Diastereoselective Intramolecular Carbolithiations of Stereodefined

Letter Cite This: Org. Lett. 2018, 20, 3518−3521

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Diastereoselective Intramolecular Carbolithiations of Stereodefined Secondary Alkyllithiums Bearing a Remote Alkynylsilane Meike Simon, Konstantin Karaghiosoff, and Paul Knochel* Department of Chemistry, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, 81377 Munich, Germany

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ABSTRACT: Various secondary alkyl iodides bearing a remote alkynylsilane underwent intramolecular carbolithiations triggered by an I/Li-exchange performed at −100 °C using tBuLi (2.5 equiv). The resulting alkenyllithiums were stereoselectively converted to tetrasubstituted cyclopentane exoalkylidenes. After Pd-catalyzed hydrogenation, cyclopentanes and cis-bicyclo[4.3.0]nonanes were obtained with stereocontrol of four contiguous centers. Scheme 1. Stereoselective Preparation of Iodides rac(2R,3R)-1a and rac-(2R,3S)-1a*

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arbometalations of organolithiums bearing a remote alkene or alkyne have been used to prepare various carbo- and heterocycles.1 The pioneering work of Bailey2 and Negishi3 has shown that primary alkyllithiums add intramolecularly to internal alkynes and alkynylsilanes. Hoppe4 demonstrated that optically enriched O-stabilized organolithium derivatives undergo trans-selective carbolithiations to ynol carbamates with high enantioselectivity. Recently, we have shown that nonstabilized, secondary alkyllithiums can be prepared from secondary alkyl iodides with retention of configuration.5 In addition, we have demonstrated that intramolecular carbolithiations provide a stereoselective access to alkylidene cyclobutanes.6 Herein, we report a highly stereoselective carbolithiation for preparing various cyclopentane derivatives with stereocontrol of up to four contiguous stereocenters. First, we have prepared the secondary iodoalkynes rac(2R,3R)-1a and rac-(2R,3S)-1a.7 Copper(I)-catalyzed addition of alkylmagnesium bromide 2 respectively to trans- and cis-2,3epoxybutane provided diastereoselectively the two alcohols rac(2S,3R)-3a and rac-(2S,3S)-3a in 86−89% (dr >99:1).8 Conversion with inversion of alcohols rac-(2S,3R)-3a and rac(2S,3S)-3a to the corresponding iodides rac-(2R,3R)-1a and rac-(2R,3S)-1a was performed under Appel conditions9 in 51− 63% (dr >99:1; Scheme 1). These alkyl iodides were stereoselectively converted to the Li-derivatives syn-4 and anti-4 using an I/Li-exchange triggered by the inverse addition of t-BuLi (2.5 equiv, Et2O, −100 °C). Quenching with iodine gave the corresponding syn- and antiiodides syn-5a and anti-5a in 71−77% yield (dr >99:1), indicating a high retention of configuration at C2 and C3. Interestingly, the reaction of iodide anti-5a with Bu(PhS)CuLi10 gave anti-6, introducing a butyl group instead of the iodide (Scheme 2).11 This reaction sequence was extended to other electrophiles such as ethyl chloroformate leading to the esters syn-5b and anti-5b in 65−77% with complete retention of the configuration (Table 1, entries 1 and 2). Quenching of syn-4 and anti© 2018 American Chemical Society

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Conditions: (a) (i) 2 (1.1 equiv), CuI (10 mol %), Et2O, 0 °C; (ii) trans- or cis-2,3-epoxybutane (1.0 equiv), rt, 16 h; (b) I2 (1.2 equiv), PPh3 (1.2 equiv), NMI (1.2 equiv), CH2Cl2, −5 °C, 2 h. The diastereomeric ratio was determined by NMR analysis. NMI = Nmethylimidazole.

4 with benzophenone gave the tertiary alcohols syn-5c (65%, dr >99:1) and anti-5c (76%, dr >99:1; entries 3−4). X-ray crystallographic analysis of syn-5c confirmed the syn-relative stereochemistry.12 Next, we examined 3-oxygenated substrates for the intramolecular carbolithiation. Since we reported that such iodides undergo a fast equilibration after I/Li-exchange providing an alkyllithium reagent in a stereoconvergent manner,5c,6 we chose to replace SiMe3 with SiPh3, which is known to facilitate carbolithiations and may therefore avoid subsequent equilibration.13 To our delight, the stereoselective performance of an I/Li-exchange on (2R,4R)-1b and (2R,4S)1b respectively produced syn-5d (99% yield, dr >99:1) and anti5d (55% yield, dr >99:1) after aqueous workup (entries 5 and 6). Received: April 23, 2018 Published: June 6, 2018 3518

DOI: 10.1021/acs.orglett.8b01290 Org. Lett. 2018, 20, 3518−3521

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>99:1; Table 2, entry 1). Alternatively, after quenching with ClCO2Et, ester syn-7b was obtained in 56% yield (dr >99:1;

Scheme 2. Stereoselective Synthesis of Alkenyl Iodides (syn5a and anti-5a)a

Table 2. Diastereoselective Synthesis of Polycyclic Alkenylsilanes

a

Conditions: Bu(PhS)CuLi (3.0 equiv), THF, −5 °C, 45 h.

Table 1. Intramolecular Diastereoselective Carbolithiation Leading to exo-Alkylidenecyclopentane Derivatives

a

Yields of isolated, analytically pure products.

entry 2). Similarly, the iodocyclohexane syn-1d underwent after treatment with t-BuLi the expected carbolithiation and gave after iodination or quenching with methyl triflate the bicyclic products syn-7c and syn-7d in 65−77% yield (dr >99:1; entries 3 and 4). Transmetalation with ZnCl2 and Negishi15 crosscoupling with naphthyl bromide using 5 mol % of Pd(OAc)2 and 10 mol % of SPhos16 stereoselectively furnished syn-7e in 99% yield (dr >99:1; entry 5). Finally, the syn-phenylsubstituted cyclohexyl iodide syn-1e underwent a carbolithiation after I/Li-exchange. Iodination at −100 °C gave syn-7f in 92% yield, dr >99:1 (entry 6). In all cases, the iodides were obtained in high stereopurity. Carbolithiation products of type 5 were used to construct cyclopentanes bearing four fully controlled contiguous stereocenters. Thus, standard carbolithiation starting from rac-

a

Yields of isolated, analytically pure products. b1 mmol scale: 71%, dr >99:1.

Using these conditions, it was possible to prepare bicyclic and tricyclic ring systems.14 Thus, the reaction of the cyclopentane iodide syn-1c with t-BuLi (−100 °C, 15 min) provided after iodolysis the bicyclic iodide syn-7a (63% yield, dr 3519

DOI: 10.1021/acs.orglett.8b01290 Org. Lett. 2018, 20, 3518−3521

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After standard I/Li-exchange on R-1f (er = 98:2), transmetalation with ZnCl2, and Negishi cross-coupling with ethyl 4iodobenzoate, the tetrasubstituted styrene derivative R-5f was obtained in 74% yield and er = 95:5. In addition, the enantiomer S-1f (er = 97:3) was exposed to the same reaction conditions to afford S-5f in 70% yield and er = 96:4. Two different isomeric bicyclic ring systems were also built with control of their four contiguous stereocenters using such an intramolecular carbolithiation (Scheme 5). Thus, the two

(2R,3R)-1a followed by a transmetalation with ZnCl2 gave zinc reagent syn-8a which, after Negishi cross-coupling with ethyl 4iodobenzoate using 5 mol % of Pd(OAc)2 and 10 mol % of SPhos,16 stereoselectively afforded the tetrasubstituted alkenylsilane syn-5e (84% yield, dr >99:1). Further iodination of syn-5e with NIS in acetonitrile provided the alkenyl iodide syn-9 (87% yield, dr >99:1), and subsequent Negishi cross-coupling with methylzinc chloride led to the tetrasubstituted olefin syn-10 (77% yield, dr >99:1). This sequence demonstrates that the carbolithiation products can be stereoselectively converted to silyl-free tetrasubstituted olefins. Pd-catalyzed hydrogenation of syn-10 gave the syn-ester syn-11 (100% yield, dr >99:1). The structure of syn-11 was confirmed by X-ray analysis of the corresponding carboxylic acid syn-12 obtained after saponification (Scheme 3).

Scheme 5. Preparation of cis-Bicyclic[4.3.0]nonanes Bearing Four Contiguous Stereocenters*

Scheme 3. Diastereoselective Preparation of Cyclopentanes Bearing Four Contiguous Tertiary Centers*

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Conditions: (a) (i) t-BuLi (3.4 equiv, inverse addition), Et2O, −100 °C; (ii) −100 °C, 15 min; (b) ZnCl2 in THF (2.0 equiv), warm to 15 °C; (c) ethyl 4-iodobenzoate (1.0 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %), DMA, rt, 16 h; (d) NIS (4.0 equiv), CH3CN, rt, 71 h; (e) MeZnCl (1.3 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %), THF, 0 °C, 4 h; (f) H2, Pd/C (10 mol %), MeOH, rt, 21 h; (g) KOH (2.0 equiv), MeOH, 40 °C, 69 h. DMA = N,N-dimethylacetamide, NIS = N-iodosuccinimide. The I/Li-exchange yields the corresponding Lispecies in about 75% yield. Therefore, an excess of the alkyl iodide has been used to perform this reaction sequence.

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Conditions: (a) (i) ZnCl2 in THF (2.0 equiv), warm to 15 °C; (ii) naphthyl bromide (1.0 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %), DMA, rt, 16 h; (b) MeSO2CF3 (2.5 equiv) (c) NIS (6.0 equiv), MeCN/CH2Cl2 (2:1), rt, 23 h; (d) NIS (2.0 equiv), CH3CN, rt, 1.5 h; (e) MeZnCl (1.3 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %), THF, 0 °C, 4 h; (f) naphthylzinc chloride (1.3 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %), THF, 0 °C, 2.5 h; (g) H2, Pd/C (10 mol %), MeOH, rt, 2 h; (h) H2, Pd/C (10 mol %), MeOH, rt, 2.5 h.

This intramolecular carbolithiation was also performed in an enantioselective fashion (Scheme 4). Scheme 4. Enantioselective Synthesis of Cyclopentane Derivatives ((R)-5f and (S)-5f)

alkenyl silanes syn-7d and syn-7e were converted with retention of configuration to the corresponding alkenyl iodides using NIS in MeCN/CH2Cl2 at 25 °C for 2−23 h to obtain the alkenyl iodides 13a and 13b in 75−85% yield.17 Stereoselective Negishi cross-coupling with methylzinc chloride and 2-naphthylzinc chloride, respectively (5 mol % of Pd(OAc)2, 10 mol % of SPhos,16 0 °C, 2.5−4 h) provided Z-14 and E-14 in 79−88% yield (dr >99:1).18 Exohydrogenation of Z-14 and E-14 using H2 (1 atm) in the presence of 10 mol % of Pd/C in MeOH (25 °C, 2−2.5 h) furnished the two epimeric cis-bicyclo[4.3.0]nonanes 15 and 16 in 76−92%. The relative configuration of 15 was established by X-ray analysis.19 In summary, we have reported highly diastereoselective intramolecular carbolithiations allowing the synthesis of stereodefined exoalkylidene cyclopentanes and related cisbicyclo[3.3.0]octanes and cis-bicyclo[4.3.0]nonanes with stereocontrol of up to four contiguous stereocenters. Further

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Conditions: (a) (i) t-BuLi (3.4 equiv, inverse addition), Et2O, −100 °C; (ii) −100 °C, 15 min; (b) ZnCl2 in THF (2.0 equiv), warm to 15 °C; (c) ethyl 4-iodobenzoate (1.0 equiv), Pd(OAc)2 (5 mol %), SPhos (10 mol %), DMA, rt, 16 h. 3520

DOI: 10.1021/acs.orglett.8b01290 Org. Lett. 2018, 20, 3518−3521

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Am. Chem. Soc. 1987, 109, 2442. (c) Bailey, W. F.; Ovaska, T. V.; Leipert, T. K. Tetrahedron Lett. 1989, 30, 3901. (d) Bailey, W. F.; Ovaska, T. V. Tetrahedron Lett. 1990, 31, 627. (e) Bailey, W. F.; Ovaska, T. V. Chem. Lett. 1993, 22, 819. (f) Bailey, W. F.; Ovaska, T. V. J. Am. Chem. Soc. 1993, 115, 3080. (3) Wu, G.; Cederbaum, F. E.; Negishi, E.-i. Tetrahedron Lett. 1990, 31, 493. (4) (a) Gralla, G.; Wibbeling, B.; Hoppe, D. Org. Lett. 2002, 4, 2193. (b) Gralla, G.; Wibbeling, B.; Hoppe, D. Tetrahedron Lett. 2003, 44, 8979. (5) (a) Seel, S.; Dagousset, G.; Thaler, T.; Frischmuth, A.; Karaghiosoff, K.; Zipse, H.; Knochel, P. Chem. - Eur. J. 2013, 19, 4614. (b) Dagousset, G.; Moriya, K.; Mose, R.; Berionni, G.; Knochel, P. Angew. Chem. 2014, 126, 1449; Angew. Chem., Int. Ed. 2014, 53, 1425. (c) Moriya, K.; Didier, D.; Simon, M.; Hammann, J. M.; Berionni, G.; Karaghiosoff, K.; Zipse, H.; Mayr, H.; Knochel, P. Angew. Chem. 2015, 127, 2793; Angew. Chem., Int. Ed. 2015, 54, 2754. (6) Moriya, K.; Schwärzer, K.; Karaghiosoff, K.; Knochel, P. Synthesis 2016, 48, 3141. (7) Morozova, V.; Skotnitzki, J.; Moriya, K.; Karaghiosoff, K.; Knochel, P. Angew. Chem., Int. Ed. 2018, 57, 5516. (8) (a) Ghribi, A.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1984, 25, 3075. (b) Alexakis, A.; Jachiet, D.; Normant, J. F. Tetrahedron 1986, 42, 5607. (c) Martin, S. F.; Fishpaugh, J. R.; Power, J. M.; Giolando, D. M.; Jones, R. A.; Nunn, C. M.; Cowley, A. H. J. Am. Chem. Soc. 1988, 110, 7226. (d) Sommer, S.; Kühn, M.; Waldmann, H. Adv. Synth. Catal. 2008, 350, 1736. (9) Appel, R. Angew. Chem. 1975, 87, 863; Angew. Chem., Int. Ed. Engl. 1975, 14, 801. (10) Posner, G. H.; Whitten, C. E.; Sterling, J. J. J. Am. Chem. Soc. 1973, 95, 7788. (11) Nakajima, R.; Delas, C.; Takayama, Y.; Sato, F. Angew. Chem., Int. Ed. 2002, 41, 3023. (12) X-ray crystallographic analysis of syn-5c confirmed the synrelative stereochemistry. (13) (a) Cason, L. F.; Brooks, H. G. J. Am. Chem. Soc. 1952, 74, 4582. (b) Cason, L. F.; Brooks, H. G. J. Org. Chem. 1954, 19, 1278. (c) Buell, G. R.; Corriu, R.; Guerin, C.; Spialter, L. J. Am. Chem. Soc. 1970, 92, 7424. (d) Igawa, K.; Tomooka, K. Angew. Chem., Int. Ed. 2006, 45, 232. (14) Examples for the preparation of bicyclic ring structures using carbolithiations: (a) Bailey, W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am. Chem. Soc. 1987, 109, 2442. (b) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 6467. (15) (a) Negishi, E.-i.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821. (b) Labaudinière, L.; Normant, J. F. Tetrahedron Lett. 1992, 33, 6139. (16) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871. (17) The relative configuration of 13a and 13b was verified by NOESY experiments. (18) The relative configuration of Z-14 and E-14 was verified by NOESY experiments. (19) The relative configuration of 16 was verified by NOESY experiments.

applications of this intramolecular carbolithiation are underway in our laboratory.

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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/acs.orglett.8b01290. Detailed experimental procedures and analytical data (PDF) Accession Codes

CCDC 1829144−1829147 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Paul Knochel: 0000-0001-7913-4332 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Deutsche Forschungsgemeinschaft (SFB749) for financial support. We also thank Albemarle (Frankfurt) and BASF SE and for the generous gift of chemicals. M.S. thanks the Fond der Chemischen Indutrie. We thank Dr. Kohei Moriya and Dr. Dorian Didier (Ludwig-Maximilians-Universität, Munich) for preliminary experiments.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b01290 Org. Lett. 2018, 20, 3518−3521