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Cationic Cascade for Building Complex Polycyclic Molecules from Simple Precursors: Diastereoselective Installation of Three Contiguous Stereogenic Centers in a One-Pot Process Georgios Alachouzos and Alison J. Frontier* Department of Chemistry, University of Rochester, 414 Hutchison Hall, 100 Trustee Road, Rochester, New York 14627-0216, United States J. Am. Chem. Soc. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 12/20/18. For personal use only.

S Supporting Information *

Scheme 1. Halo-Prins/Halo-Nazarov Strategy

ABSTRACT: An expedient strategy for the synthesis of polycyclic small molecules is described. The method first joins together two achiral building blocks (an enyne and an aldehyde or a ketone) using an alkynyl halo-Prins protocol. Then, in the same reaction vessel, acidic conditions initiate a cationic cascade that includes a stereospecific halo-Nazarov electrocyclization and a diastereoselective Friedel−Crafts allylation. The entire sequence forms three carbon−carbon bonds and a carbon−halogen bond, generating halocyclopentene adducts in one pot from simple precursors. The process occurs with excellent diastereocontrol, providing highly functionalized polycycles containing three tertiary or quaternary stereogenic centers in a linear array. It is even possible to install three contiguous all-carbon quaternary centers using this method.

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he search for new pharmaceuticals demands that chemists identify versatile, effective new methods for synthesizing polycyclic, densely functionalized, three-dimensional small molecules.1−3 The diastereoselective installation of multiple contiguous stereogenic centers, including all-carbon quaternary centers, in polycyclic systems remains one of the outstanding challenges.4−6 The stereospecificity of the Nazarov cyclization, and its ability to engage in reaction cascades, has offered valuable strategies for achieving this goal.7−12 Notably, vicinal quaternary centers can be generated using Nazarov electrocyclization methods.13−16 Still, the Nazarov cyclization typically depends upon the synthesis and reaction of dienone precursors, which has limited its ability to assemble complex ring systems from simple starting materials.11 Recently, we reported a two-step method for the synthesis of halocyclopentenes 6, using a strategy that hinged upon the largely unexplored halo-Nazarov cyclization.17 Combining simple carbonyl precursors 1 with enynes 2, we demonstrated that an alkynyl halo-Prins reaction produces 3 as a mixture of E and Z isomers (see Scheme 1). Upon exposure of 3 to acid and hexafluoroisopropyl alcohol (HFIP), two interconverting cationic intermediates (“U”- and “S” isomers) are generated,18 and electrocyclization occurs via cation “U”-4. Capture of haloallyl cation 5 by the pendent alcohol delivers spirocycles 6 (see Scheme 1). While these initial studies established the halo-Prins/halo-Nazarov sequence as a viable strategy for rapid assembly of complex cyclopentenes, two shortcomings of the © XXXX American Chemical Society

process were readily identified. First, while spirocycles 6 were initially formed diastereoselectively, epimerization was observed upon prolonged exposure to the reaction conditions. This indicated that the formation of the C−O bond was reversible, and that spirocycles 6 are particularly acid sensitive. Second, even though both steps of the sequence (halo-Prins and halo-Nazarov cyclization) are Brønsted acid-promoted, spirocycle 6 formation is only efficient if halo-Prins product 2 is isolated and purified prior to ionization. We reasoned that if haloallyl cation 5 could be captured in an irreversible process, it should be possible to execute the alkynyl halo-Prins, ionization, and halo-Nazarov cyclization all in one reaction vessel, under appropriate acidic conditions. Judging by the original two-step sequence, the new bonds would be formed with excellent stereocontrol, provided the Nazarov cyclization is stereospecific and the trapping event is diastereoselective. Such a strategy would create three contiguous stereogenic centers in a single operation and, with appropriate reactants, enable installation of all-carbon quaternary centers. In the studies outlined herein, we realize this idea. and describe a strategy for the direct synthesis of complex halocyclopentenes from two simple reactants: an aldehyde or ketone 1 and an enyne 2. Received: October 31, 2018

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DOI: 10.1021/jacs.8b11713 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society

Table 1. Optimization (in situ Ionization of 2a)

Carbon nucleophiles, including arenes, heteroarenes, alkenes and alkynes, add readily to cyclic oxyallyl cation species. This chemistry forms the basis for “interrupted” versions of the oxyNazarov cyclization,19,20 and has also been developed in conjunction with a simple ionization event.21−24 To test the feasibility of a interrupted halo-Nazarov strategy, we chose to examine aldehyde 1a, which bears an electron-rich aryl group well-suited for intramolecular capture of the type 5 haloallyl cation intermediate, with irreversible formation of a new C−C bond and all-carbon quaternary center. The halo-Prins reaction we developed proceeds under acidic conditions (with strong acids TfOH, TsOH, Tf2NH, etc.) in chloroform (CHCl3),17 generating intermediates 3a in the presence of a dehydrating agent and halide source. Because tetrabutylammonium iodide (TBAI) gives the best results, it was selected for our initial studies. When aldehyde 1a and enyne 2a were exposed to these reaction conditions, the expected ionization precursor 3a was obtained in 88% yield as a mixture of olefin isomers (Scheme 2). Upon subsequent ionization of 3a, no spiroether type 6 Nazarov product was formed, with the only product observable being aryl-trapped halo-Nazarov product 7a.

entry

solvent [Prins]

conditions for in situ ionization

1

CHCl3

2 3 4 5

CHCl3 CHCl3 DCM CHCl3

add HFIPb heat to 40 °C heat to 50 °C add HFIPb warm to rt add HFIPb warm to rt keep at −20 °C

time 1/time 2

7a (yield; dr)

10 min/2.5 h

52%; 7.5:1

10 10 20 24

23%; 7:1 74%; 14:1 49%; 5:1 −25

min/2 h min/1 h min/4 h h

a

Reaction conditions (halo-Prins): 1a (1 equiv), 2a (1.5 equiv); TBAI (2 equiv) Tf2NH (2.4 equiv), 5 Å mol. sieves, solvent, −20 °C, time 1. b10% HFIP (by volume) was added to the reaction, time 2. HFIP = hexafluoroisopropyl alcohol, DCM = dichloromethane, CHCl3 = chloroform. The dr refers to the ratio of diastereoisomers (determined by 1H NMR analysis) at the indicated (*) stereogenic center.

Having identified promising reaction conditions, we tested a series of carbonyl reactants in the cascade reaction (Scheme 3). Both aldehydes and ketones are viable, and although longer halo-Prins reaction times are required for ketones, the subsequent interrupted halo-Nazarov proceeds smoothly (7a vs 7b; 7c vs 7d). The cascades leading to 7b and 7d illustrate how ketone reactants can be employed to construct cis-fused ring systems with adjacent quaternary centers at the ring

Scheme 2. Sequential Halo-Prins/Interrupted Halo-Nazarov

a

Reaction conditions (halo-Prins step): 1a (1 equiv), 2a (1.5 equiv); TBAI (2 equiv) TfOH (1.2 equiv), 5 Å mol. sieves, CHCl3, 0 °C, 10 min. b18:3:2 mixture (C2−C3 and C4−C5 olefin isomers). cReaction conditions (ionization/halo-Nazarov step): TfOH (0.2 equiv) DCM/ HFIP 19:1, −10 °C to rt over 3 h. dUnreacted 3a was the only other product observed (1:1:1 mixture of isomers); >95% mass recovery from experiment. The dr refers to the ratio of diastereoisomers (determined by 1H NMR analysis) at the indicated (*) stereogenic center.

Scheme 3. Scope (Carbonyl Reactant 1)

Given the efficiency of the Prins cyclization, and evidence that ionization of 3a can generate 7a with high selectivity, it seemed likely that the entire sequence could be carried out without stopping to isolate 3a. Because HFIP was critical to smooth ionization/cyclization in our earlier study,17 we experimented with adding it to 3 in situ. Thus, triflimide (Tf2NH) was used to promote the Prins reaction, and HFIP was introduced at −20 °C (10% v/v HFIP/CHCl3) after formation of 3a was judged complete.25 When the resultant solution was warmed to 40 °C, 7a was obtained in 52% yield (Entry 1, Table 1). As expected, the isolated yield of 7a is lower if the reaction mixture is warmed to 50 °C without the HFIP additive (Entry 2, Table 1). When warming to room temperature after addition of HFIP the yield of 7a increases to 74%, and the diastereoselectivity improves as well (14:1 dr; Entry 3, Table 1). Dichloromethane (DCM) can be employed for the entire cascade reaction instead of CHCl3, but longer reaction times are required for both steps, and 7a is only obtained in 49% yield (Entry 4, Table 1). Without HFIP or warming past −20 °C the desired product 7a is never observed, even after a 24 h reaction time.25

a

A complete list of carbonyl compounds 1 can be found in the SI. Product 7c can only be separated from side products 8c after repeated column chromatography. cThree equiv of enyne 2a can be used to drive the reaction to completion in cases where 1 is a ketone; alternatively, 1 can be recovered. dThe halo-Prins reaction was carried out at 0 °C instead of −20 °C, and some unreacted 1e (Ar = indolyl, m = 0, R = H) was recovered. The dr refers to the ratio of diastereoisomers (determined by 1H NMR analysis) at the indicated (*) stereogenic center. b

B

DOI: 10.1021/jacs.8b11713 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society junction. During assembly of 7c and 7d, elimination products 8 are also observed (see SI). Finally, heteroaromatic systems participate in the interrupted halo-Nazarov cascade, forming complex fused halocyclopentenes 7e, 7f, and 7g. Replacing TBAI with tetrabutylammonium bromide (TBAB) in the reaction of 1a and 2a effected smooth conversion to 7h (see Scheme 4) demonstrating that the sequence is also effective for the synthesis of bromocyclopentenes. Next, a series of enyne reactants 2 were tested, to evaluate the impact of tether length and alkene substitution pattern on the efficiency of the process. Enynes 2c and 2d underwent efficient reaction with 1a to afford 7i and 7j. The tether length can be one carbon shorter (2d) or longer (2e), as indicated by the successful syntheses of 7k and 7l. Finally, two highly functionalized enynes (2f and 2g) were tested, in an effort to obtain products containing useful synthetic handles on the cyclopentene ring. Remarkably, these sensitive substrates survived the acidic reaction conditions and executed the haloPrins/interrupted halo-Nazarov sequence, albeit with lower overall yields, to furnish ester 7m and dihaloalkene 7n.

Scheme 5. Installation of Three Contiguous All-Carbon Quaternary Centers

Scheme 6. Mechanistic Rationale for Diastereoselectivity

Scheme 4. Scope (Enyne Reactant 2) observed.26−29 Our results suggest that the 3-halopentadienyl cation intermediates behave differently. The data indicate that different substitution patterns at both C1 and C4 of the 3-halopentadienyl cation 4 (see Scheme 6) lead to different diastereoselectivities in the cyclization. When comparing cyclizations of intermediates with C4 substituents R′ = H, CH3, and Br, we observe a drop in diastereoselectivity, from >19:1, to 14:1, to 4:1, in products 7i, 7a, and 7n, respectively. This suggests that as the size of R′ increases, steric interactions begin to destabilize the “1-out, 5-out” isomer, and more of the “1-out, 5-in” isomer cyclizes. Ketone-derived products are obtained with lower dr than aldehyde-derived products (cf. 7d (Rs = CH3) and 7a (Rs = H); Scheme 1). Presumably, formation and reaction of the “1-out, 5-out” isomer is not as dominant when both Rs and RL are alkyl groups. Indeed, it is remarkable that such high diastereoselectivities are observed with ketone reactants. Example 7m shows how a C4 electron-withdrawing group results in a higher diastereoselectivity, presumably because pentadienyl cation isomerization is facile and the “1-out, 5-out” isomer is readily accessible.27 The diastereomeric ratios thus reflect the relative isomerization and cyclization rates of a complex mixture of 3halopentadienyl cation isomers. The high selectivity observed in most cases can be attributed to (1) a low barrier for interconversion between the cationic isomers, and (2) a preference for cyclization of the “1-out, 5-out” isomer. The vinyl halide moiety presents a synthetic handle for further functionalization of halocyclopentenes 7. As a demonstration, we prepared carbazole derivative 9 using a Suzuki cross-coupling protocol (see Scheme 7).17,30 This reaction was high-yielding and allowed us to confirm the structural assignment of 7a, through X-ray crystallographic analysis. In conclusion, we have developed a diastereoselective strategy for synthesizing complex polycycles 7 from simple, achiral precursors 1 and 2. Three contiguous tertiary or quaternary stereogenic centers are installed during the transformation. Four new chemical bonds are made, three of which are carbon−carbon bonds (“carbonyl pinch,” see Scheme 8). The fourth is an sp2 carbon−halide bond, which

a A complete list of enynes 2 can be found in the SI. The dr refers to the ratio of diastereoisomers (determined by 1H NMR analysis) at the indicated (*) stereogenic center.

We also examined the possibility of using this method to create three contiguous all-carbon quaternary centers in one synthetic operation. The experiment involved the combination of ketone 1b with tetrasubstituted enyne 2h, and generated tricycle 7o in 57% isolated yield. Once a reliable protocol for the halo-Prins/halo-Nazarov sequence was established, we sought to rationalize the stereoselectivity observed across the cases studied (see Scheme 5). The Prins reaction affords mixtures of isomers 3, which then ionizes to produce a mixture of halopentadienyl cation intermediates (see Scheme 1). Four of these isomers (denoted as “1-out, 5-out”, “1-out, 5-in”, etc.; see Scheme 6) will have the “U” conformation required for electrocyclization, and two stereoisomers 7 and epi-7 can be generated from these four via conrotatory electrocyclization (see Scheme 6). Previous studies report that 3-oxypentadienyl cation intermediates isomerize readily under the reaction conditions, and only products from cyclization of the “out−out” isomer are C

DOI: 10.1021/jacs.8b11713 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

Journal of the American Chemical Society

(2) O’ Connor, C. J.; Beckmann, H. S. G.; Spring, D. R. Diversityoriented synthesis: producing chemical tools for dissecting biology. Chem. Soc. Rev. 2012, 41, 4444. (3) Nadin, A.; Hattotuwagama, C.; Churcher, I. Lead-Oriented Synthesis: A New Opportunity for Synthetic Chemistry. Angew. Chem., Int. Ed. 2012, 51, 1114−1122. (4) Peterson, E. A.; Overman, L. E. Contiguous stereogenic quaternary carbons: A daunting challenge in natural products synthesis. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11943−11948. (5) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740−751. (6) Quasdorf, K. W.; Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 2014, 516, 181− 191. (7) Wenz, D. R.; Read de Alaniz, J. The Nazarov Cyclization: A Valuable Method to Synthesize Fully Substituted Carbon Stereocenters. Eur. J. Org. Chem. 2015, 2015, 23−37. (8) Di Grandi, M. J. Nazarov-like cyclization reactions. Org. Biomol. Chem. 2014, 12, 5331−5345. (9) Shimada, N.; Stewart, C.; Tius, M. A. Asymmetric Nazarov cyclizations. Tetrahedron 2011, 67, 5851−5870. (10) Vaidya, T.; Eisenberg, R.; Frontier, A. J. Catalytic Nazarov Cyclization: The State of the Art. ChemCatChem 2011, 3, 1531− 1548. (11) Spencer, W. T., III; Vaidya, T.; Frontier, A. J. Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates. Eur. J. Org. Chem. 2013, 2013, 3621−3633. (12) Bender, J. A.; Arif, A. M.; West, F. G. Nazarov-initiated diastereoselective cascade polycyclization of aryltrienones. J. Am. Chem. Soc. 1999, 121, 7443−7444. (13) Jolit, A.; Vazquez-Rodriguez, S.; Yap, G. P. A.; Tius, M. A. Diastereospecific Nazarov Cyclization of Fully Substituted Dienones: Generation of Vicinal All-Carbon-Atom Quaternary Stereocenters. Angew. Chem., Int. Ed. 2013, 52, 11102−11105. (14) He, W.; Huang, J.; Sun, X.; Frontier, A. J. Total Synthesis of (±)-Merrilactone A. J. Am. Chem. Soc. 2008, 130, 300−308. (15) Harding, K. E.; Clement, K. S. A highly stereoselective, convergent synthesis of (±)-trichodiene. J. Org. Chem. 1984, 49, 3870−3871. (16) Jolit, A.; Walleser, P. M.; Yap, G. P. A.; Tius, M. A. Catalytic Enantioselective Nazarov Cyclization: Construction of Vicinal AllCarbon-Atom Quaternary Stereocenters. Angew. Chem., Int. Ed. 2014, 53, 6180−6183. (17) Alachouzos, G.; Frontier, A. J. Diastereoselective Construction of Densely Functionalized 1-Halocyclopentenes Using an Alkynyl Halo-Prins/Halo-Nazarov Cyclization Strategy. Angew. Chem., Int. Ed. 2017, 56, 15030−15034. (18) Smith, C. D.; Rosocha, G.; Mui, L.; Batey, R. A. Investigation of Substituent Effects on the Selectivity of 4π-Electrocyclization of 1,3Diarylallylic Cations for the Formation of Highly Substituted Indenes. J. Org. Chem. 2010, 75, 4716−4727. (19) Grant, T. N.; Rieder, C. J.; West, F. G. Interrupting the Nazarov reaction: domino and cascade processes utilizing cyclopentenyl cations. Chem. Commun. 2009, 5676−5688. (20) Wu, Y.-K.; Dunbar, C. R.; McDonald, R.; Ferguson, M. J.; West, F. G. Experimental and Computational Studies on Interrupted Nazarov Reactions: Exploration of Umpolung Reactivity at the αCarbon of Cyclopentanones. J. Am. Chem. Soc. 2014, 136, 14903− 14911. (21) Vander Wal, M. N.; Dilger, A. K.; MacMillan, D. W. C. Development of a generic activation mode: nucleophilic αsubstitution of ketones via oxy-allyl cations. Chem. Sci. 2013, 4, 3075−3079. (22) Stepherson, J.; Ayala, C.; Dange, N.; Kartika, R. Nucleophilic Capture of Unsymmetrical Oxyallyl Cations with Indoles under Mild Brønsted Acid Catalysis. Synlett 2016, 27, 320−330.

Scheme 7. Synthetic Utility of Products 7

Scheme 8. Carbonyl Pinch (sp2 to Tertiary/Quaternary sp3)

can be functionalized further to yield a fourth carbon−carbon bond. Studies focused on enantioselective cyclizations and applications to a variety of complex natural products are underway.

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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.8b11713. Experimental details (PDF) NMR spectra (PDF) Data for C31H31NO3 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Georgios Alachouzos: 0000-0002-3058-2246 Alison J. Frontier: 0000-0001-5560-7414 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Science Foundation (CHE1565813) for funding this research. We thank Dr. William W. Brennessel for performing X-ray crystallography of 9, and Kevin Welle for performing high-resolution mass spectrometry of all newly reported compounds.

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REFERENCES

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DOI: 10.1021/jacs.8b11713 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX