Synthesis of Spiroketals by Synergistic Gold and Scandium Catalysis

Letter pubs.acs.org/OrgLett

Synthesis of Spiroketals by Synergistic Gold and Scandium Catalysis Man Liang,† Shuai Zhang,† Jiong Jia,*,† Chen-Ho Tung,† Jianwu Wang,† and Zhenghu Xu*,†,‡ †

Key Laboratory for Colloid and Interface Chemistry of Education Ministry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China ‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China S Supporting Information *

ABSTRACT: An ultrafast synthesis of spiroketals by synergistic gold(I) and Sc(III) catalysis has been reported. Diverse 5,6-benzannulated spiroketals were rapidly constructed by the diastereoselective [4 + 2] cycloaddition between goldgenerated enol ether and Sc(III)-catalyzed o-quinone methide intermediates. Ultrafast reaction rate, ambient reaction temperature, general scope, high yields, excellent diastereoselectivity, and good scalability are attractive features of this method.

S

Scheme 1. Synthesis of Spiroketals with Gold Catalysis

piroketals are an important structural unit within a wide variety of bioactive natural products as well as pharmaceuticals (Figure 1).1 Among them, the 5,6-benzannulated

Figure 1. Natural products containing a spiroketal moiety.

spiroketals are an important type of privileged structures and are the key pharmacophore found in biological active natural products, such as berkelic acid2 and the rubromycins3 (Figure 1). In particular, berkelic acid exhibits selective activity against the ovarian cancer cell line OVCAR3; γ-rubromycin exhibits antibacterial properties as well as inhibitory effects on HIV-1 reverse transcriptase. Consequently, efficient synthetic methods4 to access these natural products and their simplified analogues are highly desirable in order to probe the promising bioactivities of those compounds. Gold-catalyzed5 intramolecular cyclization of alcohol-functionalized internal alkynes is an important approach to build spiroketal groups (Scheme 1A). In 2009, Aponick et al. developed an efficient gold-catalyzed intramolecular cyclization of monopropargylic triols to synthesize olefin-containing 5,6spiroketals.6 This approach has also been widely used in the synthesis of spiroketal-containing natural products. For example, in the synthesis of A−D rings of azaspiracid, the Forsyth group reported the first bis-spiroketalization reaction from complicated internal alkyne precursor in the presence of gold catalyst and pyridinium p-toluenesulfonate (PPTS).7a Later, similar gold/PPTS-catalyzed intramolecular bis-spiroketalization was utilized by Trost in the synthesis of (−)-ushikulide A7b and also by Fürstner in his synthesis of © 2017 American Chemical Society

spirastrellolide F methyl ester.7c All these successful examples require preparation of complicated functionalized precursors in advance. Thus, the development of a direct intermolecular approach to spiroketals from easily available fragments is highly desirable from the point of view of diversity-oriented synthesis.8 We herein report a Au(I)/Sc(OTf)3 synergistic catalytic reaction of alkyne alcohol and o-quinone methide precursor, providing an ultrafast synthesis of spiroketals under mild conditions (Scheme 1B) . o-Quinone methides (o-QMs)9,10 are versatile, highly reactive intermediates widely used in organic synthesis. With the driving force of aromatization, they reacted as a polarized 1oxobutadiene to participate in various cycloaddition and Received: March 17, 2017 Published: May 5, 2017 2526

DOI: 10.1021/acs.orglett.7b00804 Org. Lett. 2017, 19, 2526−2529

Letter

Organic Letters

reaction is completed in 5 min and the product could be isolated in 90% yield (entry 13). Without the early-transitionmetal catalyst Sc(OTf)3, a very messy reaction was observed (entry 15). When only Sc(OTf)3 was used, only the direct addition product 4 was isolated in 88% yield (see Scheme 4a). These results indicated that both catalysts are necessary for this reaction. When AgOTf was used as π-acid instead of gold(I) catalyst, much lower 37% yield of the desired product 3a was obtained together with 57% direct addition product 4 (entry 17). The high efficiency of this reaction led us to consider whether we could lower the catalyst loading. To our delight, when loading of Au catalyst decreased to 0.5 mol % and together with 1 mol % of Sc(OTf)3, the reaction still proceeded smoothly, giving the product in 74% yield in 4 h. Moreover, the scalability of this reaction was examined by carrying out the reaction with 4.0 mmol of 1a in the presence of 0.5 mol % gold catalyst. The desired product (3a) was isolated in 65% yield (0.85 g, eq 1).

conjugate addition reactions in the presence of organocatalysts and transition-metal catalysts. Following our recent interest in developing π-acid and σ metal acid bimetallic catalysis to construct fused or spiro heterocycles,11 we reasoned that goldcatalyzed 5-exo-dig cyclization of the alkynyl alcohol 2a could afford the key electron-rich vinyl ether intermediate M2. At the same time, o-hydroxybenzhydryl alcohol 1a might generate oQM intermediate M1 in the presence of lanthanide acid catalysts. The direct [4 + 2] cycloaddition between M1 and M2 would form the expected spiroketal heterocycles (Scheme 1B). The major challenge in this proposed reaction is the formation and reactivity of these two reactive intermediates should synchronize with each other. To test the viability of this hypothesis, we chose alkynyl alcohol 2a and o-hydroxybenzhydryl alcohol 1a as the model substrates. To our delight, the reaction proceeded smoothly, and the target product 3a was isolated in 64% yield as a single diastereomer in the presence of Ph3PAuCl/AgNTf2 and Sc(OTf)3 in DCM at room temperature (entry 1, Table 1). Table 1. Optimization of Reaction Conditionsa

catalyst entry

[Au]

[LA]

solvent

yieldb (%)

c

Ph3PAuCl/AgNTf2 Ph3PAuCl/AgNTf2 Ph3PAuCl/AgNTf2 Ph3PAuCl/AgNTf2 Ph3PAuCl/AgNTf2 Ph3PAuCl/AgNTf2 Ph3PAuCl/AgOTf IPrAuCl/AgOTf (CH3)2SAuCl JohnPhosAuCl/AgOTf Ph3PAuCl/AgOTf Ph3PAuCl/AgOTf Ph3PAuCl/AgOTf Ph3PAuCl/AgOTf IPrAuCl/AgOTf

Sc(OTf)3 Ga(OTf)3 La(OTf)3 In(OTf)3 Bi(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3

DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM toluene CH3CN DCE THF DCE DCE DCE

64 27 22 33 38 73 82 73 75 81 66 79 90 59 messy 0 37

1 2c 3c 4c 5c 6 7 8 9 10 11 12 13 14 15 16 17

AgOTf

Sc(OTf)3 Sc(OTf)3

After establishing the optimal reaction conditions, we started to investigate the scope of o-QM precursors 1. As summarized in Scheme 2, the reactions proceeded smoothly and completed Scheme 2. Substrate Scope of o-Hydroxybenzhydrolsa

a

Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [Au] (5 mol %), Lewis acid catalyst (10 mol %), 4 Å M.S. (80 mg), dry solvent (2 mL), room temperature, 1 h. bIsolated yields were reported. c1a (0.24 mmol), 2a (0.2 mmol).

The structure of 3a was unambiguously characterized by singlecrystal X-ray crystallography. Subsequently, a series of other σ metal acid such as Ga(OTf)3, La(OTf)3, In(OTf)3, and Bi(OTf)3 were evaluated (entries 1−5), but none of them were found to be superior than Sc(OTf)3. During this process, we noticed that the vinyl ether intermediate M2 is very reactive, and when we reversed the ratio of these two reagents, the isolated yield increased to 73% (entry 6). The yield was further improved to 82% when AgOTf was used instead of AgNTf2 (entry 7). Other gold catalysts were also explored and all could give good yields (entries 7−10). Finally, the effect of solvents was examined (entries 11−14), and DCE proved to be the most favorable solvent. Pleasingly, we observed that the

a

Standard reaction conditions were employed, and isolated yields were reported.

within 30 min, giving the corresponding products in excellent yields as single diastereomer in most cases. Importantly, not only various aryl groups (3a−j,q−t) but aliphatic group substituted substrates reacted very well in this reaction (3l− o). Substrates bearing a gem-dimethyl group could also afford the desired product (3m) containing an all-carbon quaternary center in 50% yield. The minor diastereoisomers were observed 2527

DOI: 10.1021/acs.orglett.7b00804 Org. Lett. 2017, 19, 2526−2529

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alcohol 2f produced two products indicated that the C−O bond formation in compound 4 is reversible (Scheme 3b). A nonracemic alchohol 4-ent was prepared by Sun’s method.10o When this chiral alcohol 4-ent was subjected to the standard reaction, racemic product 3a was obtained (Scheme 3c). On the basis of these experiments, a plausible mechanism was proposed as shown in Scheme 5. Sc(OTf)3 and cationic gold

when cyclohexyl or long aliphatic substituents were applied (3n,o). An alkynyl functional group was also well tolerated under the reaction conditions and gave the desired product (3p) in 65% yield. Other alkynyl alcohols and alkynyl amides were further evalutated under optimized conditions (Scheme 3). Aliphatic Scheme 3. Substrate Scope of Alkynesa

Scheme 5. Proposed Mechanism

catalyst synergistically activate substrates 1a and 2a, generating electrophilic o-QM intermediate M1 and nucelophilic vinyl ether intermediate M2, subsequent [4 + 2] cycloaddition between M1 and M2 produced the spiroketal products. The reaction of 2a with M1 forms adduct 4, which undergoes 5-exodig cyclization, and C−O bond cleavage cascade in the presence of gold catalyst could also generate intermediate M1 and M2 at the same time. In summary, we have developed a synergistic gold(I)/ Sc(OTf)3-catalyzed cascade strategy to access spiroketals. The salient features of this method include ultrafast reaction rate, mild conditions, broad substrate scope, and good scalability. The one-pot reaction method offered a practical approach for molecular complex spiroketal derivatives from simple starting materials, which may facilitate further structure-relationship studies of these biological important moieties.

a

Standard reaction condition were employed, and isolated yields were reported.

alcohol 2c could also react with 1a to afford spiroketal (3v) in 42% yield. Alkynyl amides 2d and 2e also proceeded smoothly, giving the corresponding spiroaminals in 76% and 59% yields. Substrate 2f bearing one less carbon chain reacted smoothly with 1a to generate the fused tricyclic ketal 3y in 56% yield. Controlled experiments were conducted to gain insights into the reaction mechanism. The Sc(OTf)3-catalyzed reaction of 1a and 2a afforded direct addition product 4 in 88% yield. This adduct could transform into spiroketal 3a in 85% isolated yield with single cationic gold catalyst (Scheme 4a). Both steps were completed in less than 10 min. These results showed adduct 4 is viable to the product. The crossover reaction between 4 and

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Scheme 4. Controlled Experiments

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00804. Experimental details, crystal structure of 3a, and characterization data (PDF) X-ray crystallographic data for compound 3a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Chen-Ho Tung: 0000-0001-9999-9755 Zhenghu Xu: 0000-0002-3189-0777 Notes

The authors declare no competing financial interest. 2528

DOI: 10.1021/acs.orglett.7b00804 Org. Lett. 2017, 19, 2526−2529

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2014, 53, 7923. (f) Hsiao, C.-C.; Liao, H.-H.; Rueping, M. Angew. Chem., Int. Ed. 2014, 53, 13258. (g) Zhao, W.; Wang, Z.; Chu, B.; Sun, J. Angew. Chem., Int. Ed. 2015, 54, 1910. (h) Huang, Y.; Hayashi, T. J. Am. Chem. Soc. 2015, 137, 7556. (i) Saha, S.; Schneider, C. Org. Lett. 2015, 17, 648. (j) Tsui, G. C.; Liu, L.; List, B. Angew. Chem., Int. Ed. 2015, 54, 7703. (k) Zhao, J.- J.; Sun, S.-B.; He, S.-H.; Wu, Q.; Shi, F. Angew. Chem., Int. Ed. 2015, 54, 5460. (l) Guo, W.; Wu, B.; Zhou, X.; Chen, P.; Wang, X.; Zhou, Y.-G.; Liu, Y.; Li, C. Angew. Chem., Int. Ed. 2015, 54, 4522. (m) Wang, Z.; Ai, F.; Wang, Z.; Zhao, W.; Zhu, G.; Lin, Z.; Sun, J. J. Am. Chem. Soc. 2015, 137, 383. (n) Wu, B.; Gao, X.; Yan, Z.; Chen, M.-W.; Zhou, Y.-G. Org. Lett. 2015, 17, 6134. (o) Lai, Z.; Wang, Z.; Sun, J. Org. Lett. 2015, 17, 6058. (p) Wu, B.; Yu, Z.; Gao, X.; Lan, Y.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2017, 56, 4006. (q) Chen, P.; Wang, K.l; Guo, W.; Liu, X.; Liu, Y.; Li, C. Angew. Chem., Int. Ed. 2017, 56, 3689. (11) (a) Wang, X.; Dong, S.; Yao, Z.; Feng, L.; Daka, P.; Wang, H.; Xu, Z. Org. Lett. 2014, 16, 22. (b) Wang, X.; Yao, Z.; Dong, S.; Wei, F.; Wang, H.; Xu, Z. Org. Lett. 2013, 15, 2234. (c) Zhang, S.; Xu, Z.; Jia, J.; Tung, C.-H.; Xu, Z. Chem. Commun. 2014, 50, 12084. (d) Zhang, S.; Wei, F.; Song, C.; Jia, J.; Xu, Z. Chin. J. Chem. 2014, 32, 937. (e) Wang, B.; Chen, Y.; Zhou, L.; Wang, J.; Tung, C.-H.; Xu, Z. J. Org. Chem. 2015, 80, 12718. (f) Wang, B.; Chen, Y.; Zhou, L.; Wang, J.; Xu, Z. Org. Biomol. Chem. 2016, 14, 826. (g) Wang, B.; Liang, M.; Tang, J.; Deng, Y.; Zhao, J.; Sun, H.; Tung, C.-H.; Jia, J.; Xu, Z. Org. Lett. 2016, 18, 4614. (h) Zhang, S.; Cheng, B.; Wang, S.; Zhou, L.; Tung, C.-H.; Wang, J.; Xu, Z. Org. Lett. 2017, 19, 1072.

ACKNOWLEDGMENTS We are grateful for financial support from the Natural Science Foundation of China and Shandong province (Nos. 21572118 and JQ201505), the fundamental subject construction funds (No. 104.205.2.5), and a Tang Scholar Award from Shandong University.

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REFERENCES

(1) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406. (2) (a) Stierle, A. A.; Stierle, D. B.; Kelly, K. J. Org. Chem. 2006, 71, 5357. (b) Liu, J.; De Brabander, J. K. J. Am. Chem. Soc. 2009, 131, 12562. (c) Fananás, F. J.; Mendoza, A.; Arto, T.; Temelli, B.; Rodriguez, F. Angew. Chem., Int. Ed. 2012, 51, 4930. (3) Brasholz, M.; Sörgel, S.; Azap, C.; Reißig, H.-U. Eur. J. Org. Chem. 2007, 2007, 3801. (4) For recent reviews, see: (a) Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406. (b) Wilsdorf, M.; Reissig, H.-U. Angew. Chem., Int. Ed. 2012, 51, 9486. (c) Quach, R.; Chorley, D. F.; Brimble, M. A. Org. Biomol. Chem. 2014, 12, 7423. (d) Palmes, J. A.; Aponick, A. Synthesis 2012, 44, 3699. For recent examples, see: (e) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Angew. Chem., Int. Ed. 2012, 51, 936. (f) Č orić, I.; List, B. Nature 2012, 483, 315. (g) Sun, Z.; Winschel, G. A.; Borovika, A.; Nagorny, P. J. Am. Chem. Soc. 2012, 134, 8074. (h) Ho, J. H. H.; Choy, S. W. S.; Macgregor, S. A.; Messerle, B. A. Organometallics 2011, 30, 5978. (i) Yuen, T.-Y.; Yang, S.-H.; Brimble, M. A. Angew. Chem., Int. Ed. 2011, 50, 8350. (j) Zeng, X.-P; Zhou, J. J. Am. Chem. Soc. 2016, 138, 8730. (5) For reviews on gold catalysis, see: (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271. (b) Fürstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (c) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (d) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (e) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (f) Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766. (g) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232. (h) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111, 1954. (i) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448. (j) Wei, F.; Song, C.; Ma, Y.; Zhou, L.; Tung, C.-H.; Xu, Z. Sci. Bull. 2015, 60, 1479. (k) Liu, L.; Zhang, J. Chem. Soc. Rev. 2016, 45, 506. (l) Shu, C.; Li, L.; Tan, T.; Yuan, D.; Ye, L. Sci. Bull. 2017, 62, 352. (6) (a) Aponick, A.; Li, C.-Y.; Palmes, J. A. Org. Lett. 2009, 11, 121. (b) Palmes, J. A.; Paioti, P. H. S.; de Souza, L. P.; Aponick, A. Chem. Eur. J. 2013, 19, 11613. (7) (a) Li, Y.; Zhou, F.; Forsyth, C. J. Angew. Chem., Int. Ed. 2007, 46, 279. (b) Trost, B. M.; O’Boyle, B. M.; Hund, D. J. Am. Chem. Soc. 2009, 131, 15061. (c) Benson, S.; Collin, M.; Arlt, A.; Gabor, B.; Goddard, R.; Fürstner, A. Angew. Chem., Int. Ed. 2011, 50, 8739. (8) (a) Barluenga, J.; Mendoza, A.; Rodriguez, F.; Fananás, F. J. Angew. Chem., Int. Ed. 2009, 48, 1644. (b) Wu, H.; He, Y.-P.; Gong, L.Z. Org. Lett. 2013, 15, 460. (c) Tian, T.; Li, L.; Xue, J.; Zhang, J.; Li, Y. J. Org. Chem. 2015, 80, 4189. (d) Marsini, M. A.; Huang, Y.; Lindsey, C. C.; Wu, K.; Pettus, T. R. R. Org. Lett. 2008, 10, 1477. (e) Butkevich, A. N.; Corbu, A.; Meerpoel, L.; Stansfield, I.; Angibaud, P.; Bonnet, P.; Cossy, J. Org. Lett. 2012, 14, 4998. (9) For reviews, see: (a) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367. (b) Pathak, T. P.; Sigman, M. S. J. Org. Chem. 2011, 76, 9210. (c) Willis, N. J.; Bray, C. D. Chem. - Eur. J. 2012, 18, 9160. (d) Bai, W.-J.; David, J. G.; Feng, Z.-G.; Weaver, M. G.; Wu, K.-L.; Pettus, T. R. R. Acc. Chem. Res. 2014, 47, 3655. (e) Caruana, L.; Fochi, M.; Bernardi, L. Molecules 2015, 20, 11733. (f) Wang, Z.; Sun, J. Synthesis 2015, 47, 3629. (g) Ai, W.; Liao, D.; Lei, X. Youji Huaxue 2015, 35, 1615. (10) (a) Alden-Danforth, E.; Scerba, M. T.; Lectka, T. Org. Lett. 2008, 10, 4951. (b) Jana, R.; Pathak, T. P.; Jensen, K. H.; Sigman, M. S. Org. Lett. 2012, 14, 4074. (c) Izquierdo, J.; Orue, A.; Scheidt, K. A. J. Am. Chem. Soc. 2013, 135, 10634. (d) Lv, H.; Jia, W.-Q.; Sun, L.-H.; Ye, S. Angew. Chem., Int. Ed. 2013, 52, 8607. (e) El-Sepelgy, O.; Haseloff, S.; Alamsetti, S. K.; Schneider, C. Angew. Chem., Int. Ed. 2529

DOI: 10.1021/acs.orglett.7b00804 Org. Lett. 2017, 19, 2526−2529