Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Sep 16.
Published in final edited form as: Tetrahedron. 2015 Sep 16;71(37):6349–6353. doi: 10.1016/j.tet.2015.05.092

Construction of Tertiary Chiral Centers by Pd-catalyzed Asymmetric Allylic Alkylation of Prochiral Enolate Equivalents

Yusuke Kita a, Yoshitaka Numajiri a, Noriko Okamoto a, Brian M Stoltz a,✉
PMCID: PMC4528676  NIHMSID: NIHMS695724  PMID: 26273114

Abstract

The palladium-catalyzed decarboxylative allylic alkylation of enol carbonates derived from lactams and ketones is described. Employing these substrates with an electronically tuned Pd catalyst system trisubstituted chiral centers are produced. These stereocenters have been previously challenging to achieve using Pd complex/chiral P–N ligand systems.

Keywords: palladium, alkylation, catalysis, enantioselective

Graphical abstract

graphic file with name nihms695724u1.jpg

1. Introduction

Development of straightforward and selective synthetic methods for enantioselective C-C bond formation is a fundamental goal in the area of synthetic organic chemistry.1 Asymmetric allylic alkylation of prochiral or racemic substrates is one of the most effective synthetic methods to construct stereochemically defined chiral centers.2 The well-established nucleophilic substitution of activated allylic fragments is among the most useful and direct stereoselective methods for the functionalization of a variety of carbon-nucleophiles.3 Over the last decade, our laboratory has reported Pd-catalyzed decarboxylative allylic alkylation reactions (Scheme 1). Since our initial efforts in this area, leading to the formation of α-quaternary ketones 2 from racemic β-ketoesters 1 in good yields and enantioselectivities using (S)-4-(tert-butyl)-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole [(S)-t-BuPHOX]4 as a chiral ligand,5 we have expanded the scope6 and demonstrated the use of these methods in a number of applications.7 We recently developed the asymmetric allylic alkylation, giving α-quaternary lactams 4 from racemic β-amidoesters 3 using (S)-2-(2-(bis(4-(trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phenyl)-4-(tert-butyl)-4,5-dihydrooxazole [(S)-(CF3)3-t-BuPHOX]8 as a chiral ligand.9 In the context of preparing trisubstituted tertiary stereocenters (i.e., Scheme 2, 3a), this methodology encountered problems; (1) allylic alkylation of β-amidoester 3a gave a mixture of mono-, di-allylated and unallylated lactams, and (2) the ee value of 4a produced was low (Scheme 2a). This low mono-allylation selectivity is attributed to the fact that a deprotonated β-carboxyamides can serve as a nucleophile to form α-allyl-β-carboxyamides, eventually leading to di-allylated products. Rare exceptions are found in recent work wherein we achieved the synthesis of α-secondary ketopiperazines,9b and some other groups developed asymmetric alkylation constructing trisubstituted chiral centers at the α-position of amides.10

Scheme 1.

Scheme 1

Open in a new tab

Allylic alkylation of ketones and lactams using Pd(0) complex and chiral P–N ligand system

Scheme 2.

Scheme 2

Open in a new tab

Comparison of β-amidoester (3a) and enol carbonate (7a).

Since enol carbonates cannot undergo the unwanted background deprotonation and allylic alkylation reaction, catalyst controlled decarboxylative allylic alkylation of enol carbonates should generally proceed with high mono-allylic alkylation selectivity. As expected, alkylation using enol carbonate 7a with Pd2(dba)3 and (S)-(CF3)-t-BuPHOX at 40 °C proceeded smoothly to give 4a in 90% yield with 99% ee (Scheme 2b). This high enantioselectivity and yield is probably due to easy kinetic access to an enolate allyl Pd complex, which was proposed by a DFT study in our previous report.11 Herein, we report the palladium-catalyzed decarboxylative allylic alkylation of enol carbonates derived from lactams and ketones constructing trisubstituted chiral centers at the α-position of various carbonyl groups.

2. Results and Discussion

The synthesis of enol carbonates 7a-f was difficult due to challenges associated with the formation of C-acylated compounds along with the desired O-acylated structures. In order to selectively O-acylate the corresponding enolate, we screened bases, solvents and additives using methods previously employed for synthesizing enol carbonates.10b Fortunately, 7a could be prepared from N-benzoylpiperidin-2-one by using potassium hexamethyldisilazide (KHMDS) with 18-crown-6 as an additive in THF (eq 1). O-acylation of 4-benzoylmorpholin-3-one (6b) proceeded without any additive, presumably due to a stabilization effect of the endocyclic oxygen atom to favor the enolate form (eq 2). For thiomorpholine (6c), ε-caprolactam (6d), and azocan-2-one (6e), we used NaHMDS as a base and tetramethylethylenediamine (TMEDA) as an activator (eq 3). The 2-chloroallyl group was introduced by using allyloxycarbonyl imidazole as an acylating reagent and BF3•OEt2 as an activator (eq 4).

graphic file with name nihms695724e1.jpg (1)
graphic file with name nihms695724e2.jpg (2)
graphic file with name nihms695724e3.jpg (3)
graphic file with name nihms695724e4.jpg (4)

With the enol carbonate substrates in hand, we performed allylic alkylation reactions of lactam-derived enol carbonates 7b-7f with Pd2(dba)3 (2.5 mol%) and (S)-(CF3)3-t-BuPHOX (6.25 mol%) in toluene at 23 °C for 24 h (Scheme 3). Reaction of carbonate 7b afforded morpholinone 4b in 73% yield and 94% ee. Replacement of oxygen with sulfur gave thiomorpholinone 4c in 82% yield but only 65% ee along with the formation of unallylated product 6b in 10% yield. Caprolactam 7d was also reactive with this catalytic system by using tris(4,4′-methoxydibenzylideneacetone)dipalladium(0) [Pd2(pmdba)3]12 as the palladium(0) source, furnishing lactam 4d in 83% yield and 85% ee. Chloride substitution at the 2-position of the allyl group in 7d increased the enantioselectivity, furnishing caprolactam 4f in 91% ee. Ring size of the lactam significantly affected enantioselectivity, as the reaction of the 8-membered ring substrate 7e proceeded to give the amide 4e in 84% yield and 59% ee.

Scheme 3.

Scheme 3

Open in a new tab

Substrate scope of enol carbonates. Reaction conditions: A mixture of 7 (0.20 mmol), Pd2(dba)3 (0.005 mmol), and (S)-(CF3)3-t-BuPHOX (0.0125 mmol) in toluene (0.033 M) was stirred at 23 °C for 24 h. Yield was isolated yield and enantiomeric excess was determined by chiral SFC analysis. aPerformed at 50 °C. bPerformed at 40 °C. c[Pd2(pmdba)3] was used as a catalyst.

Next, we explored the scope of the allylation of ketones, forming α-tertiary alkyl(cyclo)alkanone derivatives. We were pleased to discover that use of enol carbonate 8a, derived from the corresponding tetralone, resulted in a smooth reaction and delivered allylated tetralone 9a in high yield and enantioselectivity (eq 5). It is noteworthy that the more challenging acyclic substrate 8b was reactive with this catalytic system as well, affording the corresponding ketone 9b in 99% yield and 81% ee (eq 6).13

graphic file with name nihms695724e5.jpg (5)
graphic file with name nihms695724e6.jpg (6)

3. Conclusions

Asymmetric allylic alkylation of enol carbonates is an effective method to construct trisubstituted chiral centers, which have been difficult to introduce using previously developed systems in our laboratory. Herein, we report that a palladium/P–N catalyst system displays activity for enol carbonates derived from lactams. In addition, this system could be applied to the allylation of ketones in both cyclic and acyclic systems.

4. Experimental section

Materials and Methods

Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.14 Reaction progress was monitored by thin-layer chromatography (TLC) which was performed using E. Merck silica gel 60 F254 precoated glass plated (0.25 mm) and visualized by UV fluorescence quenching, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40-63 nm) was used for flash chromatography. 1H and 13C NMR spectra were recorded on a Varian Inova 500 (500 MHz and 126 MHz, respectively) and are reported in terms of chemical shift relative to CHCl3 (δ 7.26 and d 77.16, respectively). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septet, m = multiplet, and br s = broad singlet. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell and are reported as: [α]DT (concentration in g/100mL, solvent). Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralpak (AD-H, AS-H or IC) or Chiracel (OD-H, OJ-H or OB-H) columns (4.6 mm × 25 cm) obtained from Daicel Chemical Industries, Ltd. High resolution mass spectra were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+), or a Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (ESI/APCI).

Reagents were purchased from Sigma-Aldrich, Acros Organics, Strem or Alfa Aesar and used as received unless otherwise stated. Et3N and tetramethylethylenediamine (TMEDA) were distilled from calcium hydride prior to use. (S)-2-(2-(bis(4-(trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phenyl)-4-(tert-butyl)-4,5-dihydrooxazole [(S)-(CF3)3-t-BuPHOX]15 and tris(4,4′-methoxydibenzylideneacetone)dipalladium(0) [Pd2(pmdba)3]16 were prepared by known methods.

4.1. General Procedure for Asymmetric Allylic Alkylation Reactions

In a nitrogen-filled glove box, [Pd2(dba)3] (4.6 mg, 0.005 mmol, 0.025 equiv.) and (S)-(CF3)3-t-BuPHOX (7.4 mg, 0.0125 mmol, 0.0625 equiv.) were added to a 20 mL scintillation vial equipped with a magnetic stirring bar. The vial was then charged with toluene (4.0 mL) and stirred at 25 °C for 30 min. To the preformed catalyst solution was added a solution of enol carbonate (0.2 mmol, 1 equiv.) in toluene (2.1 mL). The vial was sealed and stirred at 23 °C for 24 h. The reaction mixture was concentrated in vacuo. Flash column chromatography (SiO2) afforded α-allylated carbonyl compounds.

4.1.1. 3-Allylpiperidin-2-one (4a)

Reaction performed in toluene at 40 °C. Compound 4a was isolated by flash chromatography (SiO2, 7 to 10% EtOAc in hexanes) as a white solid. 90% yield. Rf = 0.31 (17% EtOAc in hexanes). M.p. 66.5-67.2 °C; 99% ee, [α]D25 -77.1 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.56-7.50 (m, 2H), 7.47 (m, 1H), 7.42–7.35 (m, 2H), 5.77 (m, 1H), 5.13–5.05 (m, 2H), 3.89–3.74 (m, 2H), 2.67–2.54 (m, 2H), 2.28 (m, 1H), 2.14–2.02 (m, 2H), 1.96 (m, 1H), 1.68 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 175.8, 174.8, 136.5, 135.6, 131.5, 128.3, 127.9, 117.5, 46.2, 43.8, 35.3, 26.8, 22.1. IR (Neat Film, NaCl) 3073, 2947, 2870, 1699, 1679, 1641, 1478, 1367, 1288, 1167, 1153, 1076, 1056, 1025, 1001 cm-1. HRMS (ESI+) m/z calc'd for C15H18NO2 [M+H]+: 244.1332, found 244.1372. SFC conditions: 5% MeOH, 2.5 mL/min, Chiralpak AD-H column, λ = 254 nm, tR (min): major = 9.10, minor = 6.18.

4.1.2. 2-Allylmorpholin-3-one (4b)

Reaction performed in toluene at 50 °C. Compound 4b was isolated by flash chromatography (SiO2, 7 to 10% EtOAc in hexanes) as a white solid. 73% yield. Rf = 0.52 (33% EtOAc in hexanes). 94% ee, [α]D25 -127.5 (c 0.80, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.57–7.48 (m, 3H), 7.42–7.38 (m, 2H), 5.91 (m, 1H), 5.23–5.16 (m, 2H), 4.23 (m, 2H), 4.04 (m, 1H), 3.93–3.82 (m, 2H), 2.73 (m, 1H), 2.62 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 173.2, 171.3, 135.7, 133.4, 132.0, 128.3, 128.2, 118.5, 78.5, 63.4, 45.3, 36.3. IR (Neat Film, NaCl) 3358, 3076, 2977, 2898, 2867, 1686, 1642, 1601, 1583, 1463, 1449, 1432, 1398, 1374, 1301, 1282, 1228, 1178, 1165, 1138, 1124, 1104 cm-1. HRMS (ESI+) m/z calc'd for C14H16NO3 [M+H]+: 246.1125, found 246.1124. SFC conditions: 5% MeOH, 3.0 mL/min, Chiralpak OD-H column, λ = 254 nm, tR (min): major = 6.74, minor = 5.99.

4.1.3. 2-Allyl-4-benzoylthiomorpholin-3-one (4c)

Reaction performed in toluene at 40 °C. Compound 4c was isolated by flash chromatography (SiO2, 15% EtOAc in hexanes) as a white solid. 82% yield. Rf = 0.51 (33% EtOAc in hexanes). 65% ee, [α]D25 -31.1 (c 0.36, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.61–7.57 (m, 2H), 7.51 (m, 1H), 7.45–7.38 (m, 2H), 5.85 (m, 1H), 5.20–5.10 (m, 2H), 4.78 (ddd, J = 14.2, 4.8, 3.4 Hz, 1H), 3.79 (dd, J = 7.7, 5.7 Hz, 1H), 3.73 (ddd, J = 14.2, 11.7, 4.2 Hz, 1H), 3.16 (m, 1H), 3.10 (td, J = 11.7, 4.8 Hz, 1H), 2.76 (m, 1H), 2.35 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 173.2, 171.6, 135.6, 134.1, 132.0, 128.2, 128.1, 118.1, 43.6, 42.2, 33.3, 26.9. IR (Neat Film, NaCl) 3362, 3065, 2933, 1687, 1600, 1580, 1534, 1450, 1378, 1326, 1281, 1177, 1132, 1071, 1026 cm-1. HRMS (FAB+) m/z calc'd for C14H16NO2S [M+H]+: 262.0902, found 262.0895. SFC conditions: 5% MeOH, 3.0 mL/min, Chiralcel OD-H column, λ = 254 nm, tR (min): major = 9.26, minor = 8.79.

4.1.4. 3-Allyl-1-benzoylazepan-2-one (4d)

Reaction performed in toluene at 40 °C. Compound 4d was isolated by flash chromatography (SiO2, 10% EtOAc in hexanes) as a yellow oil. 83% yield. Rf = 0.44 (17% EtOAc in hexanes). 85% ee, [α]D25 -33.9 (c 1.90, CHCl3). 1H NMR (500 MHz, CDCl3) 7.55–7.49 (m, 2H), 7.46 (m, 1H), 7.40–7.34 (m, 2H), 5.78 (m, 1H), 5.11–5.03 (m, 2H), 4.56 (dd, J = 14.8, 5.8 Hz, 1H), 3.44 (ddd, J = 14.8, 10.7, 0.9 Hz, 1H), 2.83 (m, 1H), 2.55 (m, 1H), 2.12–1.96 (m, 3H), 1.90 (m, 1H), 1.74–1.44 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 178.7, 174.5, 136.8, 136.2, 131.4, 128.1, 127.7, 117.1, 45.9, 44.5, 36.4, 30.2, 28.8, 28.7. IR (Neat Film, NaCl) 3073, 3030, 2931, 2857, 1681, 1641, 1600, 1583, 1513, 1490, 1450, 1396, 1360, 1322, 1282, 1220, 1189, 1177, 1141, 1114, 1044, 1018, 1001 cm-1. HRMS (ESI+) m/z calc'd for C16H20NO2 [M+H]+: 258.1489, found 258.1494. SFC conditions: 5% MeOH, 3.0 mL/min, Chiralcel AD-H column, λ = 254 nm, tR (min): major = 4.48, minor = 4.88.

4.1.5. 3-Allyl-1-benzoylazocan-2-one (4e)

Reaction performed in toluene at 23°C. Compound 4e was isolated by flash chromatography (SiO2, 10% EtOAc in hexanes) as a yellow oil. 84% yield. Rf = 0.50 (17% EtOAc in hexanes). 59% ee, [α]D25 -8.6 (c 0.37, CHCl3). 1H NMR (300 MHz, CDCl3) δ 7.56–7.22 (m, 5H), 5.80 (ddt, J = 17.2, 10.5, 6.9 Hz, 1H), 5.18–5.02 (m, 2H), 4.19 (ddd, J = 15.1, 4.3, 3.0 Hz, 1H), 3.85 (ddd, J = 15.1, 12.6, 2.8 Hz, 1H), 3.01 (m, 1H), 2.53 (m, 1H), 2.21–2.05 (m, 2H), 1.92–1.70 (m, 4H), 1.70–1.35 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 180.7, 174.9, 136.8, 136.1, 131.3, 128.1, 127.9, 117.4, 45.1, 44.0, 38.0, 36.7, 31.2, 25.9, 24.5. IR (Neat Film, NaCl) 3067, 2928, 2857, 1679, 1619, 1493, 1448, 1392, 1319, 1285, 1246, 1176, 1125, 1091 cm-1. HRMS (ESI+) m/z calc'd for C17H22NO2 [M+H]+: 272.1645, found 272.1656. SFC conditions: 5% MeOH, 3.0 mL/min, Chiralcel OJ-H column, λ = 254 nm, tR (min): major = 2.97, minor = 3.87.

4.1.6. 1-Benzoyl-3-(2-chloroallyl)azepan-2-one (4f)

Reaction performed in toluene at 23 °C. Compound 4f was isolated by flash chromatography (SiO2, 15% EtOAc in hexanes) as a yellow oil. 42% yield. Rf = 0.37 (17% EtOAc in hexanes). 91% ee, [α]D25 -78.1 (c 1.20, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.56–7.50 (m, 2H), 7.46 (m, 1H), 7.41–7.29 (m, 2H), 5.26 (d, J = 1.2 Hz, 1H), 5.19 (d, J = 1.2 Hz, 1H), 4.58 (dd, J = 15.1, 5.1 Hz, 1H), 3.50 (dd, J = 15.1, 11.0 Hz, 1H), 3.23 (m, 1H), 2.85 (ddd, J = 14.6, 6.4, 1.0 Hz, 1H), 2.32 (ddd, J = 14.6, 7.7, 0.7 Hz, 1H), 2.15–1.99 (m, 2H), 1.89 (m, 1H), 1.78–1.55 (m, 2H), 1.48 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 178.0, 174.5, 140.0, 136.7, 131.6, 128.2, 127.9, 115.5, 44.7, 43.5, 41.6, 29.6, 28.9, 28.7. IR (Neat Film, NaCl) 2931, 2857, 1683, 1636, 1450, 1397, 1358, 1321, 1274, 1220, 1188, 1148, 1126 cm-1. HRMS (ESI+) m/z calc'd for C16H19ClNO2 [M+H]+: 292.1099, found 292.1104. SFC conditions: 5% MeOH, 3.0 mL/min, Chiralcel OD-H column, λ = 254 nm, tR (min): major = 5.89, minor = 4.97.

4.1.7. 2-Allyl-3,4-dihydronaphthalen-1(2H)-one (9a)

Reaction performed in toluene at 40 °C. Compound 9a was isolated by flash chromatography (SiO2, 0 to 3% EtOAc in hexanes) as a pale colorless oil. 91% yield. Rf = 0.40 (9% EtOAc in hexanes). 90% ee, [α]D25 +26.6 (c 0.61, CHCl3). 1H NMR (300 MHz, CDCl3) δ8.04 (dd, J = 7.9, 1.5 Hz, 1H), 7.46 (td, J = 7.5, 1.5 Hz, 1H), 7.36–7.16 (m, 2H), 5.95–5.75 (m, 1H), 5.18–5.01 (m, 2H), 3.00 (dd, J = 7.8, 4.5 Hz, 2H), 2.76 (m, 1H), 2.55 (m, 1H), 2.36–2.16 (m, 2H), 1.87 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 199.5, 144.2, 136.4, 133.3, 132.8, 128.8, 127.7, 126.8, 116.9, 47.4, 34.2, 28.8, 28.2. IR (Neat Film, NaCl) 3073, 2976, 2929, 1686, 1682, 1640, 1600, 1455 1435, 1359, 1293, 1280, 1220, 1156 cm-1. HRMS (ESI/APCI+) m/z calc'd for C13H15O [M+H]+: 187.1117, found 187.1110. SFC conditions: 0.5% MeCN, 3.0 mL/min, Chiralcel OD-H column, λ = 254 nm, tR (min): major = 8.11, minor = 7.74.

4.1.8. 2-Methyl-1-phenylpent-4-en-1-one (9b)

Reaction performed in toluene at 23 °C. Compound 9b was isolated by flash chromatography (SiO2, 0 to 3% EtOAc in hexanes) as a colorless oil. Quant. Rf = 0.43 (10% EtOAc in hexanes). 81% ee, [α]D25 -32.9 (c 0.50, CH2Cl2). 1H NMR (500 MHz, CDCl3) δ 8.02–7.97 (m, 2H), 7.60 (m, 1H), 7.55–7.47 (m, 2H), 5.83 (m, 1H), 5.14–5.02 (m, 2H), 3.60 (m, 1H), 2.61 (m, 1H), 2.25 (m, 1H), 1.26 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 203.6, 136.4, 135.8, 132.9, 128.7, 128.3, 116.8, 40.4, 37.6, 17.0. IR (Neat Film, NaCl) 3077, 2975, 2933, 2358, 1682, 1641, 1596, 1579, 1447, 1374, 1360, 1239, 1209 cm-1. HRMS (ESI/APCI+) m/z calc'd for C12H15O [M+H]+: 175.1117, found 175.1113. SFC conditions: 0.5% MeCN, 3.0 mL/min, Chiralcel OD-H column, λ = 254 nm, tR (min): major = 3.97, minor = 4.42.

Supplementary Material

supplement

Acknowledgments

The authors wish to thank NIH-NIGMS (R01GM080269), Amgen, the Gordon and Betty Moore Foundation, the Caltech Center for Catalysis and Chemical Synthesis, and Caltech for financial support. Y.K. expresses his special thanks to the International Engineering Science Consortium for financial support. Y.N. thanks Toray Industries Inc. for a postdoctoral fellowship. N.O. is grateful for a postdoctoral fellowship provided by Hiroshima International University. The authors thank Scott Virgil (Caltech) for instrumentation assistance and Dr. Douglas C. Behenna (Caltech) for initial experimental results.

Footnotes

Dedicated to Professor Jiro Tsuji on the occasion of his receipt of the 2014 Tetrahedron Prize for Creativity in Organic Chemistry.

Supplementary Information: Supplementary data associated with this article can be found in the online version, at www.xxxxxxx.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

7. References and notes

  • 1.For selected reviews, Wender PA, Miller BL. In: Organic Synthesis: Theory Applications. Hudlicky T, editor. Vol. 2. JAI Press; Greenwich, CT: 1993. p. 27.Trost BM. Angew Chem, Int Ed. 1995;34:259–281.Wender PA, Verma VA, Paxton TJ, Pillow TH. Acc Chem Res. 2008;41:40–49. doi: 10.1021/ar700155p.Newhouse T, Baran PS, Hoffmann RW. Chem Soc Rev. 2009;38:3010–3021. doi: 10.1039/b821200g.
  • 2.For reviews see: Trost BM, Brennan MK. Synthesis. 2009:3003–3025.Trost BM, Crawley ML. Top Organomet Chem. 2012;38:321–340.
  • 3.(a) Trost BM, van Vranken DL. Chem Rev. 1996;96:395–422. doi: 10.1021/cr9409804. [DOI] [PubMed] [Google Scholar]; (b) Trost BM, Lee C. In: Catalytic Asymmetric Synthesis. 2nd. Ojima I, editor. Wiley-VCH; New York: 2000. p. 593. [Google Scholar]; (c) Trost BM, Crawley ML. Chem Rev. 2003;103:2921–2944. doi: 10.1021/cr020027w. [DOI] [PubMed] [Google Scholar]; (d) Miyabe H, Yamamoto Y. Synlett. 2005:1641–165. [Google Scholar]
  • 4.(a) Tani K, Behenna DC, McFadden RM, Stoltz BM. Org Lett. 2007;9:2529–2531. doi: 10.1021/ol070884s. [DOI] [PubMed] [Google Scholar]; (b) Krout MR, Mohr JT, Stoltz BM. Org Synth. 2009;86:181–193. doi: 10.15227/orgsyn.086.0181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.(a) Behenna DC, Stoltz BM. J Am Chem Soc. 2004;126:15044–15045. doi: 10.1021/ja044812x. [DOI] [PubMed] [Google Scholar]; (b) Moher JT, Behenna DC, Harned AM, Stoltz BM. Angew Chem, Int Ed. 2005;44:6924–6927. doi: 10.1002/anie.200502018. [DOI] [PubMed] [Google Scholar]
  • 6.Behenna DC, Mohr JT, Sherden NH, Marinescu SC, Harned AM, Tani M, Seto M, Ma S, Novák Z, Krout MR, McFadden RM, Roizen JL, Enquist JA, Jr, White DE, Levine SR, Petrova KV, Iwashita A, Virgil SC, Stoltz BM. Chem Eur J. 2011;17:14199–14223. doi: 10.1002/chem.201003383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.(a) McFadden RM, Stoltz BM. J Am Chem Soc. 2006;128:7738–7739. doi: 10.1021/ja061853f. [DOI] [PubMed] [Google Scholar]; (b) Enquist JA, Jr, Stoltz BM. Nature. 2008;453:1228–1231. doi: 10.1038/nature07046. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Day JJ, McFadden RM, Virgil SC, Kolding H, Alleva JL, Stoltz BM. Angew Chem, Int Ed. 2011;50:6814–6818. doi: 10.1002/anie.201101842. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Hong AY, Stoltz BM. Angew Chem, Int Ed. 2012;51:9674–9678. doi: 10.1002/anie.201205276. [DOI] [PMC free article] [PubMed] [Google Scholar]; (e) Liu Y, Liniger M, McFadden RM, Roizen JL, Malette J, Reeves CM, Behenna DC, Seto M, Kim J, Mohr JT, Virgil SC, Stoltz BM, Beilstein J Org Chem. 2014;10:2501–2512. doi: 10.3762/bjoc.10.261. [DOI] [PMC free article] [PubMed] [Google Scholar]; (f) Numajiri Y, Pritchett BP, Chiyoda K, Stoltz BM. J Am Chem Soc. 2015;137:1040–1043. doi: 10.1021/ja512124c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.McDougal NT, Streuff J, Mukherjee H, Virgil SC, Stoltz BM. Tetrahedron Lett. 2010;51:5550–5554. doi: 10.1016/j.tetlet.2010.08.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.(a) Behenna DC, Liu Y, Yurino T, Kim J, White DE, Virgil SC, Stoltz BM. Nat Chem. 2012;4:130–133. doi: 10.1038/nchem.1222. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Korch KM, Eidamshaus Behenna DC, Nam S, Horne D, Stoltz BM. Angew Chem, Int Ed. 2015;54:179–183. doi: 10.1002/anie.201408609. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Numajiri Y, Jiménez-Osés G, Wang B, Houk KN, Stolz BM. Org Lett. 2015;17:1082–1085. doi: 10.1021/ol503425t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.(a) Zhang K, Peng Q, Hou XL, Wu YD. Angew Chem, Int Ed. 2008;47:1741–1744. doi: 10.1002/anie.200704629. [DOI] [PubMed] [Google Scholar]; (b) Trost BM, Michaelis DJ, Charpentier J, Xu J. Angew Chem, Int Ed. 2012;51:204–208. doi: 10.1002/anie.201105801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Keith JA, Behenna DC, Mohr JT, Ma S, Marinescu SC, Oxgaard J, Stoltz BM, Goddard WAIII. J Am Chem Soc. 2007;129:11876–11877. doi: 10.1021/ja070516j. [DOI] [PubMed] [Google Scholar]
  • 12.(a) Ukai T, Kawazura H, Ishii Y, Bonnet JJ, Ibers JA. J Organomet Chem. 1974;65:253–266. [Google Scholar]; (b) Fairlamb IJS, Kapdi AR, Lee AF. Org Lett. 2004;6:4435–4438. doi: 10.1021/ol048413i. [DOI] [PubMed] [Google Scholar]
  • 13.For a previous example using the Pd•PHOX system, see: Hanessian S, Chénard E. Org Lett. 2012;14:3222–3225. doi: 10.1021/ol301332f.
  • 14.Pangborn AM, Giardello MA, Grubbs RH, Rosen RK, Timmers FJ. Organometallics. 1996;15:1518–1520. [Google Scholar]
  • 15.McDougal NT, Streuff J, Mukherjee H, Virgil SC, Stoltz BM. Tetrahedron Lett. 2010;51:5550–5554. doi: 10.1016/j.tetlet.2010.08.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.(a) Ukai T, Kawazura H, Ishii Y, Bonnet JJ, Ibers JA. J Organomet Chem. 1974;65:253–266. [Google Scholar]; (b) Fairlamb IJS, Kapdi AR, Lee AF. Org Lett. 2004;6:4435–4438. doi: 10.1021/ol048413i. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supplement
NIHMS695724-supplement.pdf (207KB, pdf)

RESOURCES