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Supporting Information for

Enantioselective Pd(II)-Catalyzed Aerobic Oxidative Amidation of Alkenes and Insights into the Role of Electronic Asymmetry in Pyridine-Oxazoline Ligands

Richard I. McDonald, Paul B. White, Adam B. Weinstein, Chun Pong Tam, and Shannon S. Stahl*

Department of Chemistry, University of Wisconsin-Madison,

1101 University Avenue, Madison, WI, 53706 [email protected]

Table of Contents Page Additional Computational Analysis S2-S3 Experimental: General Considerations S4 Representative Procedure for PdII-Catalyzed Aerobic Cyclization S5-S6 Synthesis and Characterization Data of Pyridine-Oxazoline Ligand 3 S6-S7 Synthesis and Characterization Data of Sulfonamide Substrates S7-S18 Determination of Absolute Configuration S18-S19 Chiral HPLC Data S20-S27 Characterization Data for Oxidative Amination Products S28-S31 NOE Correlations S31 Tabulated Electronic Energies, Zero-Point Correction and Solvation-Correction S32 Gibbs Free Energies Cartesian Coordinates for Optimized Structures S33-S42 1H and 13C NMR Spectra of Isolated Products S43-S59

S2

Additional Computational Studies (see Experimental section below for details). Inherent Electronic Preference for Substrate-Binding

Preliminary assessment of the electronic asymmetry of the pyrox ligand was analyzed by comparing the two possible orientations of an amidate-alkene to a PdII center bearing the achiral, unsubstituted pyridine-oxazoline ligand (Figure S1). Crystal structures of previously reported (pyridine-oxazoline)PdCl2 complexes reveal that the Pd–Cl bond trans to the oxazoline group is slightly longer (by approximately 0.01 Å).1 This observation reflects a stronger trans influence of an oxazoline relative to a pyridine, which aligns with the higher basicity/donor-ability of the oxazoline nitrogen (oxazolinium pKa ~ 5.5; pyridinium pKa = 5.17).2 The calculated ground-state energies of the two sulfonamidate-alkene coordination modes reflects this electronic asymmetry (Figure S1): the structure with the alkene trans to the pyridine (transpy) has an electronic energy 1.76 kcal/mol lower than the structure with the alkene cis to pyridine (cispy).

N N

O

PdMsN

PdNMs

N N

O

transpy cispy+0.00 +1.76!E:

Figure S1. Electronic influence on the orientation for substrate-binding from an unsubstituted pyridine-oxazoline ligand

Reaction Path of the Asymmetric Cyclization through Aminopalladation.

The PdII-mediated steps in a cis-amidopalladation reaction, including the transition states for C–N bond formation, were calculated for a cis-disubstituted alkene substrate and a Pd catalyst bearing the experimentally relevant pyridine-oxazoline ligand (Figure S2). Pathways leading to the major and minor product enantiomers were investigated. The reaction pathway commences with the formation of a Pd κ2-N,O-sulfonamidate complex (ST1) from a Pd-trifluoroacetate species. The N,O-sulfonamidate chelate is approximately 4 kcal/mol more stable than the amidate-alkene adducts (ST2) analogous to those described in the manuscript (cf. Scheme 3). Alkene insertion into the Pd–N bond from the diastereomeric ST2 structures exhibits a relatively low barrier (ΔG‡

major = 4.9 kcal/mol, ΔG‡minor = 7.2 kcal/mol) and

results in formation of a four-membered aza-metallacyclic intermediate ST4, which isomerizes to the more-stable six-membered chelate ST5.

Analysis of the transition state structures ST3major/minor reveal the vinylic methyl group in ST3minor is in close proximity to the oxazolinyl phenyl group, whereas the vinylic methyl group in ST3major is oriented downward, away from the phenyl group (Figure S2). Alternative conformations of ST3minor were evaluated, but none exhibited a lower energy. The computational prediction that use of the (R)-antipode of ligand 3 will result in formation of the (S)-pyrrolidine product conforms with the experimental outcome of the reaction.

This steric interaction between the substrate and ligand substituents provides a clear rationale for enantioselectivities observed in the reaction of the cis-alkene substrate. These computational results highlight the importance of the synergistic electronic and steric influence of the C1-symmetric pyridine-

1 (a) Yoo, K. S.; Park, C. P.; Yoon, C. H.; Sakaguchi, S.; O'Neill, J.; Jung, K. W. Org. Lett. 2007, 9, 3933-3935. (b) Dodd, D. W.; Toews, H. E.; Carneiro, F. D.; Jennings, M. C.; Jones, N. D. Inorg. Chim. Acta 2006, 359, 2850-2858. (c) Svensson, M.; Bremberg, U.; Hallman, K.; Csöregh, I.; Moberg, C. Organometallics 1999, 18, 4900-4907. 2 (a) Yu, A.B.C.; Portmann, G.; Simmons. Drug Dev. Ind. Pharm. 1997, 23, 951-957. (b) Deslongchamps, P. Tetrahedron, 1975, 31, 2463-2490. (c) Brown, H.C. et al., in Braude, E.A. and F.C. Nachod Determination of Organic Structures by Physical Methods, Academic Press, New York, 1955.

S3

oxazoline ligand. Specifically, the electronic difference between pyridine and oxazoline donor groups provides the basis for the preferred amidate-alkene coordination geometry, and the resulting structure enables the chirality of the oxazolinyl fragment to dictate the stereochemical course of the reaction. Further work investigating the β-hydride elimination step and the product isomerism observed are currently underway.

N N

O

Pd PhO O

CF3

+N N

O

Pd PhOS N

O+ CF3CO2H

MsHN

+ +

N N

O

Pd PhN O

S OMe

N N

O

Pd PhMsN

N N

O

Pd PhMsN

N N

O

Pd PhMsN

N N

O

Pd PhOS N

O

(8.7)8.0

(12.5)11.9

(19.7)16.8

(3.7)2.6

-3.8 (-4.2)

5.0

15.0

20.0

10.0

0.0

-5.0

!G

298K

(kca

l/mol

)

Bold Line - observed enantiomer (S)Dotted Line - minor enantiomer (R) # - Free Energy for (S) product(#) - Free Energy for (R) product

ST1

ST2

ST3

ST4

ST5

0.0

N N

O

Pd PhO O

CF3

NHMs+

Figure S2. Reaction path for the asymmetric cyclization of N-methanesulfonyl-4-hexenamide. Both major and minor isomers were calculated through the C-N bond-forming transition state. [Note: The 1+ charge on all Pd structures, and the CF3CO2H molecules included with structures ST1–ST5, were omitted for clarity.]

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Experimental. 1. General Considerations.

Experimental Studies. All commercially available compounds were used as received. Solvents were

dried over alumina columns prior to use; however, purification and drying of commercial solvents is not required for the catalytic reactions described here. 1H and 13C NMR spectra were recorded on Bruker or Varian 300 MHz spectrometers. Chemical shift values are given in parts per million relative to internal TMS (0.00 ppm for 1H) or CDCl3 (77.23 ppm for 13C). Optical rotations were measured using a 1 mL cell with a 0.5 dm path length on a Randolph digital polarimeter. Chiral HPLC analysis was performed on a Shimadzu analytical HPLC system with commercial Chiralcel columns. Flash chromatography was performed using SiliaFlash® P60 (Silicycle, particle size 40-63 µm, 230-400 mesh) or activated basic aluminum oxide (Brockmann I, standard grade, particle size 58Å, ~150 mesh) from Sigma Aldrich.

Computational Studies. All computations were performed with the Gaussian 03 (G03) program3

using resources provided by TeraGrid partners.4 Spin-restricted density functional theory (DFT) calculations were performed with the hybrid density functional, rB3LYP.5,6 A combination of the Stuttgart RSC 1997 ECP/triple-ζ basis7 for Pd and the all-electron 6-31+G(d) basis set for all other atoms was used for gas-phase geometry optimizations and normal mode analyses. Full geometry optimizations were carried out in internal coordinates using the default Berny algorithm. Frequency calculations were performed at the optimized geometries to confirm that each geometry had the appropriate number of imaginary frequencies: zero for minima or one for transition states. The imaginary frequency identifying a saddle-point was visually inspected for the proper motion.

At the calculated stationary points, solvation-corrected single-point total energy calculations were carried out with the Pd basis detailed above and the 6-311+G (d,p) basis on all other atoms with electrostatic and non-electrostatic solvation effects evaluated using the polarizable-continuum model (PCM). The solvation cavity was generated using UFF radii, explicitly treating hydrogen atoms, and the radii were scaled by a factor of 1.2. The solvent chosen was toluene. Charge density analyses were carried out on each stationary point using the natural population analysis (NPA) method8 as implemented within NBO 3.1 in G03. 3 Gaussian 03, Revision E.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;

Cheeseman, J. R.; Montgomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc., Wallingford CT, 2004.

4 This research was supported in part by the National Science Foundation through TeraGrid resources provided by the NCSA under grant number TG-CHE070040

5 Becke, A.D. J. Chem. Phys. 1993, 98, 1372 –1377. 6 Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785 – 789. 7 a) Feller, D. J. Comp. Chem., 1996, 17(13), 1571-1586. b) Schuchardt, K.L.; Didier, B.T.; Elsethagen, T.; Sun,

L.; Gurumoorthi, V.; Chase, J.; Li, J.; and Windus, T.L. J. Chem. Inf. Model., 2007, 47(3), 1045-1052 8 Reed, A.E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83, 735 – 746.

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2. Representative Procedure for PdII-Catalyzed Aerobic Cyclization.

NHTs TsN

Pd(TFA)2 (5 mol%)3 (7.5 mol%)

3Å MStoluene, 25 °C

O2 (1 atm)

NN

OMe

Ph3

Most of the catalytic aerobic oxidation reactions were performed using a custom reaction apparatus that enabled several reactions to be performed simultaneously under a constant pressure of O2 (approx 1 atm) with controlled temperature and orbital agitation. A control experiment (see below) demonstrated that similar results can be obtained using a standard round-bottom flask equipped with a stir bar and a balloon of O2. Procedure for reactions performed in a custom parallel reactor: Pd(TFA)2, (8.3 mg, 0.025 mmol, 0.05 equiv), and powdered 3Å molcular sieves (133 mg, 267 mg/mmol substrate) were combined in a 30 mL glass reaction vessel (note: the powdered 3Å molcular sieves were stored on the benchtop; glovebox storage was not required to achieve the beneficial effect9). The headspace was purged with O2 for 10 min, after which a solution of the sulfonamide starting material (127 mg, 0.5 mmol, 1 equiv) and ligand 3 (8.9 mg, 0.038 mmol, 0.075 equiv) in toluene (5 mL, 0.1M) was added via syringe. The solution was shaken vigorously at room temperature for 24 h or for a time determined by TLC monitoring of the reaction progress. After 24 h, the O2 was purged from the vessel, silica gel (~0.5 g) was added, and the solvent removed at reduced pressure. The mixture was then loaded directly onto a silica gel column for purification by flash chromatography, yielding 86 mg of the product as a white solid (68% yield). Alternatively, reactions were performed in 10 mL reaction vessels with 0.075 mmol of substrate per reaction vessel. Upon reaction completion, the reaction mixtures were combined and purified as described above. Procedure for a reaction performed in a round-bottom flask:

NHTs TsN

Pd(TFA)2 (5 mol%)3 (7.5 mol%)

NN

OMe

Ph3

3Å M.S.toluene, 22 °CO2 (balloon)Ph

Ph

0.5 mmol

Pd(TFA)2 (8.3 mg, 0.025 mmol, 0.05 equiv) and 133 mg 3Å M.S. were weighed into a 100 ml 3-neck round-bottom flask equipped with a stir bar, a reflux condenser and three rubber septa. The apparatus was purged for several minutes with a flow of O2 via a needle and then a balloon of O2 was attached to the top of the reflux condenser. A solution of ligand (8.9 mg, 0.0375 mmol, 0.075 equiv) in 2 ml of toluene was added via syringe and allowed to stir for 15 minutes. A solution of substrate (164.7 mg, 0.5 mmol, 1 equiv) in 3 ml of toluene was added via syringe and the mixture was allowed to stir for 24 h at room

9 Steinhoff, B. A.; King, A. E.; Stahl, S. S. J. Org. Chem. 2006, 71, 1861-1868.

S6

temperature (22 °C). The yellow reaction mixture was transferred to a round bottom flask, adsorbed onto basic alumina, and then purified over basic alumina using a Combiflash purification system, with hexanes / ethyl acetate as the eluting solvent (153 mg, 93 % yield, 90 % ee). Characterization data matched previous literature report.22 3. Synthesis of Pyridine-Oxazoline Ligand 3.

NMeO

OH

NMeO

HN

Ph

Ph

H2NOH

OH

NMeN

O

Ph

+

isobutyl chloroformateN-methyl morpholine

CH2Cl290%

TsClDMAP, Et3N

dichloroethane85%

3

NMeHN

O PhOH

Pyridine oxazoline ligands were synthesized by a modified two-step procedure.10 To an oven-dried round bottom flask was added 6-methyl picolinic acid (700 mg, 5.1 mmol, 1 equiv). After placing the flask under an atmosphere of N2, dry CH2Cl2 (50 mL), and the flask was submerged in a brine ice bath. N-methyl morpholine (842 µL, 7.656 mmol, 1.5 equiv) was then added dropwise via syringe and the solution stirred for 15 min. Isobutylchloroformate (768 µL, 5.8 mmol, 1.15 equiv) was added dropwise via syringe and the solution stirred an additional 30 min, at which point a solution of (S)-phenyl glycinol (840 mg, 6.1 mmol, 1.2 equiv), N-methyl morpholine (645 µL, 5.9 mmol, 1.15 equiv), and CH2Cl2 (10 mL) were added dropwise via cannula, followed by rinsing the flask with additional CH2Cl2 (2 mL). The mixture was stirred for an additional hour at reduced temperature, then removed from the brine ice bath and stirred for 15 hours at room temperature, during which time the solution turned orange. The mixture was then diluted with CH2Cl2, washed in successive steps with aq NH4Cl (2 times), H2O, and brine, dried over MgSO4. Following removal of the solvent at reduced pressure, 1.18 g of the desired amide was obtained as a colorless oil (90% yield).

1H NMR (300 MHz, CDCl3) δ 2.55 (s, 3H), δ 3.99 (d, J = 5.5 Hz, 2H), δ 5.23 – 5.29 (m, 1H), δ 7.24 – 7.42 (m, 6H), δ 7.69 (t, J = 7.7 Hz, 1H), δ 7.97 (d, J = 7.7 Hz, 1H), δ 8.75 (broad d, 7.3 Hz, 1H).

13C NMR (75 MHz, CDCl3) δ 24.4, δ 56.3, δ 66.8, δ 119.6, δ 126.3, δ 127.0, δ 128.0, δ 129.0, δ 137.6, δ 139.2, δ 149.0, δ 157.5, δ 165.1.

HRMS: m/z (ESI) calculated [M+H]+ = 257.1285, measured 257.1273 (∆ = 4.7 ppm).

NN

OMe

Ph3 A dry 2-neck round bottom flask equipped with a reflux condenser was charged with the amide (1.18 g, 4.6 mmol, 1 equiv) and placed under an N2 atmosphere. Anhydrous 1,2-dichloroethane (45 mL) was added via cannula. Under positive N2 pressure, a rubber septum was quickly removed and 4-dimethylaminopyridine (56 mg, 0.46 mmol, 0.1 equiv) and p-toluenesulfonyl chloride (1.31 g, 6.9 mmol, 1.5 equiv) were added. The septum was replaced and triethylamine (2.56 mL, 18.4 mmol, 4 equiv) was added via syringe. The solution was then stirred for 3 hours at room temperature, then submerged in a pre-heated oil bath and refluxed for 15 hours, during which time the mixture turned dark red. After allowing the mixture to cool to room temperature, CH2Cl2 was added, and the organic layer was washed with saturated NaHCO3 (aq), H2O, then brine, and dried over MgSO4. Removal of the solvent at reduced

10 Miller, J. J.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752-2753.

S7

pressure provided a dark red oil, which was purified using basic Al2O3 on a CombiFlash purification system (elution solvent: Hexanes/EtOAc) to provide pyridyl oxazoline 3 as a colorless oil (929 mg, 89% yield).

1H NMR (300 MHz, CDCl3) δ 2.65 (s, 3H), δ 4.38 (t, J = 8.5 Hz, 1H), δ 4.88 (dd, J = 10.3, 8.6 Hz, 1H), δ 5.43 (dd, J = 10.3, 8.6 Hz, 1H), δ 7.25 – 7.38 (m, 6H), δ 7.66 (t, J = 7.7 Hz, 1H), δ 7.99 (d, J = 7.7 Hz, 1H).

13C NMR (75 MHz, CDCl3) δ 24.7, δ 70.3, δ 75.4, δ121.5, δ 125.6, δ 126.9, δ 127.7, δ 128.8, δ 136.8, δ 141.9, δ 146.1, δ 158.8, δ 164.0.

HRMS: m/z (ESI) calculated [M+H]+ = 239.1179, measured 239.1180 (∆ < 1 ppm). [α]21

D = –61.4° (c = 1.1, CHCl3). 4. Synthesis of Sulfonamide Substrates. Sulfonamide substrates S1-S3 (Table 1, Entries 1-3) were prepared according to previously reported procedures via the representative three-step sequence shown below.11,12

ORCH2MgBrNi(DPPP)Cl2

toluene

OH

R

1. MsCl, Et3N2. TsNH2, K2CO3

NHTs

RS1: R = MeS2: R = EtS3: R = Bn

NHTs

EtS2

Colorless oil (elution solvent – hexanes:EtOAc = 3:1). 1H NMR (300 MHz, CDCl3) δ 0.91 (t, J = 7.5 Hz, 3H), δ 1.51 (p, J = 7.5Hz), δ 1.92 – 2.05 (m, 2H), δ

2.43 (s, 3H), δ 2.93 (q, J = 7.0 Hz, 2H), δ 4.76 (t, J = 6.0 Hz, 1H), δ 5.16 – 5.25 (m, 1H), δ 5.32 – 5.41 (m, 1H), δ 7.31 (d, J = 8.1 Hz, 2H), δ 7.76 (d, J = 8.1 Hz, 2H);

13C NMR (75 MHz, CDCl3) δ 14.4, δ 20.7, δ 21.7, δ 24.4, δ 43.1, δ 127.3, δ 127.5, δ 129.9, δ 133.1, δ 137.2, δ 143.5;

HRMS: m/z (ESI) calculated [M+H]+ = 268.1366, measured 268.1356 (∆ = 3.7 ppm). NHTs

BnS3

White solid (elution solvent – hexanes:EtOAc = 4:1). 1H NMR (300 MHz, CDCl3) δ 1.56 (p, J = 7.2 Hz, 2H), δ 2.13 (apparent quartet, J = 7.3 Hz, 2H), δ

2.41 (s, 3H), δ 2.95 (q, J = 6.7 Hz, 2H), δ 3.22 (d, J = 7.4 Hz, 2H), δ 4.69 (t, J = 6.1 Hz, 1H), δ 5.35 – 5.44 (m, 1H), δ 5.53 – 5.62 (m, 1H), δ 7.12 – 7.20 (m, 3H), δ 7.25 – 7.30 (m, 4H), δ 7.74 (d, J = 8.2 Hz, 2H);

13C NMR (75 MHz, CDCl3) δ 21.7, δ 24.5, δ 29.7, δ 33.6, δ 43.0, δ 126.1, δ 127.3, δ 128.5, δ 128.6, δ 129.3, δ 129.5, δ 129.9, δ 137.1, δ 141.0, δ 143.6;

HRMS: m/z (ESI) calculated [M+Na]+ = 352.1342, measured 352.1348 (∆ = 1.7 ppm).

11 Wenkert, E.; Micheloti, E. L.; Swindell, C. S.; Tingoli, M. J. Org. Chem. 1984, 49, 4894-4899. 12 Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328-6335.

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MsCl, NEt3Et2O, rt DMF, 45 °C

NaN3

Et2O, 0 °CLiAlH4

NEt3, CH2Cl2, rt(CH3)2NSO2Cl

NsCl, NEt3

OH

Ph

OMs

Ph

N3

Ph

NH2

Ph

NHNs

Ph

NH

Ph

S NMe2O

O

CH2Cl2, rtN3

Ph

OMs

Ph To a dry single-neck round-bottom flask under a N2 atmosphere was added dry diethyl ether (35 mL), the alcohol (1.02 g, 5.83 mmol, 1 equiv) and triethyl amine (2.44 mL, 17.5 mmol, 3 equiv). The vial containing the alcohol was then washed with diethyl ether (15 mL total) and the solution transferred to the reaction flask (containing a total of 50 mL of ether). While stirring, methanesulfonyl chloride (MsCl, 0.68 mL, 8.74 mmol, 1.5 equiv) was added slowly via syringe at room temperature. The reaction was allowed to proceed overnight under N2 at room temperature. Upon completion, the reaction mixture was clear with a yellow gum/film along the bottom of the flask. The organic layer was extracted with dichloromethane (3 times). The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed to afford a yellow/orange oil which was immediately carried through to the next reaction. N3

Ph To the single-neck round-bottom flask containing the oil above was added anhydrous DMF (50 mL) under a N2 atmosphere. Under a positive pressure of N2 the septum was briefly removed to add NaN3 (871 mg, 13.4 mmol, 2.3 equiv) in one portion. The reaction mixture was heated to 45 °C and allowed to proceed overnight (~20 hrs). The reaction flask was then placed in an ice bath to cool. Once cool, 100 mL of deionized water was slowly added to the stirring mixture. The organic layer was extracted with diethyl ether (3 times). The combined organic layers were then extracted once each with water and brine in order to remove as much DMF from the product as possible. The organic layers were then dried over MgSO4 and concentrated via rotovap to approximately one-third of its original volume. Caution should be observed when concentrating the solution as azides are known explosives. The concentrated solution was then immediately carried on to the next step.

S9

NH2

Ph To a dry three-necked round-bottom flask, a single LiAlH4 pellet (500 mg, 13.1 mmol, 2.26 equiv) was added and then placed under a N2 atmosphere. The flask was placed on ice and allowed to cool. Once cool, dry diethyl ether (75 mL) was added to the flask and allowed to stir for 10 min. Afterwards, the solution containing the azide described above was cannula transferred into the reaction flask. The round-bottom that had contained the azide was washed with dry diethyl ether (3 times, 12 mL total) and the solution transferred to the reaction flask. The reaction was stirred on ice for 30 min and then removed to room temperature. As the reaction progressed, the pellet began to slowly break apart, taking overnight to reach a uniformly dispersed suspension. Upon completion, the reaction flask was placed onto ice and allowed to cool. While stirring, the cool reaction was quenched by the slow addition of water (1 mL), 15% NaOH (1 mL) and water (5 mL). The crude reaction was filtered over a fritted Buchner funnel, washed with diethyl ether and dried over MgSO4. The solvent of the resulting solution was removed to afford a crude yellow oil (1.19 g). The oil was partitioned into five equal mass vials to be carried onto other reactions.

NH

Ph

S NMe2O

O

To a dry one-necked round-bottom, dry dichloromethane (5 mL), triethyl amine (318 µL, 2.28 mmol, 2 equiv) and N,N-dimethylsulfamoyl chloride (147.1 µL, 1.36 mmol, 1.2 equiv) were added under a N2 atmosphere. A concentrated solution of free amine from the vial described above (assumed ~200 mg amine, 1.14 mmol) in dry dichloromethane (1 mL) was added to the reaction flask. The vial containing the amine was washed with dry dichloromethane (3 times, 3 mL total) and then transferred to the reaction flask. The reaction was stirred at room temperature overnight under N2. The reaction was quenched upon the addition of water (30 mL). The organic layer was extracted with diethyl ether (3 times). The combined organic layers were extracted with brine and dried over MgSO4. The solvent was removed to afford the crude product which was purified twice by silica gel chromatography (Combiflash using hexanes/ethyl acetate; TLC conditions – 3:1 hexanes:EtOAc, Rf = 0.25). The product was isolated as a clear oil (200 mg, 49% yield over 4 steps based on one-fifth of the alcohol used at the beginning).

1H NMR (500 MHz, CDCl3) δ 1.66 (p, J = 7.3 Hz, 2H), 2.22 (q, J = 7.3 Hz, 2H), 2.78 (s, 6H), 3.07 (q, J = 6.8 Hz, 2H), 3.40 (d, J = 7.3 Hz, 2H), 4.29 (bs, 1H), 5.49 (m, 1H), 5.63 (m, 1H), 7.19 (m, 3H), 7.28 (m, 2H);

13C NMR (125 MHz, CDCl3) δ 140.9, 129.4, 129.3, 128.6, 128.4, 126.1, 43.4, 38.1, 33.5, 29.9, 24.5; HRMS: m/z (ESI) calculated [M+Na]+ = 305.1295, measured 305.1304 (∆ = 2.9 ppm).

S10

NHNs

Ph To a dry one-necked round-bottom, dry dichloromethane (5 mL), triethyl amine (318 µL, 2.28 mmol, 2 equiv) and 4-nitrobenzenesulfonyl chloride (303.5 mg, 1.36 mmol, 1.2 equiv) were added under a N2 atmosphere. A concentrated solution of free amine from the vial described above (assumed ~200 mg amine, 1.14 mmol) in dry dichloromethane (1 mL) was added to the reaction flask. The vial containing the amine was washed with dry dichloromethane (3 times, 3 mL total) and then transferred to the reaction flask. The reaction was stirred at room temperature overnight under N2. The reaction was quenched upon the addition of water (30 mL). The organic layer was extracted with diethyl ether (3 times). The combined organic layers were extracted with brine and dried over MgSO4. The solvent was removed to afford the crude product which was purified twice by silica gel chromatography (Combiflash using hexanes/ethyl acetate; TLC conditions – 3:1 hexanes:EtOAc, Rf = 0.28). The product was isolated as a clear oil that crystallized over time (110 mg, 27% yield over 4 steps based on one-fifth of the alcohol used at the beginning).

1H NMR (300 MHz, CDCl3) δ 1.61 (p, J = 7.1 Hz, 2H), 2.17 (q, J = 7.2 Hz, 2H), 3.03 (q, J = 6.9 Hz, 2H), 3.35 (d, J = 7.4 Hz, 2H), 4.47 (t, J = 5.9 Hz, 1H), 5.42 (m, 1H), 5.64 (m, 1H), 7.23 (m, 5H);

13C NMR (125 MHz, CDCl3) δ 152.4, 148.3, 142.9, 132.0, 131.1, 130.9, 130.6, 130.5, 128.4, 126.8, 79.6, 79.4, 79.1, 45.3, 35.7, 31.9, 26.5;

HRMS: m/z (ESI) calculated [M]+ = 360.1139, measured 360.1145 (∆ = 1.7 ppm).

Me Me

CN 1. LDA2. Br

Me

CN

MeMe

Me 1. LiAlH4

MeMe

Me

NHTs

2. TsCl, Et3N

CN

MeMe

Me

A dry 100 ml round-bottom flask was charged with a stir bar, 44 ml dry THF and diisopylamine (1.62 ml, 16 mmol, 2.16 equiv). The reaction flask was cooled to -78 °C under an atmosphere of N2. n-Butyllithium (10.4 ml of 1.5 M solution in hexanes, 15.6 mmol, 2.11 equiv) was added via syringe and allowed to stir for 40 minutes. Isobutyronitrile (0.66 ml, 7.4 mmol, 1 equiv) was added via syringe slowly and allowed to stir for 30 minutes. Freshly prepared cis-crotyl bromide as a concentrated solution in ether was added slowly via syringe (1 g, 7.4 mmol, 1 equiv) and the reaction mixture was allowed to slowly warm to room temperature overnight. After 12 h, the reaction mixture was poured over water, extracted 3x with ether, and the combined organics were washed 2x with brine, dried over MgSO4, and gently concentrated to a yellow solution in ether. The solution was used immediately in the following step without purification.

MeMe

Me

NHTs

A dry 2-neck 50 ml round-bottom flask was charged with LiAlH4 (431 mg, 11.4 mmol, 1.5 equiv), a stir bar, and equipped with a reflux condenser. The apparatus was evacuated and back-filled with N2. 10 ml of dry ether was added via syringe. The solution of the nitrile (7.4 mmol, 1 equiv) described above was added via syringe slowly. The mixture was heated to reflux for 3 h, at which point thin-layer chromatography indicated complete consumption of the starting material. The mixture was cooled to 0 °C

S11

and quenched with 10 ml of 5:1 THF:H2O, then 10 ml 2M NaOH. The solids were removed by filtration through celite and the filtrate was washed with brine, dried over MgSO4 and concentrated. The crude product was immediately carried onto the next step without purification. A 250 ml round-bottom flask was charged with a stir bar, 70 ml CH2Cl2, and triethylamine (2 ml, 14.1 mmol, 1.9 equiv). The reaction mixture was cooled to 0 °C in an ice bath. The freshly prepared amine described above was added in a concentrated solution of dichloromethane, followed by p-toluenesulfonyl chloride (1.613 g, 8.46 mmol, 1.14 equiv) in one portion. The mixture was allowed to warm to room temperature slowly overnight. The yellow solution was washed with 2M HCl 2x, then with saturated NaHCO3 solution, and then brine. The organic layer was dried over MgSO4, concentrated, and purified on silica using a combiflash purification system with hexanes / ethyl acetate as the eluting solvent. Further purification on silica using a toluene / acetone solvent system (30:1) provided the desired substrate as a clear oil, which crystallized over time (1.242 g, 60% yield over three steps).

1H NMR (300 MHz, CDCl3) δ 0.86 (s, 6H), 1.57 (d, J = 7.1 Hz, 3H), 1.94 (d, J = 7.6 Hz, 2H), 2.43 (s, 3H), 2.70 (d, J = 7.0 Hz, 2H), 4.34 (t, J = 6.0 Hz, 1H), 5.35 (m, 1H), 5.56 (m, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H);

13C NMR (75 MHz, CDCl3) δ 143.5, 137.2, 129.9, 127.3, 126.7, 125.9, 53.3, 36.7, 35.0, 25.0, 21.7, 13.1;

HRMS: m/z (ESI) calculated [M+Na]+ = 304.1342, measured 304.1351 (∆ = 3 ppm).

CO2EtEtO2C

NaH

THF89% (2 steps)

LiCl, H2O

DMSO72%

LiAlH4

Et2O

NHTsOH

CO2EtHO PBr3

Et2O

Br


83% (3 steps)

CO2EtEtO2C

CO2EtEtO2C

To a dry 3-neck round bottom flask under a N2 atmosphere was added dimethyl malonate (423 µL, 2.8 mmol, 1 equiv) and dry THF (10 mL). The solution was cooled to 0 °C. Under positive nitrogen pressure, a septum was quickly removed and NaH (60% dispersion in mineral oil, 333 mg, 8.3 mmol, 3 equiv) was added, and the septum was replaced. The solution as removed from the ice bath and stirred at room temperature for 2 hours, at which point a solution of (Z)-crotyl bromide13 (468 µL, 6.9 mmol, 2.5 eqiuv) in dry THF (2 mL) was added dropwise via syringe. The mixture was submerged in a preheated oil bath and refluxed overnight. After cooling to room temperature, the reaction was quenched by careful, dropwise addition of sat. NH4Cl (aq). The organic layer was extracted with EtOAc (3 times). The combined organics were washed with brine and dried over MgSO4. Removal of the solvent at reduced pressure provided 662 mg of the desired product as a colorless oil (89% yield). 1H NMR (300 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 6H), δ 1.61 (d, J = 6.7 Hz, 6H), δ 2.65 (d, J = 7.4 Hz, 4H), δ 4.17 (q, J = 7.1 Hz, 4H), δ 5.20 – 5.30 (m, 2H), δ 5.54 – 5.65 (m, 2H).

13 Haynes, R. K.; Katsifis, A. G. Aust. J. Chem. 1989, 42, 1455-1471.

S12

CO2Et

The diene malonate synthesized in the previous step (662 mg, 2.5 mmol, 1 equiv) was dissolved in DMSO (5 mL), followed by addition of LiCl (324 mg, 7.7 mmol, 3.1 equiv). The mixture was placed into a preheated 195 °C oil bath and refluxed for 15 hours (monitor by TLC). After cooling to room temperature, H2O was added, and the solution was extracted by CH2Cl2 (3 times). The combined organics were then washed subsequently with H2O and brine. After drying over MgSO4, removing the solvent at reduced pressure, and purifying by silica gel chromatography (elution solvent – hexanes:EtOAc 6:1, TLC visualization by KMNO4 stain), 320 mg of a colorless oil was obtained (71% yield). 1H NMR (300 MHz, CDCl3) δ 1.26 (d, J = 7.1 Hz, 6H), δ 1.61 (d, J = 6.7 Hz, 6H), δ 2.21 – 2.43 (m, 5H), δ 4.12 (q, J = 7.1 Hz, 2H), δ 5.31 – 5.39 (m, 2H), δ 5.47 – 5.59 (m, 2H).

NHTs

A suspension of LiAlH4 (120 mg, 3.1 mmol, 1.75 equiv) in dry Et2O (4 mL) was cooled to 0 °C, followed by dropwise syringe addition of the ester synthesized in the previous step (320 mg, 1.76 mmol, 1 equiv) in Et2O (2 mL). After stirring for 12 hours at 0 °C, the reaction was carefully quenched by subsequent addition of H2O (120 µL), 10% aq. NaOH (120 µL), and H2O (360 µL). MgSO4 was then added to the solution, which was filtered through a pad of NaSO4 after 30 min of stirring. The solvent was carefully removed at reduced pressure. The alcohol was then transformed to the desired sulfonamide by a known two step process.12 Following column chromatography (elution solvent – hexanes:EtOAc = 4:1), this three step process provided 450 mg of the sulfonamide as a colorless oil (83% yield for 3 steps).

1H NMR (300 MHz, CDCl3) δ 1.55 (ddd, J = 6.8, 1.1, 0.8 Hz, 6H), δ 2.01 (apparent triplet, J = 6.9 Hz, 4H), δ 2.43 (s, 3H), δ 2.86 (t, J = 6.3 Hz, 2H), δ 4.65 (t, J = 6.4 Hz, 1H), δ 5.24 – 5.34 (m, 2H), δ 5.51 (dqt, J = 10.8, 6.8, 1.5 Hz, 2H), δ 7.31 (d, J = 8.2 Hz, 2H), δ 7.73 (d, J = 8.3 Hz, 2H).

13C NMR (75 MHz, CDCl3) δ 13.1, δ 21.7, δ 29.3, δ 39.1, δ 46.8, δ 126.2, δ 127.3, δ 127.8, δ 129.9, δ 137.2, δ 143.5.


O

H2NS

tBu

O NS

tBuONHTsMe

NHS

tBuO

Me1. HCl / MeOH2. TsCl / Et3N

92% yield(2 steps)

+Ti(OEt)2

THF69%

MeMgBrCH2Cl2

98%d.r. = 10:1

NStBuO

The N-tert-butanesulfinyl aldimine was prepared following the protocol developed by Ellman and coworkers.14 An oven-dried round bottom flask under an atmosphere of N2 was charged with (Z)-4-hexenal15 (3.26 g, 33.3 mmol, 1.1 equiv), (R)-tertbutanesulfinamide (3.67 g, 30.3 mmol, 1 equiv) and THF (100 mL). Ti(OEt)4 (14.57 mL, 69.6 mmol, 2.3 equiv) was added via syringe, and the solution allowed to stir at room temperature overnight. The solution was then poored into an erlenmeyer flask containing a rapidly stirring solution of brine. After rapidly stirring, the mixture was filtered over a pad of celite (the large colorless clump that formed while stirring was broken apart with a spatula). The filter 14 Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913-9914. 15 Synthesized via Swern oxidation of the corresponding commercially available alcohol.

S13

cake was washed with EtOAc. The filtrate was transferred to a separatory funnel, the EtOAc layer separated, and the solution extracted again with EtOAc. The organic fractions were combined, dried with MgSO4, and the solvent removed at reduced pressure to provide 4.21 g of the sulfinyl imine as a light orange oil (69% yield), which was used without further purification in the following step.

1H NMR (300 MHz, CDCl3) δ 0.99 (s, 9H), δ 1.42 (ddd, J = 6.7, 1.4, 0.7 Hz, 3H), δ 2.18 (q, J = 7.0 Hz, 2H), δ 2.35 – 2.42 (m, 2H), δ 5.14 – 5.35 (m, 2H), δ 7.87 (t, J = 4.4 Hz, 1H).

13C NMR (75 MHz, CDCl3) δ 12.6, δ 22.1, δ 22.6, δ 35.8, δ 56.2, δ 125.1, δ 128.2, δ 168.7. HRMS: m/z (ESI) calculated [M+H]+ = 202.1261, measured 202.1269 (∆ = 4.0 ppm).

NHStBuO

Me

The sulfinyl imine (750 mg, 3.73 mmol, 1 equiv) and CH2Cl2 (20 mL) were combined in an oven-dried round bottom flask and placed under a N2 atmosphere. The solution was cooled to -50 °C using a Cryotrol Temperature Controller. A solution of MeMgBr (3.0 M in Et2O, 2.48 mL, 7.45 mmol, 2 equiv) was then added dropwise via syringe. The solution was stirred at -50 °C for 3 hours, then removed from the cold bath and allowed to warm to room temperature while stirring overnight. The reaction was quenched by very slow addition of NH4Cl (aq) – CAUTION – Addition of NH4Cl (aq) results in vigorous bubbling of the solution. Use of an addition funnel for slow addition is highly recommended. The solution was then extracted with EtOAc (3 times). The organic layer was dried with MgSO4, filtered, and the solvent removed at reduced pressure to give 796 mg of a colorless oil (98% yield) with as a 10:1 mixture of diastereomers, which were separated using a CombiFlash purification system.

1H NMR (300 MHz, CDCl3) δ 1.21 (s, 9H), δ 1.29 (d, J = 6.6 Hz), δ 1.46 – 1.59 (m, 2H), δ 1.61 (d, J = 6.2 Hz, 3H), δ 2.11 (apparent quartet, J = 8.1 Hz, 2H), δ 2.91 (d, J = 7.1 Hz, 1H), δ 3.36 (septet, J = 6.5 Hz, 1H), δ 5.31 – 5.52 (m, 2H).

13C NMR (75 MHz, CDCl3) δ 12.9, δ 22.8, δ 23.4, δ 38.1, δ 52.4, δ 55.8, δ 124.5, δ 129.9. HRMS: m/z (ESI) calculated [M+H]+ = 218.1582, measured 218.1574 (∆ = 3.7 ppm).

NHTsMe

An oven-dried round bottom flask under an atmosphere of N2 was charged with the sulfinamide (469 mg, 2.16 mmol, 1 equiv) and anhydrous MeOH (10 mL). HCl (2.0M in Et2O, 5.40 mL, 10.79 mmol, 5 equiv) was then added via syringe. The solution was stirred at room temperature for 1.5 hours, followed by removal of the solvent at reduced pressure. The crude material was put under an atmosphere of N2, followed by addition of dry CH2Cl2 (7.5 mL). The flask was cooled to 0 °C and Et3N (902 µL, 6.47 mmol, 3 equiv) was added via syringe, at which point the mixture turned yellow. The septum was quickly removed and p-toluene sulfonyl chloride (430 mg, 2.27 mmol, 1.05 equiv) was added. The flask was removed from the ice bath and stirred at room temperature overnight, during which time a white precipitate formed. The reaction was quenched with NH4Cl (aq) and extracted with CH2Cl2 (3 times). The combined organic material was washed with NH4Cl (aq) and brine, dried over MgSO4, filtered, and the solvent removed at reduced pressure. The resulting oil was adsorbed onto silica gel and purified using a CombiFlash purification system to give 530 mg of a colorless oil (92% yield for 2 steps).

1H NMR (300 MHz, CDCl3) δ 1.03 (d, J = 6.5 Hz, 3H), δ 1.41 (q, 2H), δ 1.54 (dq, J = 6.7, 0.8 Hz, 3H), δ 1.85 – 2.07 (m, 2H), δ 2.43 (s, 3H), δ 3.27 – 3.41 (m, 1H), δ 4.29 (d, J = 8.3 Hz, 1H), δ 5.22 (ddq, J = 10.8, 7.0, 1.7 Hz, 1H), δ 5.37 – 5.47 (m, 1H), δ 7.30 (d, J = 8.2 Hz, 2H), δ 7.76 (d, J = 8.2 Hz, 2H).

S14

13C NMR (75 MHz, CDCl3) δ 12.8, δ 21.6, δ 21.7, δ 23.2, δ 37.3, δ 50.0, δ 124.7, δ 127.2, δ 129.4, δ 129.8, δ 138.5, δ 143.3.


D = –13.5° (c = 1.0, CHCl3).

NHTs

Me

OH

Me

ON

MePh

OH

Me

ON

MePh

OH


57% (3 steps)

HO O

NHMe

MePh

OH

N-methyl morpholineisobutylchloroformate

+

1. LDA, LiCl2. MeI

quantitative

nBuLi, iPr2NHBH3•NH3

THF

ON

MePh

OH

Me

CH2Cl284 %

ON

MePh

OH

Synthesized following a literature protocol.16

1H NMR (300 MHz, CDCl3) 2.6:1 mixture of amide rotamers δ 1.10 (d, J = 6.9 Hz, 3H; minor rotamer δ 0.98), δ 1.64 (dd, J = 6.6, 1.0 Hz, 3H) δ 2.28 – 2.50 (m, 4H), δ 2.82 (s, 3H; minor rotamer δ 2.92), δ 4.48 (p, J = 6.9 Hz, 1H; minor rotamer δ 4.01, dq, J = 6.9, 1.5 Hz), δ 4.57 (t, J = 7.8 Hz), δ 5.32 – 5.55 (m, 2H), δ 7.24 – 7.32 (m, 5H).

13C NMR (75 MHz, CDCl3) δ 13.1, δ 18.1, δ 21.7, δ 29.2, δ 29.3, δ 38.7, δ 39.1, δ 46.5, δ 46.8, δ 101.2, δ 126.2, δ 127.3, δ 127.8, δ 129.9, δ 137.2, δ 143.5, δ 170.1

HRMS: m/z (ESI) calculated [M+H]+ = 262.1802, measured 262.1807 (∆ < 1 ppm).

ON

MePh

OH

Me LiCl (1.05 g, 24.9 mmol, 6.5 equiv) was dried by pulling vacuum on an round bottom flask while submerged in a 150 °C oil bath for 15 hours (CAUTION! Use a blast shield and carefully inspect round bottom flask for any cracks). To the LiCl was added THF (5 mL) and diisopropylamine (1.21 mL, 8.57 mmol, 2.24 equiv). The mixture was cooled to -78 °C, followed by dropwise addition of n-butyllithium (2.5 M solution in hexanes, 3.21 mL, 8.04 mmol, 2.1 equiv). The solution was stirred for 5 min, warmed to 0 °C for 5 min, then cooled back to -78 °C for 20 min. A 0 °C solution of the amide (1.0 g, 3.83 mmol, 1 equiv) in THF (5 mL) was then added slowly via cannula. The solution was stirred at -78 °C for 1 hour, 0 °C for 15 min, and room temperature for 5 min. The mixture was cooled back to 0 °C and MeI (357 µL, 5.74 mmol, 1.5 equiv) was added dropwise via syringe. The solution was stirred at 0 °C for 1 hour, then quenched with aqueous NH4Cl. The solution was extracted with Et2O (3 times), the combined organics washed with H2O, then brine. The organic solution was then dried with MgSO4 and the solvent removed at reduced pressure, providing 1.05 g of a light yellow oil, which was of sufficient purity to use in the following step (99% crude yield). If desired, the product could be further purified by silica gel column

16 Keck, G. E.; Heumann, S. A. Org. Lett. 2008, 10, 4783-4786.

S15

chromatography (elution solvent – hexanes:EtOAc from 1:1.5 to 1:2, Rf = 0.37 at hexanes:EtOAc = 1:2) to provide the desired product as a colorless oil.

1H NMR (300 MHz, CDCl3) 2.9:1 mixture of amide rotamers δ 1.04 (d, J = 6.8 Hz, 3H; minor rotamer δ 1.00) δ 1.17 (d, 7.0 Hz, 3H; minor rotamer δ 1.16), δ 1.63 (d, J = 6.8 Hz, 3H; minor rotamer δ 1.59), δ 2.34 (apparent sextet, J = 7.1 Hz, 1H), δ 2.15 (apparent quintet, J = 7.1 Hz, 1H), δ 2.57 – 2.71 (m, 1H; minor rotamer δ 2.46), δ 2.80 (s, 3H; minor rotamer δ 2.92), δ 4.05 – 5.03 (m, 3H), δ 5.27 – 5.41 (m, 1H), δ 5.45 – 5.57 (m, 1H), δ 7.22 – 7.38 (m, 5H)

13C NMR (75 MHz, CDCl3) mixture of amide rotamers. major rotamer: δ 72.8, δ 72.9, δ 73.0, δ 74.0, δ 74.2, δ 76.0, δ 74.42, δ 77.2, δ 80.64, δ 80.65, δ

80.76, δ 80.81, δ 80.84, δ 81.8, δ 84.3 minor rotamer: δ 72.94, δ 73.07, δ 73.10, δ 73.7, δ 74.07, δ 74.36, δ 75.9, δ 77.12, δ 80.64, δ

80.71, δ 80.77, δ 81.72, δ 84.25 HRMS: m/z (ESI) calculated [M+H]+ = 276.1959, measured 276.1956 (∆ = 1.4 ppm).

OH

Me

To an oven-dried round-bottom flask under a nitrogen atmosphere was added THF (10 mL) and diisopropylamine (1.64 mL, 11.59 mmol, 4.2 equiv). The mixture was cooled to -78 °C, followed by dropwise addition of n-butyllithium (2.5 M solution in hexanes, 4.31 mL, 19.76 mmol, 3.9 equiv). The solution was stirred for 15 min at -78 °C, then placed in a 0 °C ice bath for 25 min. The rubber septum was removed, ammonia borane complex was added in one portion, and the septum was quickly replaced. This mixture was at 0 °C for 20 min, then removed from the ice bath and stirred another 20 min. At this point, the amide (760 mg, 2.76 mmol, 1 equiv) in THF (6 mL) was added dropwise via cannula and the solution was allowed to stir at room temperature overnight. The solution was then cooled to 0 °C, and the reaction quenched very carefully with 1M HCl. Additional H2O was then added, and the solution was extracted with minimal amounts of Et2O (3 times). The combined organics were dried over MgSO4, and the solvent removed by short path distillation with a 50 mm vigreux column. The product was obtained as a solution in THF and used without further isolation. 1H NMR (300 MHz, CDCl3) δ 0.93 (d, J = 6.7 Hz, 3H), δ 1.26 (bs, 1H), δ 1.60 – 1.75 (m, 4H), δ 1.88 – 2.19 (m, 2H), δ 3.42 – 3.74 (m, 2H), δ 5.38 – 5.59 (m, 2H).

NHTs

Me

Following the mesylation/p-toluene sulfonamide two step procedure described previously, the desired product was obtained in 57% yield (3 steps); coloress oil (elution solvent – hexanes:EtOAc = 4:1).

1H NMR (300 MHz, CDCl3) δ 0.87 (d, J = 6.7 Hz, 3H), δ 1.53 – 1.70 (m, 3H), δ 1.83 – 2.07 (m, 2H), δ 2.43 (s, 3H), δ 2.72 – 2.92 (m, 2H), δ 4.91 (t, J = 6.2 Hz, 1H), δ 5.23 – 5.55 (m, 2H), δ 7.31 (d, J = 7.9 Hz, 2H), δ 7.76 (d, J = 8.3 Hz, 2H).

13C NMR (75 MHz, CDCl3) δ 13.0, δ 17.6, δ 31.5, δ 33.8, δ 125.9, δ 127.2, δ 127.8, δ 129.8, δ 137.2, δ 143.4.

HRMS: m/z (ESI) calculated [M+H]+ = 268.1366, measured 268.1356 (∆ = 3.7 ppm). [α]21

D = –3.0° (c 1.1, CHCl3).

S16

TsNH2NaOH

TDMSClimidazoleref. 15

NHTs

TBSO

OTs

TBSO

OTs

HOBr

TsO

O+

DMF73%

DMF96%

OTs

TBSO

The alcohol17 (1.5 g, 5.55 mmol, 1 equiv) was dissolved in dry DMF (10 mL), followed by addition of imidazole (756 mg, 11.1 mmol, 2 equiv), then t-butyldimethylsilyl chloride (1.09 g, 7.22 mmol, 1.3 equiv). The solution was stirred overnight at room temperature. Et2O and H2O were then added. The solution was extract 3 times with Et2O, and the combined organics washed with H2O, brine, then dried with MgSO4. After removing the solvent, 1.96 g of the desired product was obtained as a colorless oil (92% yield).

1H NMR (300 MHz, CDCl3) δ 0.00 (s, 3H), δ 0.02 (s, 3H), δ 0.825 (m, 9H), δ 1.56 (m, 3H), δ 2.20 (t, J = 5.6, 2H), δ 2.44 (s, 3H), δ 3.81 – 3.92 (m, 3H), δ 5.31 (dddq, J = 10.8, 9.2, 7.4, 1.8 Hz, 1H), δ 5.53 (dqt, J = 10.8, 6.8, 1.5 Hz, 1H), δ 7.33(d, J = 8.3 Hz, 2H), δ 7.77 (d, J = 8.3 Hz, 2H).



NHTs

TBSO

The tosyl ether synthesized in the previous step (1.031 g, 2.68 mmol, 1 equiv) was dissolved in dry DMF (30 mL), followed by addition of p-toluenesulfonamide (1.8 g, 8.04 mmol, 3 equiv) and NaOH (161 mg, 4.02 mmol, 1.5 equiv). The solution was submerged in a pre-heated 65 °C oil bath, and the reaction progress was monitored by TLC. After stirring overnight, the solution was allowed to cool to room temperature, followed by addition of saturated NH4Cl and Et2O. The solution was extracted with Et2O (3 times) and washed with saturated NH4Cl (2 x). The combined organic fractions were then dried over MgSO4 and the solvent removed at reduced pressure. The oily residue was further purified on a CombiFlash purification system (elution solvent hexanes/EtOAc) to provide 750 mg (73% yield) of the desired product as a colorless oil.

1H NMR (300 MHz, CDCl3) δ 0.03 (s, 3H), δ 0.07 (s, 3H), δ 0.88 (m, 9H), δ 1.63 (m, 3H), δ 2.26 (t, J = 7.1 Hz, 2H), δ 2.45 (s, 3H), δ 2.88 – 3.03 (m, 2H), δ 3.76 - .83 (m, 1H), δ 4.65 (t, J = 6.1 Hz, 1H), δ 5.32 (dddq, J = 10.9, 9.2, 7.5, 1.7 Hz, 1H), δ 5.59 (dqt, J = 10.9, 6.8, 1.5 Hz, 1H), δ 7.36 (d, J = 8.1 Hz, 2H), δ 7.77 (d, J = 8.1 Hz, 2H).



D = –12.0° (c 1.1, CHCl3).

17 Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am. Chem. Soc. 2005, 127, 17921-17937.

S17

NHTs

Me

OH

Me

OTBDPS

Me

OTBDPS

OMe

PPh3CH2CH3KOtBu


68% (3 steps)THF79%

TBAF

THF

OTBDPS

Me An oven-dried 3-neck round bottom flask was charged with KOtBu (790 mg, 7.05 mmol, 2 equiv) and put under a N2 atmosphere. Dry THF (15 mL) was then added and the solution cooled to 0 °C. While under positive N2 pressure, a septum was quickly removed and ethyl triphenylphosphonium bromide (2.75 g, 7.40 mmol, 2.1 equiv) was added in one portion. The suspension was then removed from the ice bath and stirred at room temperature for 45 min. After cooling back to 0 °C, a solution of the aldehyde18 (1.2 0 g, 3.52 mmol, 1 equiv) in dry THF (6 mL) was added slowly via cannula to the flask. The solution was removed from the ice bath and stirred overnight, at which point the reaction was quenched with H2O and extracted with hexanes (3 times). The combined organic layers were then washed with brine and dried over MgSo4, followed by filtration and removal of the solvent at reduced pressure. To remove triphenylphosphine byproducts, the material was suspended in hexanes and filtered over celite, washing four times with additional hexanes. The oily residue was further purified on a CombiFlash purification system (elution solvent pure hexanes) to provide 984 mg (79% yield) of the desired product as a colorless oil.

1H NMR (300 MHz, CDCl3) δ 0.92 (d, J = 6.8 Hz, 3H), 1.05 (m, 9H), δ 1.40 – 1.57 (m, 2H), δ 1.60 (dd, J = 6.8, 1.7 Hz, 3H), δ 2.65 – 2.79 (m, 1H), δ 3.64 (dd, J = 6.9, 6.1 Hz, 2H), δ 5.11 (ddq, J = 10.8, 9.5, 1.7 Hz, 1H), δ 5.37 (dqd, J = 10.8, 6.8, 0.9 Hz, 1H), δ 7.34 – 7.44 (m, 6H), δ 7.65 – 7.69 (m, 4H).


HRMS: m/z (ESI) calculated [M-tBu] •+ = 295.1513, measured 295.1502 (∆ = 3.7 ppm). OH

Me The silyl protected substrate (900 mg, 2.55 mmol, 1 equiv) was dissolved in dry THF (25) and cooled to 0 °C. TBAF (1M solution in THF, 7.66 mL, 7.66 mmol, 3 equiv) was then added dropwise via syringe and the solution stirred at room temperature overnight. The reaction was quenched by slow addition of H2O, then extracted 3 times with minimal amounts of Et2O. After washing with brine, the organic layer was dried over MgSO4, and the ether removed by short path distillation with a 50 mm vigreux column. The solution was used without further isolation in the following step. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, J = 6.6 Hz, 3H), δ 1.63 (dd, J = 6.7, 1.7 Hz, 3H), δ 1.40 – 1.58 (m, 2H), δ 2.57 – 2.72 (m, 1H), δ 3.61 (apparent q, J = 6.2 Hz, 2H), δ 5.14 – 5.22 (m, 1H), δ 5.43 (dqd, J = 10.8, 6.9, 0.5 Hz, 1H)

18 Fuerstner, A.; Bouchez, L. C.; Morency, L.; Funel, J.-A.; Liepins, V.; Poree, F.-H.; Gilmour, R.; Laurich, D.; Beaufils, F.; Tamiya, M. Chem. Eur. J. 2009, 15, 3983-4010.

S18

NHTs

Me Following the mesylation/p-toluene sulfonamide two step procedure described previously, the desired product was obtained in 82% yield (3 steps); coloress oil (elution solvent – hexanes:EtOAc = 4:1).

1H NMR (300 MHz, CDCl3) δ 0.89 (d, J = 6.5 Hz, 3H), δ 1.26 – 1.40 (m, 1H), δ 1.44 – 1.61 (m, 4H), δ 2.40 – 2.53 (m, 4H), δ 2.92 (q, J = 6.9 Hz, 2H), δ 4.33 (t, J = 5.8 Hz, 1H), δ 5.06 (dq, J = 10.8, 1.7 Hz, 1H), δ 5.39 (dq, J = 10.8, 6.9 Hz, 1H), δ 7.31 (d, J = 8.2 Hz, 2H), δ 7.73 (d, J = 8.1 Hz, 2H).


HRMS: m/z (ESI) calculated [M+H]+ = 268.1366, measured 268.1371 (∆ = 2 ppm). [α]21

D = –6.3° (c 1.0, CHCl3).

5. Determination of Absolute Configuration. Pyrrolidine products were oxidized to provide tosyl proline.19 Comparison with the HPLC spectra of authentic samples of (R)-tosyl proline and (S)-tosyl proline was then used to determine absolute configuration.

TsN

NaIO4RuCl3•3H2O

TsN COOH

CCl4/H2O/CH3CN The pyrrolidine (28 mg, 0.11 mmol, 1 equiv) was dissolved in CCl4 (0.25 mL), deionized H2O (0.35 mL) and NaIO4 (113 mg, 0.53 mmol, 5 equiv) was added. The mixture was stirred rapidly, followed by addition of a solution of RuCl3•3H2O (1.1 mg, 5.3 μmol, 0.05 equiv) in CH3CN (0.25 mL). The mixture was allowed to continue stirring overnight, then CH2Cl2 and H2O was added, followed by extraction with CH2Cl2 (3 times). The combined organics were dried over MgSO4, filtered, and the solvent removed at reduced pressure. The crude mixture was used for HPLC analysis without further purification.

19 Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 727407276.

S19

TsN

OH

O

(R) Chiralcel AD-H, 20% iPrOH, 1 mL/min, 230 nm

Minutes

6 7 8 9 10 11

mA

u

0

50

100

150

mA

u

0

50

100

15020

2766

4 6

.72

S P D - M 2 0 A - 2 1 6 n m

R E M 0 4 2 5 9 . 2 0 D

AreaRetention Time

TsN

OH

O

(S) Chiralcel AD-H, 20% iPrOH, 1 mL/min, 230 nm

Minutes

6 7 8 9 10 11

mA

u

0

200

400

600

mA

u

0

200

400

600

5693

744

8.5

7

S P D - M 2 0 A - 2 1 6 n m

R E M 0 4 2 5 9 . 3 0 L

AreaRetention Time

Absolute configuration of isomerized product 7 (Scheme 7) was determined by comparison with an enantiopure sample synthesized by the following route:

TsN

OH

O TsN

OHTsN

I

TsNNaBH4 / BF3

THF

I2, imidazolePPh3

Et2O / CH3CN

CuBr•SMe2HMPA

THF

BrMg

S20

6. Chiral HPLC Data. TsN

Racemic sample: Chiralcel AD-H, 10% iPrOH, 1 mL/min, 230 nm

Minutes

8.75 9.00 9.25 9.50 9.75 10.00 10.25

mA

u

0

100

200

300

mA

u

0

100

200

30020

9677

1 9

.004

2081

303

9.8

56

S P D - M 2 0 A - 2 3 0 n m

R E M 0 4 1 8 1 . 1 P R

AreaRetention Time

NHTs Ts

N

Enantiomerically enriched (Table 1, Entry 1): 98% ee

Minutes

8.0 8.5 9.0 9.5 10.0

mA

u

0

250

500

750

1000

mA

u

0

250

500

750

1000

7493

415

8.4

64

6972

2 9

.328

S P D - M 2 0 A - 2 4 0 n m

R E M 0 4 2 5 0 . 2 1 4

AreaRetention Time

S21

NHTs TsN

Enantiomerically enriched: 50% ee

Minutes

9.0 9.2 9.4 9.6 9.8 10.0 10.2 10.4

mA

u

0

100

200

300

400

mA

u

0

100

200

300

40035

4850

0 9

.176

1202

253

10.

072

S P D - M 2 0 A - 2 3 0 n m

R E M 0 4 2 4 4 . 2 2 2 0

AreaRetention Time

S22

TsN


Minutes

7.2 7.4 7.6 7.8 8.0 8.2

mA

u

0

50

100

150

200

mA

u

0

50

100

150

200

9938

72 7

.228

1019

471

7.8

96

S P D - M 2 0 A - 2 5 4 n m

R E M 0 4 1 8 2 . 3 A B

AreaRetention Time

TsN


Minutes

7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0

mA

u

0

200

400m

Au

0

200

400

3833

583

7.8

96

5923

1 8

.672

S P D - M 2 0 A - 2 5 4 n m

R E M 0 4 2 4 4 . 3 1 4

AreaRetention Time

S23

TsN Ph

Racemic sample: Chiralcel OJ-H, 15% iPrOH, 1 mL/min, 230 nm

Minutes

20 22 24 26 28

mA

u

0

100

200

300

400

mA

u

0

100

200

300

400

6164

210

21.

036

6114

053

26.

280

S P D - M 2 0 A - 2 3 0 n m

R E M 0 4 1 9 8 . 3 0 3

AreaRetention Time

TsN Ph


Minutes

18 20 22 24 26

mA

u

0

100

200

300

400

mA

u

0

100

200

300

400

2877

99 1

9.28

4

7923

991

24.

256

S P D - M 2 0 A - 2 6 0 n m

R E M 0 4 2 4 4 . 4 1 1

AreaRetention Time

S24

TsN

Racemic sample: Chiralcel AS-H, 10% iPrOH, 1 mL/min, 230 nm

Minutes

12 14 16 18 20 22

mA

u

0

20

40

mA

u

0

20

40

3960

20 1

2.83

6630

80 1

3.78

4321

87 1

9.36

6892

00 2

1.30

S P D - M 2 0 A - 2 3 0 n m

0 5 0 6 4 r a c . 5 F 6 1

AreaRetention Time

TsN

Enantiomerically enriched (Table 1, Entry 5): major diastereomer: 93% ee minor diastereomer: 95% ee

Minutes

12 14 16 18 20 22

mA

u

0

200

400

600

mA

u

0

200

400

600

5008

70 1

2.87

2825

06 1

3.82

1391

8622

19.

28

1052

9651

21.

29

S P D - M 2 0 A - 2 3 0 n m

0 5 0 6 4 f o r e e . 0 0 2

AreaRetention Time

S25

TsN

MeMe

Racemic sample: Chiralcel AS-H, 15% iPrOH, 1 mL/min, 230 nm

TsN

MeMe


S26

NsN Ph


NsN Ph


S27

SO2NMe2N Ph


SO2NMe2N Ph


S28

7. Characterization Data for Oxidative Amination Products. TsN

Table 1, Entry 1. 68% yield, 98% ee. Purified by column chromatography using AgNO3 impregnated silica gel,20 eluting solvent – hexanes:EtOAc = 4:1. Characterization data agrees with literature report.21 See NMR spectra below. TsN

Table 1, Entry 2. 62% yield, 97% ee. Purified by column chromatography using basic Al2O3, eluting solvent – hexanes:EtOAc = 4:1. Characterization data agrees with literature report.22 See NMR spectra below. TsN Ph

Table 1, Entry 3. 98% yield, 93% ee. Purified by column chromatography, eluting solvent – hexanes:EtOAc = 4:1. Characterization data agrees with literature report.22 See NMR spectra below.

TsN

MeMe

Table 1, Entry 4. 58% yield, 92% ee. Purified by column chromatography on basic alumina using a Combiflash purification system, eluting solvent – hexanes / EtOAc. See NMR spectra below.

1H NMR (300 MHz, CDCl3) δ 0.69 (s, 3H), 1.06 (s, 3H), 1.57 (dd, J = 12.8, 8.3 Hz, 1H), 1.74 (ddd, J = 12.6, 7.6, 0.9 Hz, 1H), 2.43 (s, 3H), 3.14 (dd, J = 10.1, 0.8 Hz, 1H), 3.20 (d, J = 10.1 Hz, 1H), 4.02 (qt, J = 7.6, 0.8 Hz, 1H), 5.07 (dt, J = 10.1, 1.0 Hz, 1H), 5.18 (dt, J = 17.2, 1.1 Hz, 1H), 5.87 (ddd, J = 17.2, 10.1, 7.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.71 (dt, J = 8.1, 1.5 Hz, 2H);

13C NMR (75 MHz, CDCl3) δ 143.4, 140.0, 135.6, 129.7, 127.8, 115.4, 62.7, 61.7, 47.7, 37.7, 26.7, 26.3, 21.7;

HRMS: m/z (ESI) calculated [M+Na]+ = 302.1186, measured 302.1197 (∆ = 3.6 ppm).

TsN

Table 1, Entry 5. 86% yield, d.r. = 1.4:1, 93% ee (major diastereomer), 95% ee (minor diastereomer). Colorless oil. Purified by column chromatography, eluting solvent – hexanes:EtOAc = 5:1.

1H NMR (300 MHz, CDCl3) major diastereomer δ 1.33 – 1.46 (m, 1H), δ 1.56 (ddd, J = 6.8, 1.7, 0.9 Hz, 3H), δ 1.70 – 1.79 (m, 1H), δ 1.83 – 1.97 (m, 1H), δ 2.00 – 2.12 (m, 2H), δ 2.44 (s, 3H), δ 3.03 (dd, J = 10.9, 9.2 Hz, 1H), δ 3.52 – 3.61 (m, 1H), δ 3.94 (qt, J = 7.2, 0.9 Hz, 1H), δ 5.09 (dt, J = 10.2, 1.1 Hz, 1H), δ 5.17 – 5.30 (m, 2H), δ 5.43 – 5.54 (m, 1H), δ 5.74 – 5.94 (m, 1H), δ 7.31 (d, J = 8.1 Hz, 2H), δ 7.69 – 7.74 (m, 2H). minor diastereomer δ 1.52 (ddd, J = 6.8, 1.7, 0.9 Hz, 3H), δ 1.58 – 1.65 (m, 1H), δ 1.70 – 1.79 (m, 1H), δ 1.83 – 1.97 (m, 1H), δ 2.00 – 2.12 (m, 1H), δ 2.17 – 2.30 (m, 1H), δ 2.44 (s, 3H), δ

20 Li, T.-S.; Li, J.-T.; Li, H.-Z. J. Chromatogr. A 1995, 715, 372-375. 21 Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585. 22 Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem. 1994, 59, 4172-4178.

S29

2.81 (t, J = 9.2 Hz, 1H), δ 3.52 – 3.61 (m, 1H), δ 4.21 (m, 1H), δ 5.11 (dt, J = 10.2, 1.2 Hz, 1H), δ 5.17 – 5.30 (m, 2H), δ 5.43 – 5.54 (m, 1H), δ 5.74 – 5.94 (m, 1H), δ 7.31 (d, J = 8.1 Hz, 2H), δ 7.69 – 7.74 (m, 2H).

13C NMR (75 MHz, CDCl3) major diastereomer δ 13.05, δ 21.7, δ 30.0, δ 38.2, δ 39.7, δ 54.5, δ 63.2, δ 115.3, δ 125.9, δ 127.8, δ 129.9, δ 135.4, δ 139.7, δ 143.5. minor diastereomer δ 12.99, δ 21.7, δ 29.8, δ 37.2, δ 38.1, δ 53.9, δ 61.8, δ 115.4, δ 125.8, δ 127.5, δ 129.8, δ 135.3, δ 139.0, 143.5.

HRMS: m/z (ESI) calculated [M+Na]+ = 328.1342, measured 328.1357 (∆ = 4.5 ppm). SO2NMe2N Ph


1H NMR (300 MHz, CDCl3) δ 0.69 (s, 3H), 1.06 (s, 3H), 1.57 (dd, J = 12.8, 8.3 Hz, 1H), 1.74 (ddd, J = 12.6, 7.6, 0.9 Hz, 1H), 2.43 (s, 3H), 3.14 (dd, J = 10.1, 0.8 Hz, 1H), 3.20 (d, J = 10.1 Hz, 1H), 4.02 (qt, J = 7.6, 0.8 Hz, 1H), 5.07 (dt, J = 10.1, 1.0 Hz, 1H), 5.18 (dt, J = 17.2, 1.1 Hz, 1H), 5.87 (ddd, J = 17.2, 10.1, 7.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.71 (dt, J = 8.1, 1.5 Hz, 2H);

13C NMR (75 MHz, CDCl3) δ 143.4, 140.0, 135.6, 129.7, 127.8, 115.4, 62.7, 61.7, 47.7, 37.7, 26.7, 26.3, 21.7;

HRMS: m/z (ESI) calculated [M+Na]+ = 303.1138, measured 303.1130 (∆ = 2.6 ppm). NsN Ph


1H NMR (300 MHz, CDCl3) δ 1.83 (m, 2H), 1.99 (m, 2H), 3.49 (t, J = 6.4 Hz, 2H), 4.46 (m, 1H), 5.88 (dd, J = 15.7, 7.6 Hz, 1H), 6.54 (d, J = 15.7 Hz, 1H), 7.28 (m, 5H), 7.98 (dt, J = 8.7, 1.7 Hz, 2H), 8.25 (dt, J = 8.7, 1.7 Hz, 2H);

13C NMR (75 MHz, CDCl3) δ 150.0, 145.4, 136.1, 132.0, 128.8, 128.7, 128.2, 126.5, 124.3, 62.4, 48.8, 33.2, 24.3;

HRMS: m/z (ESI) calculated [M+Na]+ = 381.0880, measured 381.0888 (∆ = 2.1 ppm). TsNMe

Table 1, Entry 9. 88% yield, >20:1 d.r. Colorless oil. Purified by column chromatography, eluting solvent – hexanes:EtOAc = 5:1.

1H NMR (300 MHz, CDCl3) δ 1.36 (d, J = 6.4 Hz, 3H), δ 1.45 – 1.71 (m, 4H), δ 2.42 (s, 3H), δ 3.73 (sextet, J = 6.3 Hz, 1H), δ 4.10 – 4.16 (m, 1H), δ 5.12 (dt, J = 10.3 Hz, 1.4 Hz, 1H), δ 5.31 (dt, J = 17.0, 1.4 Hz, 1H), δ 5.84 (ddd, J = 17.0, 10.3, 5.5 Hz, 1H), δ 7.31 (d, J = 8.2 Hz, 2H), δ 7.72 (d, J = 8.2 Hz, 2H).


HRMS: m/z (ESI) calculated [M+H]+ = 266.1210, measured 266.1211 (∆ <1 ppm).

S30

TsNMe

Table 1, Entry 10. 23% yield, 7:1 d.r. Colorless oil. Purified with a CombiFlash purification system on basic Al2O3, eluting solvent – hexanes:EtOAc = 4:1.

1H NMR (300 MHz, CDCl3) δ 1.29 (d, J = 6.4 Hz, 3H), δ 1.46 – 1.54 (m, 1H), δ 1.59 – 1.72 (m, 1H), δ 2.00 – 2.15 (m, 1H), δ 2.13 – 2.28 (m, 1H), δ 2.41 (s, 3H), δ 4.03 (apparent quintet, J = 6.4 Hz, 1H), δ 4.34 (t, J = 7.8 Hz, 1H), δ 4.99 (d, J = 10.0 Hz, 1H), δ 5.17 (d, J = 17.0 Hz, 1H), δ 5.57 (ddd, J = 17.0, 10.0, 1.6 Hz, 1H), δ 7.24 (d, J = 8.3 Hz, 2H), δ 7.71 (d, J = 8.0 Hz, 2H).


TsN

Me Table 1, Entry 12. 87% yield, d.r. = 17:1. Colorless oil. Purified by column chromatography, eluting solvent – hexanes:EtOAc = 4:1.

1H NMR (300 MHz, CDCl3) δ 0.95 (d, J = 6.5 Hz, 3H), δ 1.28 – 1.39 (m, 1H), δ 1.68 – 1.84 (m, 1H), δ 2.08 (dt, J = 12.9, 6.7 Hz, 1H), δ 2.43 (s, 3H), δ 2.94 (dd, J = 10.6, 9.8 Hz, 1H), δ 3.59 (dd, J = 10.6, 7.4 Hz, 1H), δ 3.97 (q, J = 7.4 HZ, 1H), δ 5.08 (d, J = 10.2 Hz, 1H), δ 5.21 (d, J = 17.0 Hz, 1H), δ 5.88 (ddd, J = 17.0, 10.2, 7.1 Hz, 1H), δ 7.31 (d, J = 8.2 Hz, 2H), δ 7.71 (d, J = 8.2 Hz, 2H).


TsN

Me Table 1, Entry 13. 90% yield, >20:1 d.r. Colorless oil. Purified by column chromatography, eluting solvent – hexanes:EtOAc = 4:1.

1H NMR (300 MHz, CDCl3) δ 0.87 (d, J = 6.7 Hz, 3H), δ 1.33 (ddd, J = 12.2, 10.5, 8.4 Hz, 1H), δ 1.75 (ddd, J = 8.4, 6.0, 2.5 Hz, 1H), δ 2.21 – 2.38 (m, 1H), δ 2.43 (s, 3H), δ 2.71 (t, 9.2 Hz, 1H), δ 3.56 (dd, J = 9.2, 7.0 Hz, 1H), δ 4.17 – 4.23 (m, 1H), δ 5.11 (dt, J = 10.2, 1.3 Hz, 1H), δ 5.27 (dt, J = 17.1, 1.3 Hz, 1H), δ 5.81 (ddd, J = 17.1, 10.2, 5.9 Hz, 1H), δ 7.31 (d, J = 8.0 Hz, 2H), δ 7.72 (d, J = 8.3 Hz, 2H).

13C NMR (75 MHz, CDCl3) δ 17.1, δ 21.7, δ 31.5, δ 40.3, δ 55.6, δ 61.9, δ 115.2, δ 127.7, δ 129.7, δ 135.1, δ 139.1, δ 143.4

HRMS: m/z (ESI) calculated [M+Na]+ = 288.1029, measured 288.1028 (∆ <1 ppm).

TsN

TBSO Table 1, Entry 15. 97% yield, >20:1 d.r. Colorless oil. Purified by column chromatography, eluting solvent – hexanes:EtOAc = 5:1.

1H NMR (300 MHz, CDCl3) δ –0.06 (s, 6H), δ 0.73 (s, 9H), δ 1.78 – 1.88 (m, 2H), δ 2.42 (s, 3H), δ 3.19 (dd, J = 10.9, 2.6 Hz, 1H), δ 3.66 (dd, J = 10.9, 4.6 Hz, 1H), δ 4.03 (apparent quartet, J = 7.3 Hz, 1H), δ 4.23 – 4.28 (m, 1H), δ 5.14 (dd, J = 10.3, 1.3 Hz, 1H), δ 5.22 (dd, J = 17.2, 1.3 Hz, 1H), δ 5.92 (ddd, J = 17.0, 10.3, 7.4 Hz, 1H), δ 7.3 (d, J = 8.2 Hz, 2H), δ 7.72 (d, J = 8.2 Hz, 2H).

S31



TsN

TBSO Table 1, Entry 16. 92% yield, >20:1 d.r. Colorless oil. Purified by column chromatography, eluting solvent – hexanes:EtOAc = 5:1.

1H NMR (300 MHz, CDCl3) δ 0.00 (s, 6H), δ 0.83 (s, 9H), δ 1.70 (dt, J = 13.0, 4.6 Hz, 1H), δ 2.05 (ddd, J = 13.0, 8.4, 5.4 Hz, 1H), δ 2.43 (s, 3H), δ 3.26 (dd, J = 10.7, 4.0 Hz, 1H), δ 3.49 (dd, J = 10.7, 5.4 Hz, 1H), δ 4.10 (quintet, J = 4.4 Hz, 1H), δ 4.15 – 4.22 (m, 1H), δ 5.03 (dd, J = 10.1, 0.8 Hz, 1H), δ 5.19 (dd, J = 17.1, 0.8 Hz, 1H), δ 5.95 (ddd, J = 17.1, 10.1, 7.9 Hz, 1H), δ 7.30 (d, J = 8.1 Hz, 2H), δ 7.72 (d, J = 8.1 Hz, 2H).

13C NMR (75 MHz, CDCl3) δ -4.8, δ 18.1, δ 21.7, δ 25.8, δ 41.8, δ 56.5, δ 61.9, δ 70.8, δ 115.5, δ 127.7, δ 129.7, δ 136.0, δ 139.6, δ 143.5.

TsN

Me Table 1, Entry 18. 92% yield, >20:1 d.r. Colorless solid. Purified by column chromatography, eluting solvent – hexanes:EtOAc = 4:1.

1H NMR (300 MHz, CDCl3) δ 0.75 (d, J = 6.2 Hz, 3H), δ 1.13 – 1.26 (m, 1H), δ 1.87 – 1.99 (m, 2H), δ 2.43 (s, 3H), δ 3.37 – 3.43 (m, 3H), δ 5.14 (dd, J = 10.2, 1.3 Hz, 1H), δ 5.21 (dd, J = 17.0, 1.3 Hz, 1H), δ 5.80 (ddd, J = 17.0, 10.2, 7.3 Hz, 1H), δ 7.31 (d, J = 8.1 Hz, 2H), δ 7.71 (d, J = 8.1 Hz, 2H).


HRMS: m/z (ESI) calculated [M+H]+ = 266.1210, measured 266.1222 (∆ = 4.5 ppm). 8. NOE Correlations. NOE correlations were used to determine the relative stereochemistry of the following compounds. Subsequent assignments were made by analogy.

TsN

TsN

TsN

H H

TBSOH

MeH

MeH H

HH

HH

HH

Table 1, Entry 5 Table 1, Entry 10 Table 1, Entry 13

S32

9. Tabulated Electronic Energies, Zero-Point Correction and Solvation-Corrected Gibbs Free Energies. Table S2. Compiled electronic energies (Egas), zero-point correction and solvation-corrected Gibbs free energies (Gsol,298K) in kcal/mol including the three lowest frequencies for the alkene-insertion step of all possible geometric rearrangements of the substrate.

Table S3. Compiled electronic energies (Egas), zero-point correction and solvation-corrected Gibbs free energies (Gsol,298K) in kcal/mol including the three lowest frequencies for the reaction path of the major enantiomer pathway.

Label Egas ZPE Gsol,298K Freq. (cm-1)

ST1major -1111332.20 297.84 -1111286.49 11.6, 13.7, 20.6

ST2major -1111328.15 298.51 -1111282.61 22.3, 27.2, 34.2

ST3major -1111322.22 298.08 -1111277.70 -206.6, 9.3, 21.4

ST4major -1111339.25 299.64 -1111291.91 14.9, 20.8, 25.1

ST5major -1111348.66 299.69 -1111298.33 18.7, 20.3, 29.1

Table S4. Compiled electronic energies (Egas), zero-point correction and solvation-corrected Gibbs free energies (Gsol,298K) in kcal/mol including the three lowest frequencies for the reaction path of the minor enantiomer pathway.


ST1minor -1111331.60 297.87 -1111539.98 9.6, 14.5, 20.1

ST2minor -1111326.94 298.36 -1111539.37 18.7, 28.2, 29.7

ST3minor -1111321.02 298.06 -1111533.50 -208.4, -2.3, 15.2

ST4minor -1111338.13 299.72 -1111549.45 8.7, 26.7, 33.1

ST5minor -1111348.27 299.74 -1111557.75 20.9, 26.0, 29.0 Numerous unsuccessful attempts were made to remove the extra imaginary frequency. The magnitude of this

frequency is very small, and therefore we assume that its effect inconsequential in light of the larger imaginary frequency.


transpyre -966337.42 247.68 -966522.66 21.0, 32.2, 35.2

transpyreTS -966335.50 247.32 -966520.73 -156.5, 25.9, 30.4

transpysi -966336.34 247.61 -966521.32 18.0, 29.0, 31.9

transpysiTS -966334.99 247.34 -966520.00 -148.9, 18.1, 30.2

cispysi -966334.25 247.80 -966520.17 24.9, 33.1, 46.2

cispysiTS -966332.80 247.52 -966518.93 -176.6, 24.5, 30.0

cispyre -966334.39 247.87 -966519.22 26.6, 41.4, 44.7

cispyreTS -966332.11 247.57 -966517.66 -157.2, 24.9, 35.6

S33

10. Cartesian Coordinates for Optimized Structures. transpy SCF Energy: -1461.336183 Hart.a Pd -4.787382 -1.548258 -1.696698 C -5.571998 -1.415093 0.357627 C -4.437310 -0.617756 0.333456 C -3.115599 -0.990943 0.966103 C -2.075105 -1.625171 0.018383 C -2.435117 -3.059064 -0.378879 N -3.573431 -3.151831 -1.322794 S -4.589492 -4.478064 -1.067007 O -4.927436 -4.659139 0.359134 O -5.683164 -4.308902 -2.045405 C -3.595037 -5.904453 -1.553068 N -4.543073 -1.796112 -3.832935 C -3.801106 -2.719287 -4.445225 C -3.759937 -2.820322 -5.841260 C -4.514715 -1.937130 -6.609616 C -5.294301 -0.968037 -5.966530 C -5.277387 -0.933747 -4.577006 C -6.040822 0.021176 -3.765121 N -5.981363 0.008005 -2.472504 O -6.820077 0.927132 -4.342420 C -7.417893 1.723941 -3.259889 C -6.882042 1.060825 -1.963794 H -7.679589 0.610852 -1.364109 H -5.550429 -2.405367 0.808584 H -6.558577 -0.993828 0.181078 H -4.548678 0.431542 0.059660 H -2.687676 -0.076225 1.393541 H -3.296242 -1.682526 1.797800 H -1.111907 -1.657932 0.541669 H -1.928253 -1.001502 -0.873256 H -1.561320 -3.506466 -0.874438 H -2.629977 -3.630940 0.538451 H -2.700310 -5.951880 -0.928806 H -4.220310 -6.783230 -1.375137 H -3.339343 -5.824239 -2.610733 H -3.241280 -3.374368 -3.786323 H -3.144444 -3.584071 -6.305312 H -4.502526 -1.996399 -7.693646 H -5.899945 -0.260083 -6.521985 H -7.083966 2.753129 -3.400598 H -8.500249 1.661184 -3.376783 H -6.327830 1.762063 -1.332704 cispy SCF Energy: -1461.333434 Hart.a Pd -4.645850 1.849435 -1.263469 N -4.901277 1.828115 0.823745 C -3.803616 1.931514 1.488959 O -3.879462 2.032386 2.810826 C -5.317563 1.977887 3.145776 C -6.027811 1.905614 1.767648 N -2.597360 1.909947 -0.550552

C -2.503924 1.958595 0.805690 C -1.288508 2.039492 1.476238 C -0.111212 2.070064 0.722158 C -0.201985 2.021722 -0.666783 C -1.464232 1.943827 -1.263044 C -4.223603 2.475539 -3.331854 C -4.155778 1.090868 -3.336329 C -5.204876 0.178965 -3.935521 C -6.319570 -0.287044 -2.975552 C -7.255964 0.849712 -2.563428 N -6.663883 1.769465 -1.565789 S -7.236098 3.354318 -1.662164 O -7.231810 3.871664 -3.045089 O -6.498344 4.101385 -0.622695 C -8.963629 3.224591 -1.152647 H -9.359700 4.243222 -1.173223 H -9.011712 2.810912 -0.144190 H -6.665554 1.024463 1.660733 H -5.461114 1.092687 3.767483 H -5.542161 2.879570 3.716138 H -6.611344 2.799668 1.535363 H -1.275010 2.080019 2.560070 H 0.854595 2.132990 1.213952 H 0.683621 2.045549 -1.293225 H -1.562086 1.911161 -2.342966 H -3.336837 3.089160 -3.188385 H -5.095449 2.997362 -3.721717 H -3.197667 0.615947 -3.124247 H -4.689586 -0.704419 -4.329851 H -5.673062 0.686255 -4.788017 H -6.918196 -1.043528 -3.496859 H -5.894704 -0.775699 -2.089100 H -7.575854 1.384394 -3.468763 H -8.149925 0.406233 -2.101445 H -9.507013 2.600428 -1.864714 a. Gas-phase energies. The thermochemistry and normal mode calculations were not performed. transpyre Pd 0.181579 -0.052617 0.162166 N -0.345616 0.059263 2.165300 C 0.614421 -0.116236 3.278865 C 2.054233 -0.239910 2.778304 C 2.312831 -1.579647 2.045799 C 1.146280 -2.018990 1.209746 C 1.119272 -2.072988 -0.162782 H 0.545195 0.770423 3.927056 H 0.366263 -0.995779 3.889021 H 2.743182 -0.146935 3.625401 H 2.272250 0.590583 2.094258 H 3.221336 -1.503138 1.437464 H 2.479851 -2.365344 2.795243 H 0.299934 -2.443947 1.746179

S34

H 2.016422 -1.861764 -0.739944 H 0.321903 -2.615606 -0.665486 S -1.812784 -0.751811 2.340145 C -2.665453 0.137823 3.659930 H -2.841568 1.167137 3.343838 H -2.070557 0.094881 4.574831 H -3.614397 -0.384029 3.809196 O -2.540101 -0.521826 1.076459 O -1.633996 -2.140356 2.816015 N -0.702306 1.936567 -0.235500 C -1.190121 1.959681 -1.505868 C -0.997477 2.956515 0.590187 C -0.614125 0.930119 -2.374146 C -2.072077 2.920706 -1.976754 C -1.893069 3.964009 0.171829 C -0.327609 3.075277 1.931274 N 0.233720 0.056285 -1.936119 O -0.899140 0.918622 -3.672175 C -2.456404 3.936063 -1.095094 H -2.429349 2.877709 -2.999529 H -2.121511 4.773048 0.858745 H -0.216261 4.133027 2.189717 H -0.914953 2.591544 2.716397 H 0.657094 2.606597 1.920618 C 0.752489 -0.703472 -3.104717 C -0.212766 -0.251317 -4.232352 H -3.154008 4.706339 -1.409464 H 0.642361 -1.774617 -2.915658 C 2.219738 -0.362626 -3.379872 H -0.983504 -0.987546 -4.472478 H 0.292600 0.076399 -5.141710 H 2.853750 -0.604050 -2.521209 H 2.581370 -0.937202 -4.240065 H 2.339030 0.703936 -3.601302 transpyreTS Pd 0.054201 0.142487 0.066020 N 0.247244 0.018945 2.140244 C 1.531586 0.049999 2.854214 C 2.552174 -0.892597 2.204765 C 1.902135 -2.283322 2.063094 C 0.641472 -2.216701 1.266270 C 0.588291 -1.912161 -0.104396 H 1.931794 1.073132 2.851582 H 1.380182 -0.257311 3.895144 H 3.458165 -0.953197 2.817910 H 2.848058 -0.511343 1.219386 H 2.600251 -2.956802 1.544888 H 1.691329 -2.699066 3.052051 H -0.265590 -2.594939 1.730128 H 1.531347 -1.887321 -0.652453 H -0.265393 -2.312501 -0.650775 S -1.129910 -0.433613 2.999223 C -1.660018 1.022611 3.928361 H -1.956102 1.806425 3.230364 H -0.850727 1.349951 4.584907

H -2.517021 0.699155 4.524991 O -2.154513 -0.717370 1.979856 O -0.786915 -1.457992 4.002028 N -0.550579 2.348268 -0.216125 C -1.149934 2.482312 -1.430024 C -0.530417 3.416564 0.602195 C -0.984479 1.326965 -2.316592 C -1.811074 3.630301 -1.847990 C -1.189655 4.611137 0.245473 C 0.268736 3.349447 1.871384 N -0.340642 0.264907 -1.960923 O -1.460922 1.371982 -3.558617 C -1.846355 4.718859 -0.971813 H -2.273182 3.664643 -2.828149 H -1.165388 5.447878 0.936607 H -0.099728 4.066980 2.609877 H 0.248378 2.344657 2.288349 H 1.315435 3.604426 1.656631 C -0.235125 -0.630446 -3.142512 C -1.199468 0.054191 -4.147601 H -2.360420 5.634661 -1.247386 H -0.605214 -1.623064 -2.870173 C 1.207776 -0.725927 -3.645208 H -2.164394 -0.449288 -4.243153 H -0.763124 0.222056 -5.133215 H 1.870710 -1.132845 -2.876248 H 1.255022 -1.387594 -4.517440 H 1.586677 0.259780 -3.937920 transpysi N -0.299294 0.221979 -0.244860 C -0.378438 0.026771 1.219297 C 0.905181 -0.584087 1.783390 C 2.110541 0.387814 1.699143 C 2.131398 1.197058 0.435948 C 3.018582 1.038744 -0.603001 H -1.213365 -0.658743 1.429980 H -0.588366 0.974317 1.731516 H 0.741355 -0.871010 2.828411 H 1.145846 -1.502626 1.231733 H 3.044638 -0.174703 1.810765 H 2.046318 1.099680 2.532936 H 1.465947 2.057134 0.405338 H 3.844789 0.335657 -0.517123 H 3.105871 1.818855 -1.353441 Pd 1.352443 -0.258263 -1.395473 N 2.713436 -0.716662 -2.902089 C 3.823078 0.012380 -3.581374 C 2.406432 -1.731832 -3.640781 C 4.323966 -1.060357 -4.575748 H 4.598346 0.255351 -2.850447 C 3.310710 1.282127 -4.270267 O 3.193988 -1.990009 -4.683376 C 1.236935 -2.574538 -3.391768 H 5.177150 -1.636497 -4.207270 H 4.527472 -0.679524 -5.576853

S35

H 2.823084 1.960515 -3.565167 H 4.149264 1.812973 -4.734993 H 2.582129 1.035278 -5.050567 N 0.458211 -2.179234 -2.348303 C 0.980256 -3.688781 -4.181622 C -0.611823 -2.938973 -2.036231 C -0.150455 -4.452715 -3.886017 H 1.649009 -3.939641 -4.997161 C -0.936672 -4.074433 -2.808371 C -1.448212 -2.604789 -0.835684 H -0.401172 -5.326636 -4.479539 H -1.815098 -4.651412 -2.537918 H -0.908122 -2.872702 0.081460 H -1.650248 -1.535283 -0.787020 H -2.384236 -3.168580 -0.849760 S -0.912097 1.683215 -0.829864 C -2.687964 1.405641 -0.975971 H -2.863369 0.611230 -1.703220 H -3.093033 1.148685 0.005493 H -3.118959 2.348284 -1.323794 O -0.346781 1.816719 -2.189376 O -0.727408 2.788026 0.132208 transpysiTS N 0.157484 -0.228879 0.105000 C 0.437966 -0.324392 1.543907 C 1.790910 0.309918 1.885592 C 1.815313 1.751735 1.332836 C 1.517264 1.790376 -0.130344 C 2.389562 1.344146 -1.135096 H 0.447867 -1.379644 1.850258 H -0.348887 0.190117 2.106676 H 1.943774 0.316928 2.970701 H 2.607348 -0.275278 1.443761 H 2.814120 2.180337 1.497135 H 1.085207 2.363912 1.869713 H 0.643775 2.353390 -0.446572 H 3.418456 1.112823 -0.852871 H 2.256742 1.791236 -2.118228 Pd 1.556401 -0.604815 -1.394243 N 2.825840 -0.960337 -2.978572 C 3.586662 -0.104197 -3.929932 C 2.916666 -2.182379 -3.386125 C 4.425791 -1.162466 -4.686017 H 4.231543 0.574367 -3.364592 C 2.643314 0.685465 -4.843624 O 3.726623 -2.423933 -4.416781 C 2.164676 -3.282425 -2.779623 H 5.442876 -1.273181 -4.300422 H 4.444223 -1.026086 -5.767654 H 1.969371 1.329410 -4.271983 H 3.228135 1.318165 -5.520817 H 2.028637 0.008417 -5.447388 N 1.330683 -2.916926 -1.766200 C 2.317967 -4.586678 -3.231908 C 0.626674 -3.885942 -1.154058

C 1.568410 -5.589502 -2.609503 H 3.002221 -4.801290 -4.045023 C 0.727020 -5.231687 -1.568738 C -0.262308 -3.543044 0.006230 H 1.649002 -6.623015 -2.932345 H 0.132331 -5.980407 -1.053981 H 0.186974 -3.904933 0.940382 H -0.402428 -2.467195 0.080432 H -1.235509 -4.036023 -0.093248 S -1.257520 0.544650 -0.384330 C -2.575521 -0.687149 -0.296055 H -2.372549 -1.483056 -1.013680 H -2.645805 -1.069990 0.724521 H -3.495091 -0.159045 -0.561706 O -1.052023 0.882202 -1.803957 O -1.613775 1.603016 0.577529 cispysi N 0.021164 -0.107289 -0.000871 C 0.514940 -0.266196 1.408057 C 1.845900 0.469077 1.668557 C 1.753132 1.921567 1.142163 C 1.669296 1.973805 -0.357169 C 2.614797 1.401897 -1.180443 H 0.636271 -1.338546 1.607504 H -0.236668 0.130692 2.102309 H 2.048608 0.472857 2.746288 H 2.674663 -0.058451 1.180423 H 2.664282 2.463763 1.441184 H 0.891138 2.430769 1.578520 H 0.872260 2.574611 -0.791047 H 3.526266 1.016037 -0.733157 H 2.675519 1.733389 -2.215654 Pd 1.326974 -0.401316 -1.558325 S -1.334187 0.807705 -0.281350 C -2.666096 -0.042044 0.593158 H -2.773274 -1.059659 0.216817 H -2.465174 -0.049525 1.666679 H -3.578061 0.532292 0.404156 O -1.592643 0.715459 -1.744891 O -1.257084 2.160877 0.336297 N 0.119804 -1.887774 -2.328036 C -1.208567 -2.509240 -1.967784 C 0.443065 -2.218008 -3.535940 C -1.628251 -3.206158 -3.306741 H -1.887085 -1.687429 -1.739914 C -1.041254 -3.476447 -0.789862 O -0.429664 -3.004035 -4.232934 C 1.709494 -1.814223 -4.121729 H -2.475463 -2.732097 -3.802466 H -1.762916 -4.284179 -3.214912 H -0.666062 -2.937107 0.084248 H -2.005639 -3.933644 -0.536543 H -0.334589 -4.276061 -1.041076 N 2.508710 -1.067862 -3.278129 C 2.095909 -2.223896 -5.386911

S36

C 3.795572 -0.831857 -3.669938 C 3.379751 -1.889149 -5.828093 H 1.407406 -2.799968 -5.992552 C 4.227639 -1.221739 -4.954521 C 4.794476 -0.204686 -2.731911 H 3.717165 -2.176066 -6.817562 H 5.249452 -1.001560 -5.241444 H 4.761481 0.889735 -2.769900 H 4.622112 -0.530585 -1.704549 H 5.803785 -0.511138 -3.022352 cispysiTS N 0.180384 0.049715 -0.020677 C 0.157217 0.016511 1.450698 C 1.569491 -0.025193 2.052029 C 2.417039 1.030933 1.322394 C 2.478117 0.739901 -0.140617 C 3.012068 -0.447912 -0.663373 H -0.422643 -0.852844 1.786990 H -0.340616 0.918438 1.825258 H 1.529326 0.181702 3.127051 H 2.009381 -1.022262 1.931383 H 3.446645 1.010284 1.710231 H 2.008502 2.030959 1.487034 H 2.263728 1.557790 -0.824129 H 3.529683 -1.100646 0.036450 H 3.449084 -0.382827 -1.660606 Pd 1.148059 -1.392742 -1.169777 S -0.503756 1.377377 -0.789891 C -2.230468 1.440024 -0.242990 H -2.736514 0.504664 -0.480436 H -2.268403 1.646237 0.827902 H -2.677634 2.272093 -0.793300 O -0.473875 1.056649 -2.227473 O 0.095630 2.639421 -0.318406 N -0.615449 -2.217343 -2.018001 C -2.072559 -1.956336 -2.004391 C -0.339960 -2.919493 -3.060270 C -2.557321 -2.693262 -3.287260 H -2.205940 -0.877349 -2.115725 C -2.728723 -2.457827 -0.718349 O -1.339086 -3.269249 -3.868961 C 1.022469 -3.376645 -3.348484 H -2.990308 -2.032811 -4.040024 H -3.235875 -3.524093 -3.080448 H -2.300040 -1.959884 0.156576 H -3.805619 -2.253541 -0.737820 H -2.587263 -3.538189 -0.601424 N 1.958853 -2.983007 -2.434889 C 1.292213 -4.206455 -4.427517 C 3.196857 -3.517683 -2.530788 C 2.593174 -4.692352 -4.574114 H 0.496676 -4.466939 -5.116359 C 3.530333 -4.365607 -3.605465 C 4.227410 -3.257045 -1.467286 H 2.855442 -5.336305 -5.407978

H 4.537299 -4.767173 -3.655033 H 4.767612 -2.320822 -1.644651 H 3.766492 -3.211813 -0.478307 H 4.966815 -4.062294 -1.464341 cispyre Pd -0.046791 -0.396507 0.080734 N -0.370556 0.044989 2.088514 C 0.744653 0.351627 3.020759 C 2.079809 0.515860 2.291200 C 2.629047 -0.833130 1.757192 C 1.535141 -1.768624 1.336960 C 1.299425 -2.231894 0.069124 H 0.502267 1.296327 3.527789 H 0.848900 -0.423602 3.792871 H 2.810313 0.965726 2.972857 H 1.950591 1.214062 1.454560 H 3.336142 -0.659097 0.938358 H 3.176914 -1.335216 2.567003 H 0.939478 -2.201878 2.138286 H 1.990370 -2.005137 -0.740008 H 0.625607 -3.071570 -0.069180 S -1.525954 -1.033714 2.686899 C -2.359417 -0.093379 3.984264 H -2.812234 0.798334 3.548621 H -1.641368 0.163914 4.765621 H -3.127446 -0.757713 4.389209 O -2.471886 -1.252045 1.577342 O -0.911468 -2.208347 3.341135 N -0.003698 -0.319191 -2.155047 C -0.110834 0.985470 -2.550811 C 0.215925 -1.251568 -3.105089 C -0.651402 1.872160 -1.516884 C 0.135086 1.425451 -3.842406 C 0.481830 -0.865746 -4.436250 C 0.101318 -2.716618 -2.781318 N -0.949849 1.425091 -0.346254 O -0.936993 3.144611 -1.783029 C 0.479502 0.470630 -4.804727 H 0.034126 2.477984 -4.083080 H 0.669480 -1.641097 -5.172466 H 1.075764 -3.170973 -2.569795 H -0.561082 -2.880917 -1.930196 H -0.315539 -3.244888 -3.644180 C -1.674677 2.482719 0.394216 C -1.418590 3.717199 -0.512058 H 0.693800 0.766118 -5.827275 H -1.211692 2.599424 1.376688 C -3.153956 2.114837 0.540142 H -0.629173 4.379059 -0.147095 H -2.317206 4.290876 -0.741148 H -3.262168 1.139109 1.020911 H -3.670092 2.873192 1.140364 H -3.641302 2.063880 -0.440632 cispyreTS

S37

Pd 0.064604 -0.473920 -0.043418 N -1.908981 -0.039727 0.431482 C -2.390805 -0.116244 1.817261 C -1.995513 -1.441944 2.478546 C -2.419132 -2.597708 1.549450 C -1.807068 -2.457830 0.193107 C -0.439441 -2.576231 -0.075067 H -1.982243 0.723095 2.397806 H -3.484774 -0.037134 1.828719 H -2.479920 -1.538333 3.456725 H -0.911541 -1.472183 2.646487 H -2.084714 -3.550981 1.982932 H -3.508578 -2.625117 1.459706 H -2.489386 -2.413212 -0.651589 H 0.197984 -2.984585 0.711030 H -0.181654 -2.853136 -1.094060 S -3.022173 0.224986 -0.792318 C -3.698426 1.876797 -0.493620 H -2.903164 2.618627 -0.560475 H -4.183536 1.897954 0.484273 H -4.441507 2.040689 -1.278518 O -2.236779 0.247556 -2.037394 O -4.170617 -0.693090 -0.669436 N 2.263694 -0.635528 -0.257547 C 2.853880 0.509358 0.202609 C 3.072549 -1.659786 -0.608941 C 1.939334 1.642711 0.364457 C 4.217681 0.649882 0.417137 C 4.466044 -1.577246 -0.409964 C 2.507653 -2.887715 -1.266646 N 0.675836 1.527155 0.150015 O 2.410486 2.855444 0.660545 C 5.044895 -0.436971 0.125433 H 4.609421 1.591242 0.785884 H 5.080786 -2.424118 -0.696966 H 2.050182 -3.565961 -0.539314 H 1.756302 -2.618803 -2.013084 H 3.305147 -3.439718 -1.770202 C 0.086274 2.886500 0.146895 C 1.224587 3.715615 0.795482 H 6.117295 -0.378345 0.284536 H -0.810229 2.888192 0.772687 C -0.246642 3.312873 -1.287278 H 1.083882 3.897015 1.864388 H 1.444169 4.650304 0.278549 H -0.889938 2.575891 -1.776745 H -0.752871 4.285290 -1.284275 H 0.668597 3.407011 -1.883247

ST1major C -1.495858 2.295037 1.398322 N -0.492459 1.858526 0.610783 C 0.298300 2.786076 -0.016964 C 0.074469 4.151204 0.042562 C -1.004905 4.606856 0.808446 C 1.452584 2.203074 -0.702069

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S38

C 2.648156 1.338379 -0.772983 C 2.961590 2.823426 -0.414446 C -0.640578 2.744925 0.057139 N -1.496402 1.753157 -0.299900 C -2.819702 2.001124 -0.276700 C -3.298327 3.230439 0.221742 C -2.420242 4.211278 0.660702 C -1.047080 3.978418 0.548278 C -3.788881 0.996625 -0.833179 Pd -0.385317 -0.142083 -0.672929 N -1.958460 -1.257631 0.092003 S -1.541623 -1.566139 1.694604 O -0.708436 -0.412255 2.103716 C 3.316553 0.338472 0.158220 C 1.127702 -1.418964 -1.839583 C 1.095783 -1.068545 -3.304700 C 0.330278 -2.352343 -1.205912 C -0.695397 -3.208114 -1.892759 C -1.896521 -3.572756 -1.016575 C -2.685555 -2.323695 -0.613291 O -1.015200 -2.925947 1.923139 C -3.105554 -1.451263 2.594481 H -3.115195 -1.856106 -1.508670 H -3.540006 -2.628836 0.008660 H -1.563581 -4.110774 -0.124611 H -2.563368 -4.240015 -1.576582 H -1.030003 -2.750472 -2.830601 H -0.169520 -4.135246 -2.172057 H 0.632976 -2.680709 -0.211773 H 2.031979 -1.136738 -1.308462 H 2.961411 1.133589 -1.801351 H 3.246707 3.427020 -1.279623 H 3.693433 2.932267 0.385477 H -0.310219 4.726482 0.817927 H -2.791336 5.154001 1.051209 H -4.370119 3.401314 0.242063 H -3.362588 0.491113 -1.702642 H -4.031757 0.228378 -0.094747 H -4.712562 1.498995 -1.134520 H -3.521016 -0.451328 2.461672 H -3.795868 -2.222555 2.247715 H -2.854777 -1.626460 3.643926 H 1.420149 -0.037291 -3.475172 H 1.801357 -1.721546 -3.839754 H 0.112363 -1.198172 -3.762137 C 4.549013 -0.212381 -0.226050 C 5.236009 -1.077684 0.628985 C 4.690175 -1.408182 1.873054 C 3.458670 -0.869585 2.257065 C 2.773898 0.004325 1.407368 H 4.976699 0.036050 -1.196054 H 6.190485 -1.495663 0.321399 H 5.219137 -2.085946 2.537111 H 3.021913 -1.131870 3.216405 H 1.808947 0.393641 1.719107

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S39

H 5.863097 -2.435409 -0.019107 H 3.194517 -1.440763 3.211864 H 5.063281 -2.814780 2.308204 ST4major N -2.020298 -1.206387 -0.190091 C -3.366347 -1.023502 -0.865877 C -3.579698 -2.292321 -1.690428 C -2.162067 -2.592225 -2.194086 C -1.275039 -2.339476 -0.967080 C 0.129291 -1.761040 -1.139280 H -3.291466 -0.143189 -1.508716 H -4.146810 -0.850884 -0.121678 H -3.952642 -3.099587 -1.052101 H -4.296189 -2.134724 -2.502486 H -1.907022 -1.913503 -3.014783 H -2.043502 -3.617306 -2.557250 H -1.264107 -3.239943 -0.344088 H 0.810179 -2.164507 -0.386278 Pd -0.331471 0.118232 -0.492263 N 1.561213 0.998941 -0.598793 C 2.940358 0.487223 -0.831062 C 1.642494 2.248392 -0.284004 C 3.815641 1.748778 -0.553214 H 3.014075 0.206786 -1.886488 O 2.853905 2.805078 -0.242079 C 0.479741 3.096335 0.011906 H 4.395035 2.079418 -1.416806 H 4.465734 1.634501 0.315724 N -0.720345 2.462333 -0.013038 C 0.636200 4.455336 0.264926 C -1.825907 3.202839 0.177363 C -0.513506 5.216021 0.495666 H 1.626119 4.896778 0.273846 C -1.747665 4.585020 0.442063 C -3.173322 2.544347 0.069130 H -0.440468 6.279597 0.701870 H -2.664624 5.145608 0.598357 H -3.689364 2.885000 -0.837535 H -3.070156 1.462736 0.013759 H -3.812553 2.804241 0.920357 S -2.188880 -1.731218 1.519000 C -2.603510 -0.218351 2.403508 H -1.803737 0.509183 2.263308 H -3.569600 0.158125 2.065573 H -2.669397 -0.521864 3.452276 O -0.855469 -2.166580 1.932255 O -3.333107 -2.643817 1.589316 C 0.734269 -1.814323 -2.533885 H 1.769939 -1.468573 -2.526323 H 0.752261 -2.854214 -2.896175 H 0.185602 -1.221839 -3.272960 C 3.318277 -0.708157 0.023182 C 4.097643 -1.729701 -0.536036 C 2.964339 -0.782267 1.377735 C 4.519267 -2.809587 0.245364

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S40

C -1.398358 3.021250 0.012431 C -0.846091 4.231252 -0.430517 C -1.457157 2.761278 1.388848 C -0.365128 5.170627 0.486358 H -0.792668 4.444483 -1.496647 C -0.971595 3.696985 2.305794 H -1.873677 1.824573 1.750295 C -0.426521 4.904381 1.857122 H 0.055234 6.106888 0.129459 H -1.021246 3.483866 3.370146 H -0.054155 5.633195 2.571633 ST1minor C 4.157997 1.690026 0.214191 O 3.112191 2.698490 0.460701 C 1.974706 2.157330 0.039097 N 2.010749 0.947933 -0.403222 C 3.387526 0.409273 -0.240991 C 0.717272 2.903981 0.048484 N -0.356249 2.184625 -0.408381 C -1.536349 2.820877 -0.559335 C -1.664668 4.175363 -0.182306 C -0.588632 4.881792 0.329348 C 0.646544 4.232980 0.432154 Pd 0.170360 0.157624 -0.848457 C -5.293356 -0.092307 2.271532 C -3.981224 -0.309813 2.457902 C -3.203318 -1.583387 2.234717 C -2.057111 -1.431045 1.209545 C -2.583180 -1.227822 -0.216740 N -1.561538 -0.932594 -1.261996 S -0.699009 -2.217068 -1.800749 O -1.084307 -3.545752 -1.335195 C -2.724182 2.109171 -1.136842 C -0.764044 -2.201470 -3.597199 O 0.735411 -1.739186 -1.435599 H -3.286947 -0.394102 -0.241147 H -3.140349 -2.117857 -0.532595 H -1.426302 -0.574606 1.490605 H -1.418749 -2.321918 1.241275 H -3.862014 -2.403271 1.926177 H -2.758395 -1.895458 3.190260 H -3.386516 0.521237 2.845423 C -6.336445 -1.061189 1.785492 H -5.672903 0.900104 2.520839 H -0.516482 -1.200778 -3.954002 H -1.775887 -2.487460 -3.893209 H -0.036884 -2.937715 -3.949598 H 1.538183 4.738988 0.785710 H -2.630606 4.654201 -0.308558 H -3.288405 2.793780 -1.778170 H -2.432317 1.233582 -1.717460 H -3.400114 1.787691 -0.334520 H -0.694428 5.921628 0.623071 H 3.737844 0.076939 -1.222145 H 4.812161 2.097559 -0.558986

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S41

H -1.876007 0.448633 2.801983 H -1.616770 5.508703 0.702452 H 2.294404 -0.360049 -2.062957 H 2.648969 1.729850 -3.109849 H 3.785853 2.191003 -1.803821 H 2.246417 -3.379410 1.292147 H 2.403531 -1.638087 1.516114 H 1.035049 -2.506403 2.243242 C 3.725609 -0.084109 -0.490631 C 4.514901 -1.141234 -0.961626 C 4.078007 0.550774 0.709706 C 5.640382 -1.560740 -0.244986 H 4.255864 -1.637880 -1.895077 C 5.198993 0.130082 1.428275 H 3.474730 1.371723 1.090683 C 5.982846 -0.926859 0.951909 H 6.246254 -2.379562 -0.622793 H 5.462596 0.627572 2.357544 H 6.856520 -1.251281 1.509994 ST3minor C -0.347471 -2.209497 0.060442 Pd 0.350221 -0.203955 -0.139416 N -1.436828 0.696633 0.512284 C -2.632444 0.249526 1.280155 C -1.316994 1.974703 0.667829 C -3.107056 1.574059 1.957521 H -2.297159 -0.462006 2.041135 O -2.218709 2.603851 1.417596 C -0.250045 2.757966 0.033418 H -2.981567 1.578119 3.042080 H -4.127744 1.851585 1.692937 N 0.687339 2.014435 -0.606498 C -0.255907 4.148480 0.051419 C 1.624177 2.651479 -1.335170 C 0.748888 4.812854 -0.656175 H -1.027247 4.682583 0.594670 C 1.677228 4.058755 -1.362774 C 2.577683 1.836527 -2.162395 H 0.791649 5.897797 -0.667575 H 2.451747 4.543849 -1.948433 H 2.935689 0.971382 -1.606010 H 2.064619 1.463421 -3.058488 H 3.428460 2.439277 -2.490884 C -1.240089 -2.531409 -1.130092 H -1.520791 -3.594781 -1.118527 H -2.162271 -1.950930 -1.091344 H -0.757827 -2.327264 -2.090990 C 0.958833 -2.760996 0.166766 C 1.613116 -3.579198 -0.898106 H 1.378477 -2.840821 1.165932 C 3.064495 -3.141275 -1.159479 H 1.032182 -3.554860 -1.823708 H 1.605524 -4.618828 -0.534583 C 3.055907 -1.617473 -1.312940 H 3.706785 -3.421801 -0.321905

H 3.448801 -3.624438 -2.064976 H 4.086436 -1.237767 -1.343334 H 2.578284 -1.324860 -2.254857 S 3.110781 -0.770460 1.250347 C 4.074197 0.752972 1.106139 H 3.395739 1.593374 0.954557 H 4.608236 0.858419 2.054222 H 4.788529 0.656496 0.285820 O 2.059974 -0.536084 2.256576 O 4.079262 -1.861029 1.443112 N 2.312087 -0.951431 -0.229126 H -0.865937 -2.149381 1.020322 C -3.702603 -0.403625 0.425471 C -4.365305 -1.542277 0.901627 C -4.089180 0.149127 -0.804429 C -5.398113 -2.124417 0.160019 H -4.076747 -1.978598 1.856090 C -5.116356 -0.434943 -1.548649 H -3.581722 1.030446 -1.190136 C -5.773297 -1.573006 -1.067588 H -5.905656 -3.006128 0.541173 H -5.405510 -0.001731 -2.502199 H -6.574008 -2.024630 -1.646336 ST4minor C 0.157875 -2.132448 0.203835 Pd 0.371643 -0.130409 -0.090798 N -1.503950 0.535852 0.584900 C -2.652431 -0.088927 1.294383 C -1.602482 1.816969 0.721876 C -3.274729 1.128988 2.043967 H -2.260126 -0.815370 2.011945 O -2.612703 2.291560 1.452531 C -0.681107 2.774105 0.093141 H -3.049450 1.141589 3.113405 H -4.346068 1.241620 1.879557 N 0.374057 2.211821 -0.549260 C -0.927236 4.142636 0.128228 C 1.194965 3.016643 -1.245698 C -0.047648 4.982822 -0.561250 H -1.782481 4.529082 0.670832 C 1.007496 4.413255 -1.260620 C 2.301175 2.398621 -2.056256 H -0.196768 6.058397 -0.559921 H 1.695466 5.033354 -1.827740 H 2.441817 1.352438 -1.787653 H 2.051264 2.441055 -3.124230 H 3.244937 2.939006 -1.924719 C -0.826226 -2.749131 -0.778981 H -0.794961 -3.847966 -0.707758 H -1.848530 -2.438442 -0.558248 H -0.619064 -2.484764 -1.821524 C 1.639438 -2.490886 0.049913 C 2.109940 -3.356811 -1.132523 H 2.037432 -2.899883 0.982096 C 3.439633 -2.725207 -1.568453

S42

H 1.393539 -3.321844 -1.958230 H 2.215644 -4.402630 -0.829514 C 3.151165 -1.230256 -1.435476 H 4.255023 -3.010803 -0.897805 H 3.720523 -2.995530 -2.591100 H 4.050031 -0.614739 -1.357004 H 2.551571 -0.865777 -2.274092 S 3.301358 -0.700956 1.258973 C 3.645881 1.057720 1.079747 H 2.705801 1.608897 1.087092 H 4.249348 1.310298 1.956253 H 4.221467 1.233222 0.170197 O 2.420732 -0.894863 2.410963 O 4.563267 -1.436916 1.147077 N 2.306228 -1.096414 -0.187087 H -0.166860 -2.262372 1.240955 C -3.636787 -0.782202 0.367035 C -4.308982 -1.925522 0.821470 C -3.946635 -0.265193 -0.898228 C -5.276900 -2.543442 0.024909 H -4.073802 -2.339669 1.800270 C -4.910238 -0.885684 -1.697476 H -3.428043 0.614783 -1.270209 C -5.578286 -2.024826 -1.237568 H -5.789810 -3.429420 0.388646 H -5.139309 -0.479370 -2.678863 H -6.327905 -2.505479 -1.859771 ST5minor C -0.782900 -1.533131 -0.121997 Pd -0.140582 0.404469 0.077107 N 1.733760 0.076637 -0.724779 C 2.508945 -1.103255 -1.187474 C 2.468217 1.130844 -0.870802 C 3.784345 -0.436372 -1.790833 H 1.938708 -1.603404 -1.976307 O 3.674089 0.973604 -1.418937 C 2.040555 2.472989 -0.456092 H 3.820992 -0.479789 -2.881795 H 4.713985 -0.815413 -1.365817 N 0.809470 2.520113 0.109700 C 2.854585 3.586522 -0.637822 C 0.336526 3.710265 0.523374 C 2.368224 4.823050 -0.206218

H 3.829993 3.481535 -1.099173 C 1.107988 4.880065 0.375384 C -1.033353 3.765948 1.138840 H 2.965575 5.722263 -0.323536 H 0.702488 5.825399 0.721561 H -1.121913 3.046255 1.957643 H -1.244643 4.767623 1.522061 H -1.797978 3.508757 0.397747 C -0.806295 -2.210592 1.243969 H -1.137004 -3.256930 1.161129 H 0.195701 -2.225959 1.682579 H -1.480152 -1.708099 1.943510 C -2.096549 -1.538602 -0.906679 C -2.582693 -2.915658 -1.403163 H -1.987038 -0.892249 -1.791246 C -4.047288 -2.655748 -1.784667 H -2.512033 -3.656524 -0.599443 H -1.979530 -3.264538 -2.246787 C -4.553044 -1.672561 -0.709922 H -4.101118 -2.188861 -2.774098 H -4.650170 -3.567682 -1.813431 H -5.186067 -0.891172 -1.143450 H -5.108781 -2.180144 0.085112 S -3.358705 0.496820 0.348276 C -4.538025 0.502494 1.702328 H -4.204588 -0.202664 2.464756 H -4.553386 1.524394 2.088891 H -5.522131 0.237439 1.310601 O -2.024634 0.788382 0.985165 O -3.811445 1.423155 -0.696391 N -3.298823 -1.099743 -0.113939 H -0.038387 -2.011186 -0.767428 C 2.802698 -2.101282 -0.081044 C 2.697476 -3.473167 -0.344199 C 3.242043 -1.680099 1.182439 C 3.028394 -4.412740 0.636884 H 2.359286 -3.812645 -1.321516 C 3.568780 -2.617321 2.164966 H 3.324818 -0.619345 1.407286 C 3.463403 -3.985773 1.894099 H 2.945556 -5.473815 0.418385 H 3.906474 -2.279783 3.141008 H 3.720266 -4.713584 2.658627

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