Enantio- and Diastereoselective Spiroketalization Catalyzed by Chiral

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Enantio- and Diastereoselective Spiroketalization Catalyzed by Chiral Iridium Complex James Y. Hamilton, Simon L. Rössler, and Erick M. Carreira* Eidgenössische Technische Hochschule Zürich, Vladimir-Prelog-Weg 3, HCI H335, 8093 Zürich, Switzerland S Supporting Information *

Scheme 1. Representative Ir-Catalyzed Enantio- and Diastereoselective Spiroketalization (this work)

ABSTRACT: Iridium−(P,olefin) complex-catalyzed enantio- and diastereoselective formation of substituted spiroketals from racemic, allylic carbonates is reported, which enables the installation of multiple stereogenic centers in a single operation. The protocol was effective for the preparation of a collection of spiroketals of various ring sizes and substituents, including heteroatoms with high enantio- and diastereoselectivity. Furthermore, cascade reactions that couple this enantio- and diastereoselective transformation to additional reversible processes have been achieved to exert concomitant stereocontrol over additional stereogenic centers.

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hiral spiroketal motifs are found in a broad array of biologically active natural products from insect, plant, bacterial, and marine sources as well as in anthropogenic therapeutic agents.1 The significance of this moiety is highlighted by the diversity of structures and bioactivity of the compounds that feature them, ranging from simple bis-oxacycles in insect pheromones2a (i.e., oleans) to anticancer agents of daunting sizes and complexities such as spongistatins2b and halichondrins.2c Furthermore, multitudes of antiphytopathogenic, antibiotic, and antidiabetic naturally occurring molecules as well as ionophores incorporate stereodefined spiroketals.2d−f The inherently rigid spiroketal moiety plays an integral role in bioactive agents by directly interacting with cognate groups in molecular targets and/or through the positioning of substituents and their attendant functional groups.2g Accordingly, control of configuration at the spirocyclic carbon and other stereogenic centers decorating the periphery is of paramount importance in any synthetic sequence. Herein, we disclose an applicable and highly enantio- and diastereoselective spiroketalization strategy, catalyzed by a chiral Ir−(P,olefin) complex generated in situ from [{Ir(cod)Cl}2] and (S)-L (Scheme 1). This approach enables access to a wide range of spiroketals with concomitant formation of multiple stereogenic centers with high enantio- and diastereocontrol. The versatility of the process allows for tandem intermolecular hemiacetalization−spiroketalization of a ketoaldehyde and bis-spiroketalization of hydroxydiketone, generating three stereogenic centers in a single operation. A classical approach toward optically active spiroketal compounds involves acid-catalyzed, diastereoselective, dehydrative cyclization of chiral dihydroxyketones (Scheme 2a).1 In studies by List, chiral Brønsted acids were demonstrated to catalyze highly enantioselective spiroketalization of achiral precursors, effecting control at the stereogenic spirocyclic © 2017 American Chemical Society

Scheme 2. Previous Asymmetric Approaches to Spiroketals

carbon (Scheme 2b).3,4 Despite the merits of these approaches, development of catalytic methods that are enantio- and diastereoselective for preparation of spiroketals containing additional substituents and stereogenic centers, which are often essential for biologically active targets, would be highly beneficial for applications in target oriented synthesis.5 Iridium-catalyzed, asymmetric allylic substitution has attracted attention, allowing utilization of a wide range of carbon and heteroatom reaction partners, led by Hartwig, Helmchen, Stoltz, You, and others.6,7 Encouraged by our studies in allylic etherification8a and other methodologies8 catalyzed by a chiral Ir−(P,olefin) complex,8b,c we were intrigued by the prospect of a process within which are embedded numerous dynamic equilibria that ultimately sort themselves out to stereoselectively furnish functionalized spiroketals, in analogy to the classic dynamic diastereoselective processes employed for the synthesis of complex polyketides.9 Accordingly, the use of a chiral iridium Received: March 22, 2017 Published: June 9, 2017 8082

DOI: 10.1021/jacs.7b02856 J. Am. Chem. Soc. 2017, 139, 8082−8085

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Journal of the American Chemical Society Table 1. Ir-Catalyzed Enantio- and Diastereoselective Spiroketalizationa

Standard conditions: 1 (0.4 mmol), cat.: [{Ir(cod)Cl}2]:(S)-L = 1:4, Zn(OTf)2 (2 mol %), acetone (0.25 M), 4 °C, 24 h. bIsolated yields of purified products after flash chromatography. cDiastereomeric ratio was determined by 1H NMR integration after purification. Enantiomeric ratio was determined by GC or SFC on chiral stationary phase. Absolute stereoconfiguration was assigned by X-ray crystallography of 2g and analogy; d Yield (based on 1g) and d.r. in parentheses were obtained after treating the initially obtained 2g with (±)-camphorsulfonic acid (0.5 equiv) at 25 °C. a

out as the ideal cocatalyst.11 Additionally, the use of acetone as solvent was identified as crucial for high enantioselectivity. Moreover, technical grade acetone without any special precautions to exclude air or moisture was found sufficient, rendering this protocol operationally convenient. The optimized conditions involved conducting the reaction at 4 °C for further enhancement in enantioselectivity, furnishing 2a as a single diastereomer in 93% yield and 99:1 e.r. (Table 1, entry 1).12 Having established the optimized conditions (Table 1, entry 1), we explored the scope of the method.13 In addition to [6,6]-

complex as catalyst would be responsible for triggering the stereoconvergent formation of a functionalized spiroketal with diastereo- and enantiocontrol (Scheme 1).10 Our investigation commenced by evaluating the reactivity and product profile of racemic hydroxyketone derivative 1a (Table 1) in the presence of {Ir(cod)Cl}2] and (S)-L. Extensive experimentation using this standard substrate (see Supporting Information for full details) revealed a number of critical reaction parameters. In particular, employing a suitable acidic promoter was required to achieve high conversion with Zn(OTf)2 singled 8083

DOI: 10.1021/jacs.7b02856 J. Am. Chem. Soc. 2017, 139, 8082−8085

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Journal of the American Chemical Society

the synthetic versatility of substituted spiroketal 2a was demonstrated through its conversion to other useful building blocks (Scheme 4). To this end, 2a was efficiently converted to

spiroketal 2a, spirocycles of varying ring sizes could be obtained. For example, [6,5]- and [6,7]-spiroketals (2b and 2c) were synthesized in high yields with excellent diastereo- and enantioselectivities (Table 1, entries 2 and 3). Furthermore, [5,6]-spirocycle 2d was obtained, albeit with reduced diastereoselectivity (entry 4). Hydroxyketones featuring geminaldimethyl substituents (1e) and phenol (1f) also smoothly underwent enantio- and diastereoselective spiroketalization in superb yields (entries 5 and 6). Notably, heteroatoms in the chain were well tolerated, allowing the access to highly enantiomerically enriched heterocyclic spiroketals (2g and 2h) (entries 7 and 8). Under the conditions described, 2g was initially obtained as a mixture of diastereomers (1.2:1 d.r.). However, the thermodynamically more stable diastereomer could be selectively produced without deterioration of the product’s optical purity by subjecting this mixture to Brønsted acid-mediated equilibrating conditions (entry 7). We next examined asymmetric spiroketalization of substrates containing additional substituents to prepare synthetically valuable spiroketals rich in stereogenic centers. Hydroxy β-ketoester 1i (1:1 d.r.) cyclized to give spiroketals 2i and 2i′ as a readily separable 1:1 mixture with excellent enantio- and diastereomeric ratios for each diastereomer (entry 9). Closer inspection of the reaction mixture revealed the ratio between 2i and 2i′ remained unchanged throughout the reaction, indicating the presence of the adjacent substituent had a minimal effect on efficiency of the catalytic process.14 Finally, carbohydrate-derived substrate 1j underwent catalyst-controlled asymmetric spiroketalization to deliver spiroketals 2j and 2j′ (entries 10 and 11), which lack full anomeric stabilization, as observed in a process mediated by an achiral Pd-catalyst.10a,15 We subsequently found the iridium-catalyzed spiroketalization could be embedded within cascade processes. Thus, under the conditions described above in the presence of additional benzyl alcohol, aldehyde 3 underwent tandem, intermolecular hemiacetalization−spiroketalization reaction to afford 4 in high enantioselectivity (Scheme 3a). Moreover, enantio- and diastereoselective bis-spiroketalization of hydroxydiketone 5 was realized to provide 6 (Scheme 3b).16

Scheme 4. Synthetic Elaboration of Spiroketal 2aa,b

a

Reagents and conditions: (a) Pd(Quinox)Cl2 (5 mol %), AgSbF6 (12 mol %), TBHP (12 equiv), CH2Cl2, 3 h, 81%; (b) 9-BBN−H (1.5 equiv), 0 to 25 °C, THF, then H2O, NaBO3, 0 to 25 °C, 92%; (c) Hoveyda-Grubbs II (10 mol %), allyl chloride (10 equiv), CH2Cl2, 40 °C, 22 h, 78%; (d) BzONBn2 (1.2 equiv), Cu(OAc)2 (4 mol %), (±)-DTBM-SEGPHOS (4.4 mol %), diethoxymethylsilane (2.0 equiv), THF, 40 °C, 36 h, 91%; (e) Pd/C (5 mol %), H2, EtOAc, 3 h, 90%. bAll products were obtained as single diastereomers without erosion of e.r. (99:1).

ketone 7 employing the ketone-selective Wacker oxidation reaction developed by Sigman.19 In addition, 2a smoothly underwent hydroboration/oxidation or cross-metathesis with allyl chloride to give alcohol 8 and chloride 9, respectively. Cucatalyzed hydroamination of 2a yielded aliphatic amine 10 in excellent yield with exclusive anti-Markovnikov selectivity.20 Finally, insect pheromone 11, a cephalic secretion of cleptoparasitic bee, was prepared via standard hydrogenation of 2a.21 In summary, we developed an iridium-catalyzed enantio- and diastereoselective spiroketalization of racemic, allylic carbonates. The method enables the preparation of synthetically valuable substituted spiroketals by installing multiple stereogenic centers employing a single chiral catalyst under mild and operationally convenient conditions. High stereoselectivity was observed for a broad range of products of various ring sizes, incorporating heteroatoms and additional substituents. Furthermore, substituted substrates underwent the catalyst-controlled diastereoselective spiroketalization to afford spirocycles rich in stereogenic centers. Finally, stereoselective cascade processes led to the installation of three stereogenic centers in a single operation. The strategy enables access to a wide range of spiroketals with concomitant formation of multiple stereogenic centers, rendering them amenable to further elaboration for use as building blocks. Further studies regarding the development of related transformations and applications of the new method are ongoing and will be reported in due course.

Scheme 3. Cascade Spirocyclization Reactions

The spiroketal building blocks produced from the method we describe may find utility in complex molecule synthesis endeavors. For example, the pyrrolidine alkaloids broussonetines G and H are potent inhibitors of glycosidases, which incorporate pendant spiroketal side chains.17 An approach by Trost showcases a strategy to these that links a functionalized spirocyclic fragment to an amino arabinose core.18 Accordingly,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b02856. 8084

DOI: 10.1021/jacs.7b02856 J. Am. Chem. Soc. 2017, 139, 8082−8085

Communication

Journal of the American Chemical Society

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Am. Chem. Soc. 2002, 124, 15164. For recent selected examples of asymmetric Ir-catalyzed allylic substitutions, see: (d) Giacomina, F.; Riat, D.; Alexakis, A. Org. Lett. 2010, 12, 1156. (e) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461. (f) Gärtner, M.; Mader, S.; Seehafer, K.; Helmchen, G. J. Am. Chem. Soc. 2011, 133, 2072. (g) Ye, K.-Y.; He, H.; Liu, W.-B.; Dai, L.-X.; Helmchen, G.; You, S.-L. J. Am. Chem. Soc. 2011, 133, 19006. (h) Chen, W.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 15249. (i) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626. (j) Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298. (k) Chen, W.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 377. (l) Chen, W.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2068. (m) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47, 2558. (n) Zhang, X.; Yang, Z.-P.; Huang, L.; You, S.-L. Angew. Chem., Int. Ed. 2015, 54, 1873. (o) Chen, M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2016, 55, 11651. (p) Madrahimov, S. T.; Li, Q.; Sharma, A.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 14968. (q) Yang, Z.-P.; Wu, Q.-F.; Shao, W.; You, S.-L. J. Am. Chem. Soc. 2015, 137, 15899. (r) Yang, Z.-P.; Zheng, C.; Huang, L.; Qian, C.; You, S.-L. Angew. Chem., Int. Ed. 2017, 56, 1530. (8) (a) Roggen, M.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 5568. (b) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (c) Rössler, S. L.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2017, 139, 3603. (d) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2013, 135, 994. (e) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science 2013, 340, 1065. (f) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Angew. Chem., Int. Ed. 2013, 52, 7532. (g) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3006. (h) Hamilton, J. Y.; Hauser, N.; Sarlah, D.; Carreira, E. M. Angew. Chem., Int. Ed. 2014, 53, 10759. (i) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Angew. Chem., Int. Ed. 2015, 54, 7644. (9) Totah, N. I.; Schreiber, S. L. J. Org. Chem. 1991, 56, 6255. (10) (a) For spiroketalization mediated by an achiral Pd-catalyst, see: Palmes, J. A.; Paioti, P. H. S.; de Souza, L. P.; Aponick, A. Chem. - Eur. J. 2013, 19, 11613. (b) The reaction design relied on rapid and reversible ring-chain tautomerism and mutarotation preceding the slower and irreversible asymmetric allylic etherification in order to achieve high enantio- and diastereoselectivity.. (11) Schafroth, M. A.; Sarlah, D.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2012, 134, 20276. (12) When the reaction was stopped at 55% conversion under otherwise the optimized conditions, the starting material could be reisolated as a single enantiomer (>99:1 e.r.), indicating high degree of kinetic resolution is operative. (13) Throughout this study, no competing macrocyclic etherification was observed. (14) Introduction of chiral substituent adjacent to the hydroxy group also showed minimal effect on the cyclization (S32→S33, see Supporting Information for details). (15) (a) Kirby, A. J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen; Springer: New York, 1983. (b) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Pergamon Press: Oxford, U. K., 1983. (16) The configuration of the distal spiroketal carbon, displaying 3:1 d.r. is favored presumably as a consequence of dipole-dipole repulsion, consistent with a previous report, see: McGarvey, G. J.; Stepanian, M. W.; Bressette, A. R.; Ellena, J. F. Tetrahedron Lett. 1996, 37, 5465. (17) Shibano, M.; Nakamura, S.; Akazawa, N.; Kusano, G. Chem. Pharm. Bull. 1998, 46, 1048. (18) Trost, B. M.; Horne, D. B.; Woltering, M. J. Angew. Chem., Int. Ed. 2003, 42, 5987. (19) Michel, B. W.; Camelio, A. M.; Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2009, 131, 6076. (20) Zhu, S.; Niljianskul, N.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 15746. (21) (a) Tengö, J.; Bergström, G.; Borg-Karlson, A.-K.; Groth, I.; Francke, W. Z. Naturforsch., C: J. Biosci. 1982, 37c, 376. (b) Stok, J. E.; Lang, C.-S.; Schwartz, B. D.; Fletcher, M. T.; Kitching, W.; De Voss, J. J. Org. Lett. 2001, 3, 397.

Full experimental details and characterization data (PDF) Crystallographic data (CIF)

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Simon L. Rössler: 0000-0002-5057-0576 Erick M. Carreira: 0000-0003-1472-490X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS ETH Zürich and the Swiss National Science Foundation (200020_152898) are gratefully acknowledged for financial support. We are grateful to Dr. B. Schweizer, Dr. N. Trapp, and M. Solar for X-ray crystallographic analysis and W. Desiante for synthetic support. The authors also thank the colleagues of Prof. A. Togni and Prof. H. Wennemers groups for their support with chiral chromatography analysis.

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REFERENCES

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DOI: 10.1021/jacs.7b02856 J. Am. Chem. Soc. 2017, 139, 8082−8085