《有机化学》课程教学资源（文献资料）Applications of 1-Alkenyl-1,1-Heterobimetallics in the Stereoselective Synthesis of Cyclopropylboronate Esters.pdf

Applications of 1-Alkenyl-1,1-Heterobimetallics in the Stereoselective Synthesis of Cyclopropylboronate Esters, Trisubstituted Cyclopropanols and 2,3-Disubstituted Cyclobutanones Mahmud M. Hussain, Hongmei Li, Nusrah Hussain, Mercedes Uren˜ a, Patrick J. Carroll, and Patrick J. Walsh* P. Roy and Diana T. Vagelos Laboratories, UniVersity of PennsylVania, Department of Chemistry, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323 Received January 14, 2009; E-mail: pwalsh@sas.upenn.edu Abstract: 1-Alkenyl-1,1-heterobimetallics are potentially very useful in stereoselective organic synthesis but are relatively unexplored. Introduced herein is a practical application of 1-alkenyl-1,1-heterobimetallic intermediates in the synthesis of versatile cyclopropyl alcohol boronate esters, which are valuable building blocks. Thus, hydroboration of 1-alkynyl-1-boronate esters with dicyclohexylborane generates 1-alkenyl- 1,1-diboro species. In situ transmetalation with dialkylzinc reagents furnishes 1-alkenyl-1,1-borozinc heterobimetallic intermediates. Addition of the more reactive ZnsC bond to aldehydes generates the key B(pin) substituted allylic alkoxide intermediates. An in situ alkoxide directed cyclopropanation proceeds with the formation of two more CsC bonds, affording cyclopropyl alcohol boronate esters with three new stereocenters in 58-89% isolated yields and excellent diastereoselectivities (>15:1 dr). Oxidation of the BsC bond provides trisubstituted R-hydroxycyclopropyl carbinols as single diastereomers in good to excellent yields (75-93%). Facile pinacol-type rearrangement of the R-hydroxycyclopropyl carbinols provides access to both cis- and trans-2,3-disubstituted cyclobutanones with high stereoselectivity (>17:1 dr in most cases) from a common starting material. This methodology has been applied in the synthesis of quercus lactones A and B. 1. Introduction The development of new methods for the stereoselective construction of CsC bonds remains a fundamental and important goal in organic synthesis.1-3 With modern synthetic design demanding high efficiency, an appealing strategy is the advancement of novel tandem reactions whereby sequential transformations can be performed without isolation or purification of intermediates.4-10 Such a strategy minimizes the number of synthetic steps while maximizing the molecular complexity and yield. One approach to efficiently introduce molecular complexity entails generation of functionalized 1,1-heterobimetallic intermediates, wherein each metal-carbon bond exhibits distinct reactivity that can be selectively exploited in CsC bond-forming reactions or functional group manipulations.11-13 Despite the potential usefulness of these reagents, 1,1-bimetallics are rarely applied to synthesis, most likely because of their high reactivity and difficult preparation and handling. The vast majority of investigations of 1,1-bimetallic reagents involve sp3 -hybridized bimetallics.11,13-16 In contrast, 1-alkenyl-1,1-bimetallics have received considerably less attention, largely due to difficulties controlling double bond geometry,12,13 multistep preparations, or limited functional group tolerance.17,18 The challenges in generation and reactions of 1-alkenyl-1,1-bimetallics are highlighted in Scheme 1. (1) Walsh, P. J.; Kozlwoski, M. C. Fundamentals of Asymmetric Catalysis; University Science Books: Sausalito, CA, 2008. (2) Augustine, R. L., Ed. In Carbon-Carbon Bond Formation; Marcel Dekker, Inc: New York, 1979; Vol. 1, p 461. (3) No´gra´di, M. StereoselectiVe Synthesis; VCH Publishers, Inc: New York, 1995; p 370. (4) Ho, T. L. Tandem Organic Reactions; Wiley and Sons: New York, 1992; p 502. (5) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p 27. (6) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (7) Schmalz, H.-G.; Geis, O. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; Wiley: New York, 2002; Vol. 2, p 2377. (8) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551. (9) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. 1993, 32, 131. (10) Posner, G. H. Chem. ReV. 1986, 86, 831. (11) Marek, I.; Normant, J. -F. Chem. ReV. 1996, 96, 3241. (12) Marek, I. Chem. ReV. 2000, 100, 2887. (13) Marek, I. Actual. Chim. 2003, 15. (14) Normant, J.-F. Acc. Chem. Res. 2001, 34, 640. (15) Matsubara, S.; Oshima, K.; Utimoto, K. J. Organomet. Chem. 2001, 39, 617. (16) Marek, I.; Normant, J.-F. In Organozinc Reagents. A Practical Approach; Knochel, P., Jones, P. Eds.; Oxford University Press: 1999, p 119. (17) Waas, J. R.; Sidduri, A.; Knochel, P. Tetrahedron Lett. 1992, 33, 3717. (18) Shimizu, M.; Kurahashi, T.; Kitagawa, H.; Hiyama, T. Org. Lett. 2003, 5, 225. Published on Web 04/21/2009 6516 9 J. AM. CHEM. SOC. 2009, 131, 6516–6524 10.1021/ja900147s CCC: $40.75  2009 American Chemical Society

Early work by Knochel and co-workers explored the chemistry of 1-alkenyl-1,1-heterobimetallics wherein bimetallics of boron and zinc or copper were generated to synthesize R-hydroxy ketones.17 Further development and applications of these reagents were thwarted by loss of double-bond stereochemistry during the formation of the bimetallic reagent. Srebnik and coworkers successfully addressed this limitation by generation of bimetallics of boron and zirconium via hydrozirconation of B(pin) alkynes with Schwartz’s reagent (Cp2ZrHCl). Transmetalation from zirconium to zinc was followed by a Negishi coupling to give B(pin) substituted dienes.19-21 Use of stoichiometric Schwartz’s reagent remains prohibitively expensive (>$2,000/mol) at this time. Soderquist and co-workers generated 1-alkenyl-1,1-diboro intermediates by hydroboration of alkynylborinates with dicyclohexylborane, which were selectively protodeborylated with acetic acid to form (Z)-vinyl boranes.22 To address the challenges in the synthesis and applications of 1-alkenyl-1,1-bimetallics, we recently reported a practical generation of 1,1-heterobimetallics from air-stable B(pin)- substituted alkynylboronate esters and demonstrated their utility in a variety of one-pot transformations to provide boronate substituted allylic alcohols, dienols, R-hydroxy ketones, and protected R,-dihydroxy ketones with high diastereoselectivity (Scheme 2).23 Thus, hydroboration of air stable alkynyldioxaborolane with dicyclohexylborane proceeded regioselectively to cleanly generate the new 1,1-diboro intermediates, as judged by 1 H, 11B{1 H}, and 13C{1 H} NMR spectroscopy. Our 1,1- diboro bimetallic intermediates were recently employed in the stereoselective synthesis of (Z)-alkenyl pinacolboronates by Molander.24 The key to success of the tandem reactions in Scheme 2 is the selective transmetalation of the Cy2B-vinyl bond with dialkylzinc reagents to generate the 1,1-bimetallic intermediates of zinc and B(pin).25 The difference in reactivity between vinylzinc and vinylboronate esters is enormous, as demonstrated by the selective reaction of the 1,1-heterobimetallic intermediates with aldehydes at the ZnsC bond to generate functionalized boronate esters with complete control over the double bond geometry (Scheme 2). The allylic alcohol product is the net trans hydroboration of a propargylic alcohol. Of course, trans hydroboration is extremely rare.26 Herein we disclose an efficient and highly diastereoselective tandem route to the synthesis of substituted cyclopropanes based on our 1,1-heterobimetallic chemistry. Numerous natural and unnatural products containing cyclopropyl groups exhibit important biological activity.27-29 These strained cycloalkanes are also valuable intermediates in organic synthesis, allowing access to either functionalized cyclopropanes or ring-opened products.30 As a result, their synthesis has received much attention.31,32 An (19) Deloux, L.; Skrzypczak-Jankun, E.; Cheesman, B. V.; Srebnik, M.; Sabat, M. J. Am. Chem. Soc. 1994, 116, 10302. (20) Deloux, L.; Srebnik, M. J. Org. Chem. 1994, 59, 6871. (21) Deloux, L.; Srebnik, M.; Sabat, M. J. Org. Chem. 1995, 60, 3276. (22) Soderquist, J. A.; Rane, A. M.; Matos, K.; Ramos, J. Tetrahedron Lett. 1995, 36, 6847. (23) Li, H.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 3521. (24) Molander, G. A.; Ellis, N. M. J. Org. Chem. 2008, 73, 6841. (25) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170. (26) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc. 2000, 122, 4990. (27) Pietruszka, J. Chem. ReV. 2003, 103, 1051. (28) Wessjohann, L. A.; Brandt, W.; Thiemann, T. Chem. ReV. 2003, 103, 1625. (29) Donaldson, W. A. Tetrahedron 2001, 57, 8589. (30) De Meijere, A., Ed. Small Ring Compounds in Organic Synthesis VI; Springer: Berlin, 2000; Vol. 207. Scheme 1. Challenges in the Generation and Reactions of 1-Alkenyl-1,1-bimetallics Scheme 2. Generation and Reactions of 1-Alkenyl-1,1-bimetallics J. AM. CHEM. SOC. 9 VOL. 131, NO. 18, 2009 6517 Heterobimetallics in the Synthesis of Cyclopropylboronate Esters ARTICLES

efficient route to stereodefined cyclopropyl boronate esters and their oxidation to trisubstituted R-hydroxycyclopropyl carbinols is outlined below. We also document their facile acid-catalyzed pinacol-type rearrangement to either cis- or trans-2,3-disubstituted cyclobutanones with high stereoselectivity from a common starting material. This methodology has been applied to the synthesis of quercus lactones A and B from a common precursor. 2. Experimental Section General Methods. All reactions were performed under a nitrogen atmosphere with oven-dried glassware. All manipulations involving dicyclohexylborane, dimethylzinc, and diethylzinc were carried out under an inert atmosphere in a Vacuum Atmospheres drybox with an attached MO-40 Dritrain or using standard Schlenk or vacuum line techniques. Chemicals were obtained from Aldrich, Acros, or GFS Chemicals unless otherwise specified. Solvents were purchased from Fisher Scientific. Toluene, dichloromethane, diethyl ether, and hexanes were dried through activated alumina columns. Tetrahydrofuran was distilled from sodium and benzophenone. HPLC grade chloroform was used. Liquid substrates were distilled prior to use. B(pin) substituted alkynes were prepared by literature methods.33-38 Dimethylzinc and diethylzinc (1.0 or 2.0 M in toluene) was prepared and stored in a Vacuum Atmospheres drybox. NMR spectra were obtained on a Bru¨ker 300, 360, 400, or 500 MHz Fourier transform spectrometer at the University of Pennsylvania NMR facility. 1 H and 13C{1 H} NMR spectra were referenced to residual solvent. 11B{1 H} NMR spectra were referenced to BF3 · OEt2. The infrared spectra were obtained using a Perkin-Elmer 1600 series spectrometer. HRMS data were obtained on a Waters LC-TOF mass spectrometer (model LCT-XE Premier) using electrospray ionization in positive or negative mode, depending on analyte. Melting points were determined on a Unimelt Thomas-Hoover melting point apparatus and are uncorrected. Thin-layer chromatography was performed on Whatman precoated silica gel 60 F-254 plates and visualized by ultraviolet light or by staining with ceric ammonium molybdate or phosphomolybdic acid solutions. Silica gel (Silicaflash, P60, 40-63 µm, Silicycle) was used for air-flashed chromatography, and deactivated silica gel was prepared by addition of 15 mL of Et3N to 1 L of silica gel. Complete experimental procedures and characterization are located in the Supporting Information. Caution. Dialkylzinc reagents are pyrophoric. Care must be used when handling them. General Procedure A: Synthesis of Cyclopropyl Boronate Esters. To a suspension of HBCy2 (107 mg, 0.60 mmol) in toluene (1.0 mL) under N2 was added alkyne-4,4,5,5-tetramethyl-[1,3,2]- dioxaborolane (0.60 mmol), and the reaction mixture was stirred for 30 min at room temperature (rt), after which it was homogeneous. The reaction vessel was cooled to -78 °C and treated with Me2Zn (0.30 mL, 2.0 M in toluene, 0.60 mmol) for 30 min. The solution was then warmed to -10 °C, and the aldehyde (0.40 mmol) was added. The reaction mixture was stirred at -10 °C until TLC showed complete consumption of the aldehyde. The volatile materials were removed under reduced pressure and Et2Zn (1.0 mL, 2.0 M in toluene, 2.0 mmol), CF3CH2OH (0.15 mL, 2.0 mmol), and CH2I2 (0.16 mL, 2.0 mmol) were sequentially added at 0 °C. The reaction vessel was wrapped in aluminum foil to exclude light and allowed to stir at rt for 24 h. The reaction mixture was then diluted with EtOAc (4 mL) and quenched with saturated NH4Cl (4 mL) at 0 °C. The organic layer was separated and the aqueous solution was extracted with EtOAc (3 × 20 mL). The combined organic solution was dried over MgSO4, filtered through Celite and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel. [2-Butyl-1-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-cyclopropyl]-cyclohexyl-methanol (Table 2, entry 7). The product was prepared by General Procedure A using cyclohexanecarbaldehyde (44.9 mg, 0.40 mmol) and 2-hex-1-ynyl-4,4,5,5-tetramethyl- [1,3,2]-dioxaborolane (125.9 mg, 0.60 mmol). The crude product was purified by flash column chromatograghy on silica gel (hexanes/ EtOAc ) 96:4) to afford an oil (115.7 mg, 86%). 1 H NMR (CDCl3, 500 MHz) δ 0.49-0.50 (m, 1H), 0.64-0.66 (m, 1H), 0.74-0.78 (m, 1H), 0.86-0.96 (m, 5H), 1.09-1.17 (m, 1H), 1.19 (s, 12H), 1.28-1.41 (m, 6H), 1.52-1.56 (m, 1H), 1.61-1.68 (m, 2H), 1.71-1.80 (m, 4H), 2.01-2.04 (m, 1H), 2.11 (br, 1H), 2.29 (br, 1H); 13C{1 H} NMR (CDCl3, 125 MHz) δ 14.3, 17.6, 22.8, 24.8, 24.9, 26.5, 26.80, 26.82, 30.1, 30.4, 32.3, 44.8, 83.0, 85.4; 11B{1 H} NMR (CDCl3, 128 MHz) δ 31.4; IR (neat) 3461, 2930, 1420, 1147 cm-1 ; HRMS m/z 318.2679 [(M - H2O)+; calcd for C20H35BO2: 318.2671]. General Procedure B: Synthesis of r-Hydroxycyclopropyl Carbinols. To a solution of cyclopropanol boronate ester (2.0 mmol) in a 1:1 mixture of THF/H2O (20 mL each) was added NaBO3 · H2O (599 mg, 6.0 mmol) at rt. The reaction suspension was stirred at rt for 2-6 h until the reaction was complete by TLC. Water was added (20 mL), and the solution was extracted with Et2O (3 × 30 mL). The combined diethyl ether phase was washed with brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel to obtain the pure R-hydroxycyclopropyl carbinols as white crystalline solids. 2-Butyl-1-(hydroxy(cyclohexyl)methyl)cyclopropanol (Table 3, entry 1). The product was prepared by General Procedure B using [2-butyl-1-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-cyclopropyl]-cyclohexyl-methanol (149 mg, 0.44 mmol), NaBO3 ·H2O (133 mg, 1.33 mmol) in THF/H2O (6 mL/6 mL). The crude product was purified by flash column chromatography on silica gel (hexanes/ EtOAc ) 80:20) to obtain the cyclopropanol as a white crystalline solid (89 mg, 89% yield). MP 91-93 °C; 1 H NMR (CDCl3, 500 MHz) δ 0.25 (t, J ) 5.7 Hz, 1H), 0.59 (dd, J ) 5.1, 9.5 Hz, 1H), 0.72-0.80 (m, 1H), 0.84-1.00 (m, 5H), 1.07-1.44 (m, 8H), 1.56-1.85 (m, 6H), 2.05 (d, J ) 12.4 Hz, 1H), 2.33 (br, 1H), 2.56 (d, J ) 8.9 Hz, 1H), 2.68 (br, 1H); 13C{1 H} NMR (CDCl3, 125 MHz) δ 14.3, 17.0, 22.9, 24.2, 26.2, 26.3, 26.7, 26.9, 29.5, 30.2, 32.0, 41.0, 60.6, 83.5; IR (neat) 3300, 2919, 2846, 1449, 1240 cm-1 ; HRMS m/z 209.1914 [(M - OH)+; calcd for C14H25O: 209.1905]. The product was crystallized from MeOH/H2O and the single-crystal X-ray structure has been obtained. See Supporting Information, Part 2. General Procedure C: Synthesis of cis-2,3-Disubstituted Cyclobutanones. To a solution of the R-hydroxycyclopropyl carbinol (0.34 mmol) in CHCl3 (5 mL) was added a catalytic amount of p-TsOH · H2O (6.5 mg, 0.034 mmol) at rt. The reaction mixture was stirred at rt until the reaction was complete by TLC (20 min to 2 h). The reaction mixture was then quenched with saturated NaHCO3 (3 mL) at 0 °C. The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined diethyl ether phase was washed with brine, dried with anhydrous MgSO4, and the solvent was removed under reduced pressure to afford the cis-2,3-disubstituted cyclobutanone as an oil. In most cases, the crude product was pure by 1 H NMR (purity >95%), and further purification by flash column chromatography was usually avoided. This procedure consistently gave better yields than with General Procedure D. (31) Lebel, H.; Marcoux, J.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977. (32) Charette, A. B.; Marcoux, J. Synlett 1995, 1197. (33) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 2631. (34) Kim, M.; Lee, D. Org. Lett. 2005, 7, 1865. (35) Renaud, J.; Graf, C.; Oberer, L. Angew. Chem., Int. Ed. 2000, 39, 3101. (36) Brown, H. C.; Sinclair, J. A. J. Organomet. Chem. 1977, 131, 163. (37) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2005, 127, 3252. (38) Buettner, M. W.; Naetscher, J. B.; Burschka, C.; Tacke, R. Organometallics 2007, 26, 4835. 6518 J. AM. CHEM. SOC. 9 VOL. 131, NO. 18, 2009 ARTICLES Hussain et al

General Procedure D: Synthesis of cis-2,3-Disubstituted Cyclobutanones. To a solution of the R-hydroxycyclopropyl carbinol (0.16 mmol) in dry THF (4 mL) was added a catalytic amount of BF3 ·OEt2 (4 µL, 4.5 mg, 0.032 mmol) at rt. The reaction mixture was stirred at rt until the reaction was complete by TLC (2-6 h). The reaction mixture was then hydrolyzed with H2O (3 mL). The solution was extracted with CH2Cl2 (3 × 4 mL), washed with brine, dried with anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on deactivated silica gel (pentane/diethyl ether) to afford the cis-2,3-disubstituted cyclobutanone as an oil. General Procedure E: Synthesis of trans-2,3-Disubstituted Cyclobutanones with p-TsOH·H2O at rt. To a solution of the R-hydroxycyclopropyl carbinol (0.14 mmol) in CHCl3 (3 mL) was added a catalytic amount of p-TsOH · H2O (5.1 mg, 0.027 mmol) at rt. The reaction was stirred at rt for 12 h, after which the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (pentane/ diethyl ether) to afford the trans-2,3-disubstituted cyclobutanone as an oil. Yields are usually higher with this procedure than General Procedure F. General Procedure F: Synthesis of trans-2,3-Disubstituted Cyclobutanones with p-TsOH·H2O at Reflux. To a solution of the R-hydroxycyclopropyl carbinol (0.14 mmol) in CHCl3 (3 mL) was added a catalytic amount of p-TsOH · H2O (5.1 mg, 0.027 mmol) at rt. The reaction was refluxed for 1 h, and then let it cool to rt, after which the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (pentane/diethyl ether) to afford the trans-2,3- disubstituted cyclobutanone as an oil. cis-3-Butyl-2-cyclohexylcyclobutanone (Table 4, entry 1). The product was prepared by General Procedure C using 2-butyl-1- (hydroxy(cyclohexyl)methyl)cyclopropanol (51.8 mg, 0.23 mmol) and p-TsOH·H2O (4.4 mg, 0.023 mmol) in CHCl3 (3 mL) to obtain the cyclobutanone as an oil (44.6 mg, 94% yield). 1 H NMR (CDCl3, 500 MHz) δ 0.90 (t, J ) 7.0 Hz, 3H), 0.96-1.07 (m, 1H), 1.08-1.45 (m, 9H), 1.54-1.81 (m, 6H), 2.16 (d, J ) 13.2 Hz, 1H), 2.28-2.47 (m, 2H), 2.92-3.10 (m, 2H); 13C{1 H} NMR (CDCl3, 125 MHz) δ 14.3, 22.9, 26.0 (two overlapping carbons), 26.6, 27.5, 29.8, 30.4, 31.6, 32.8, 35.0, 49.8, 67.8, 211.0; IR (neat) 2925, 2853, 1776, 1450 cm-1 ; HRMS m/z 209.1898 [(MH)+; calcd for C14H25O: 209.1905]. trans-3-Butyl-2-cyclohexylcyclobutanone (Table 4, entry 1). The product was prepared by General Procedure E using 2-butyl- 1-(hydroxy(cyclohexyl)methyl)cyclopropanol (37.1 mg, 0.16 mmol) and p-TsOH·H2O (6.2 mg, 0.032 mmol) in CHCl3 (3 mL) to obtain the cyclobutanone as an oil (30.0 mg, 90% yield). 1 H NMR (CDCl3, 500 MHz) δ 0.90 (t, J ) 7.0 Hz, 3H), 0.94-1.07 (m, 2H), 1.08-1.39 (m, 7H), 1.41-1.51 (m, 1H), 1.52-1.77 (m, 6H), 1.90 (d, J ) 13.4 Hz, 1H), 2.03-2.14 (m, 1H), 2.49 (ddd, J ) 3.5, 6.9, 17.5 Hz, 1H), 2.57-2.65 (m, 1H), 2.93 (ddd, J ) 2.8, 8.9, 17.5 Hz, 1H); 13C{1 H} NMR (CDCl3, 125 MHz) δ 14.2, 22.8, 26.1, 26.3, 26.5, 29.0, 30.7, 30.8, 31.4, 36.8, 38.6, 49.9, 71.6, 211.7; IR (neat) 2925, 2853, 1775, 1450 cm-1 ; HRMS m/z 190.1722 [(M - H2O)+; calcd for C14H22: 190.1722]. 3. Results and Discussion 3.1. Stereoselective Synthesis of Cyclopropyl Boronate Esters. The importance of selectively functionalized cyclopropane moieties in natural product and medicinal chemistry, as well as their utility in synthesis, inspired us to develop an efficient route to substituted cyclopropanes beginning with 1,1- bimetallic intermediates. Thus, regioselective hydroboration of alkynyldioxaborolane followed by chemoselective transmetalation affords the 1,1-borozinc bimetallic, which adds to aldehydes to generate allylic alkoxides (Scheme 3).23 We envisaged an in situ alkoxide directed cyclopropanation would afford the cyclopropyl boronate esters. Performing these reactions in tandem would result in formation of three C–C bonds and stereocenters. 3.1.1. Optimization of Tandem Carbonyl Addition/Cyclopropanation Reactions. The Simmons-Smith cyclopropanation is a well-established method for cyclopropane synthesis39,40 that has been further developed since its introduction.31,41 Perhaps the most significant improvement is the Furukawa modification, which allows generation of the carbenoid by alkyl exchange between Et2Zn and CH2I2 to form the active species EtZnCH2I or Zn(CH2I)2. 42-44 Wittig45-48 and Denmark’s49,50 halomethylzinc reagents, (XCH2)2Zn (X ) Cl, Br) and ClZnCH2I, and Shi’s tunable zinc reagents (YsZnsCH2I, Y ) EtO-, CF3CH2O-, CF3CO2 -, PhCO2 -, etc.) are also notable modifications.51-53 The generated B(pin) substituted allylic alkoxide intermediate in Scheme 3 was treated with these cyclopropanation reagents to optimize diastereoselectivity and yields (Table 1). EtZnCH2I 42-44,54,55 was prepared from Et2Zn (5 equiv) and CH2I2 (5 equiv) and gave 40% conversion of the allylic alkoxide to the cyclopropane after 2 days at rt (entry 1). IZnCH2I was not an effective reagent in this transformation, giving less than 10% conversion (entry 2). Conversions as high as 95% were obtained with Zn(CH2I)2, 45,47 generated from Et2Zn (5 equiv) and CH2I2 (10 equiv). The separation of the desired cyclopropanes from trace amounts of B(pin) allylic alcohol product (5%) was difficult and thus complete conversion of the allylic alkoxide to the cyclopropyl alcohol was required. The cyclopropanation reached completion when conducted at 40 °C with Zn(CH2I)2 (entry 4); however, some isomerization of the vinyl boronate esters was observed. We hypothesized that the dicyclohexylmethylborane byproduct, formed in the transmetalation step, (39) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323. (40) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256. (41) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1. (42) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1966, 7, 3353. (43) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53. (44) Sawada, S.; Inouye, Y. Bull. Chem. Soc. Jpn. 1969, 42, 2669. (45) Wittig, G.; Schwarzenbach, K. Justus Liebigs Ann. Chem. 1961, 650, 1. (46) Wittig, G.; Wingler, F. Justus Liebigs Ann. Chem. 1962, 656, 18. (47) Wittig, G.; Wingler, F. Chem. Ber. 1964, 97, 2146. (48) Wittig, G.; Jautelat, M. Justus Liebigs Ann. Chem. 1967, 702, 24. (49) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974. (50) Yamamoto, H.; Furuta, K.; Maruyama, T. Synlett 1991, 439. (51) Yang, Z. Q.; Lorenz, J. C. Tetrahedron Lett. 1998, 39, 8621. (52) Lorenz, J. C.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. J. Org. Chem. 2004, 69, 327. (53) Charette, A. B.; Beauchemin, A.; Francoeur, S. J. Am. Chem. Soc. 2001, 123, 8139. (54) Lehnert, E. K.; Sawyer, J. S.; Macdonald, T. L. Tetrahedron Lett. 1989, 30, 5215. (55) Charette, A. B.; Marcoux, J. J. Am. Chem. Soc. 1996, 118, 4539. Scheme 3. Tandem Carbonyl Addition/Alkoxide-Directed Cyclopropanation J. AM. CHEM. SOC. 9 VOL. 131, NO. 18, 2009 6519 Heterobimetallics in the Synthesis of Cyclopropylboronate Esters ARTICLES

reacted with the cyclopropanation reagent. Therefore, after formation of the allylic alkoxide, all volatile materials were removed under reduced pressure, followed by addition of cyclopropanation reagents to the reaction mixture. In entries 5 and 6, Shi’s zinc reagents51-53 CF3COOZnCH2I and CF3CH2OZnCH2I failed to achieve full conversion to the cyclopropanes. To increase the likelihood of complete conversion, we conducted the cyclopropanation at higher concentrations. We were pleased to observe complete reaction under more concentrated conditions. Thus, after removal of the volatile materials, Et2Zn (2 M in toluene) and neat CF3CH2OH and CH2I2 (5 equiv each) were added to form the carbenoid CF3CH2OZnCH2I. Noteworthy is the difference between using 1 (entry 6) and 2 M Et2Zn (entry 7) in the cyclopropanation step, highlighting the importance of the concentration of active zinc reagents. 3.1.2. Substrate Scope of the Carbonyl Addition/Cyclopropanation Reactions. Employing the optimized conditions in Table 1 (entry 7), a series of aromatic and aliphatic aldehydes were investigated in the tandem addition/cyclopropanation reactions. As shown in Table 2, benzaldehyde and its derivatives with substitution at the meta or para position (entries 1-6) underwent the addition/cyclopropanation in 58-89% isolated yield and excellent diastereoselectivities (>20:1 in all cases). Likewise, aliphatic aldehydes gave the corresponding cyclopropylboronate esters in 58-86% isolated yield and excellent diastereoselectivities (>15:1, entries 7-10). The dr’s in Table 2 were determined by 1 H NMR of the crude reaction products. The relative stereochemistry was determined by X-ray crystallography after derivatization, as outlined in subsequent sections. Under the conditions outlined in Table 1, ketones do not undergo reaction with 1,1-bimetallic reagents. The scalability of this method was demonstrated in the synthesis of cyclopropylboronate ester in entry 1 on a 5 and 10 mmol scale, affording 1.7 (79% yield) and 2.5 g (75% yield), respectively. It is generally accepted that Simmons-Smith cyclopropanations proceed via a “butterfly-type” transition state.41,56 On the basis of this model, a possible transition state for the cyclopropanation is shown in Figure 1. 3.2. Stereoselective Synthesis of r-Hydroxycyclopropyl Carbinols. Substituted cyclopropanols exhibit diverse reactivity and are valuable synthetic intermediates.57-60 For instance, they formally act as homoenolates via ring cleavage reactions and readily undergo ring expansion.57 Recognizing the importance Table 1. Optimization of Tandem Carbonyl Addition/ Cyclopropanation of 1-Alkenyl-1,1-heterobimetallics entry reagents (equiv) active intermediate temp (°C) conv (% yield)a 1 Et2Zn (5) EtZnCH2I rt 40 CH2I2 (5) 2 I2 (2.5) IZnCH2I rt <10 Et2Zn (2.5) CH2I2 (2.5) 3 Et2Zn (5) Zn(CH2I)2 rt 95 CH2I2 (10) 4 Et2Zn (5) Zn(CH2I)2 40 100 (62) CH2I2 (10) 5 Et2Zn (5) CF3COOZnCH2I rt 80 CF3COOH (5) CH2I2 (5) 6 Et2Zn (5) CF3CH2OZnCH2I rt 75 CF3CH2OH (5) CH2I2 (5) 7 Et2Zn (5) CF3CH2OZnCH2I rt 100 (72)b CF3CH2OH (5) CH2I2 (5) a Isolated yields. b All volatiles are removed in vacuo after the addition step. Subsequent cyclopropanation is conducted using 2 M Et2Zn solution in toluene. Table 2. Stereoselective Synthesis of Cyclopropyl Boronate Esters via Tandem Carbonyl Addition/Cyclopropanation of 1-Alkenyl-1,1-heterobimetallics a Isolated yields Figure 1. Proposed transition state for diastereoselective cyclopropanation of B(pin) substituted allylic alkoxides. 6520 J. AM. CHEM. SOC. 9 VOL. 131, NO. 18, 2009 ARTICLES Hussain et al