f
9	DCE	AgSbF6	rt^e	5a	53%^f
10	DCE	AgBF4	rt^e	5a	49%^f
11	Benzene^g	AgNTf2	rt^e	5a	11%^f
12	THF^g	AgNTf2	rt^e	5a	27%^f
13	EtOH^g	AgNTf2	rt^e	5a	nd
14	CH3CN^g	AgNTf2	rt^e	5a	53%^f
15	DMF^g	AgNTf2	rt^e	5a	nd
16	DMSO^g	AgNTf2	rt^e	5a	nd

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Substrate scope investigation

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 R¹ and R² groups of propargyl ester formed a ring system (i.e., cyclohexyl and cyclopentyl), the reaction with bromide 2a (R⁴, R⁵, R⁶ = H) proceeded smoothly providing tricyclic products 5b and 5c in 53% and 55% yield, respectively. Moreover, with the R¹ as H, R² 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 R⁴/R⁵ groups. In the case of substrate 2b with R⁴ and R⁵ being Me and H, respectively, the expected product 5h was obtained in 36% yield and 1/1 dr ratio. When both R⁴ and R⁵ 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 configuration 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 confirmed 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 five-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).

Table 2 Exploration of the generality of the tandem reaction of cyclic alkanes as migrating groups^a

a Unless specified, all reactions were conducted using 1 (0.5 mmol, 2.5 eq.), 2 (0.2 mmol, 1.0 eq.), CuOAc (30 mol%), Cs₂CO₃ (50 mol%), AuPPh₃Cl (10 mol%), and AgNTf₂ (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 CHCl₃ was used as the solvent after Castro–Stephens coupling. d AuCl₃ (10 mol%) in 2 mL HFB (hexafluorobenzene) was used instead of the combination of AuPPh₃Cl and AgNTf₂ after Castro–Stephens coupling; the structure shows the relative configuration of the major isomer.

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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%), Cs₂CO₃ (50 mol%), AuPPh₃Cl (10 mol%), and AgNTf₂ (10 mol%) in a reaction tube in DCE (2 mL) at indicated temperature.

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Scheme 2 New synthetic strategy design toward corresponding sesquiterpenes.

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 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).

Synthetic application

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 hexafluorobenzene as the solvent.¹⁸ The relative configuration of 5p and its diastereoisomer 5q was confirmed 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 K₂CO₃-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.

Scheme 3 Synthetic utility of the tetracyclic skeleton of waihoensene. Reagents and conditions: (a) pyrrolidine, Et₃N, neat, 85 °C, then TBDPSCl, imidazole, CH₂Cl₂, 0 °C (98%); (b) Tf₂O, 2,6-di-tert-butyl-4-methylpyridine, DCE, reflux, then CCl₄/H₂O reflux (54%); (c) 2-bromopropene, t-BuLi, THF, −78 °C (85% brsm); (d) TESOTf, 2,6-lutidine, CH₂Cl₂, 0 °C (94%); (e) SeO₂, TBHP, CH₂Cl₂, 0 °C – rt (73% brsm); (f) CBr₄, PPh₃, imidazole, CH₂Cl₂, rt (90%); (g) prop-2-yn-1-yl acetate, CuOAc, Cs₂CO₃, DCE, 70 °C, then AuCl₃, PTS, HFB (hexafluorobenzene), rt (40%, dr = 3.2 : 1); (h) TBAF, THF, 0 °C (93%); (i) IBX, EtOAc, reflux (91%); (j) K₂CO₃, MeOH/H₂O = 100 : 1, 0 °C – rt (64%); (k) HCl, THF, rt (89%). TBDPSCl = tert-butyl diphenylchlorosilane, DCE = 1,2-dichloroethane, TESOTf = triethylsilyl trifluoromethanesulphonate, IBX = 2-iodoxybenzoic acid.

Conclusions

In summary, targeting a highly functionalized spirocyclo[4.5]decane skeleton, a purification free tandem Castro–Stephens coupling/1,3-acyloxy shift/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.

Conflicts of interest

The authors declare no competing interests.

Acknowledgements

We greatly thank the NSFC (No. 21502080, 21772071, 21871117, 21772076, 21702136, and 91956203), the ‘111’ Program and Central Universities program (lzujbky-2018-134) of MOE, the Major project (2018ZX09711001-005-002) of MOST, the STCSM (19JC1430100), and the Department of Education of Guangdong Province (2019KZDXM035) for their financial support.

Notes and references

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8. For selected examples of the Au-catalyzed 1,3-OAc shift of propargylic ester and cyclization: (a) M. Brandstätter, N. Huwylera and E. M. Carreira, Gold(I)-catalyzed stereoselective cyclization of 1,3-enyne aldehydes by a 1,3-acyloxy migration/Nazarov cyclization/aldol addition cascade, Chem. Sci., 2019, 10, 8219–8223; (b) S. K. Thummanapelli, S. Hosseyni, Y. Su, N. G. Akhmedov and X. Shi, Ligand-controlled gold-catalyzed cycloisomerization of 1,n-enyne esters toward synthesis of dihydronaphthalene, Chem. Commun., 2016, 52, 7687–7690; (c) C. Chen, Y. Zou, X. Chen, X. Zhang, W. Rao and P. W. H. Chan, Gold-catalyzed tandem 1,3-migration/double cyclopropanation of 1-ene-4,n-diyne esters to tetracyclodecene and tetracycloundecene derivatives, Org. Lett., 2016, 18, 4730–4733; (d) Z. Cao and F. Gagosz, Gold-catalyzed tandem cycloisomerization/Cope rearrangement: an efficient access to the hydroazulenic motif, Angew. Chem., Int. Ed., 2013, 52, 9014–9018; (e) Y. Chen, M. Chen and Y. Liu, Gold-catalyzed cascade cyclizations of 1,6-diynyl carbonates to benzo[b]fluorenes involving arylation of oxocarbenium ion intermediates and decarboxylative etherification, Angew. Chem., Int. Ed., 2012, 51, 6493–6497; (f) D. Lebœuf, A. Simonneau, C. Aubert, M. Malacria, V. Gandon and L. Fensterbank, Gold-catalyzed 1,3-acyloxy migration/5-exo-dig cyclization/1,5-acyl migration of diynyl esters, Angew. Chem., Int. Ed., 2011, 50, 6868–6871; (g) S. Bhunia and R.-S. Liu, Gold-catalyzed 1,3-addition of a sp³-hybridized C–H bond to alkenylcarbenoid intermediate, J. Am. Chem. Soc., 2008, 130, 16488–16489; (h) F.-Q. Shi, X. Li, Y. Xia, L. Zhang and Z.-X. Yu, DFT study of the mechanisms of in water Au(I)-catalyzed tandem [3,3]-rearrangement/Nazarov reaction/[1,2]-hydrogen shift of enynyl acetates:  a proton-transport catalysis strategy in the water-catalyzed [1,2]-hydrogen shift, J. Am. Chem. Soc., 2007, 129, 15503–15512; (i) A. Buzas and F. Gagosz, Gold(I) catalyzed isomerization of 5-en-2-yn-1-yl acetates: an efficient access to acetoxyl bicyclo[3.1.0]hexenes and 2-cycloalken-1-ones, J. Am. Chem. Soc., 2006, 128, 12614–12615; (j) J. Zhao, C. O. Hughes and F. D. Toste, Synthesis of aromatic ketones by a transition metal-catalyzed tandem sequence, J. Am. Chem. Soc., 2006, 128, 7436–7437; (k) L. Zhang and S. Wang, Efficient synthesis of cyclopentenones from enynyl acetates via tandem Au(I)-catalyzed 3,3-rearrangement and the Nazarov reaction, J. Am. Chem. Soc., 2006, 128, 1442–1443.
9. For selected reviews: (a) D. Pflasterer and A. S. Hashmi, Gold catalysis in total synthesis – recent achievements, Chem. Soc. Rev., 2016, 45, 1331–1367; (b) Y. Zhu, L. Sun, P. Lu and Y. Wang, Recent advances on the Lewis acid-catalyzed cascade rearrangements of propargylic alcohols and their derivatives, ACS Catal., 2014, 4, 1911–1925; (c) R. Kazem Shiroodi and V. Gevorgyan, Metal-catalyzed double migratory cascade reactions of propargylic esters and phosphates, Chem. Soc. Rev., 2013, 42, 4991–5001; (d) N. Krause and C. Winter, Gold-catalyzed nucleophilic cyclization of functionalized allenes: a powerful access to carbo- and heterocycles, Chem. Rev., 2011, 111, 1994–2009.
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12. For detailed optimization of tandem reaction conditions, see ESI.†.
13. M. Jia and M. Bandini, Counterion effects in homogeneous gold catalysis, ACS Catal., 2015, 5, 1638–1652.
14. For the X-ray crystallography of corresponding derivatives, please see ESI.†.
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17. H. Lee, T. Kang and H. Y. Lee, Total synthesis of (±)-waihoensene, Angew. Chem., Int. Ed., 2017, 56, 8254–8257.
18. For detailed optimization of reaction conditions, see ESI.†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1962272, 1962275, 1962276, 1962295, 1962296 and 1962417. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0sc00102c

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