Modular Synthesis of Chiral Beta-Aminophosphine P, N-Ligands

Modular Synthesis of Chiral -Aminophosphine P,N- Ligands and Their Applications in Asymmetric Catalysis

Yixiong Song

A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Chemistry University of Toronto

Modular Synthesis of Chiral -Aminophosphine P,N-Ligands and Their Applications in Asymmetric Catalysis

Yixiong Song

Master of Science

Graduate Department of Chemistry University of Toronto

2015 Abstract

A series of chiral -aminophosphine ligands bearing different carbon backbones and electronically differentiated diarylphosphino groups were prepared using a modular approach.

These P,N-ligands were found to induce a modest level of enantioselectivities in the Pd- catalyzed asymmetric decarboxylative allylation reaction. Thiourea-phosphine bifunctional catalysts derived from the chiral -aminophosphine building blocks were prepared and applied to the asymmetric Morita-Baylis-Hillman (MBH) reaction of methyl acrylate and 4- nitrobenzaldehyde. The electronically unmodified diarylphosphino-thiourea was found to be optimal for achieving high activity and enantioselectivity in this particular MBH reaction. We also reported the synthesis of a P-chiral C2-symmetric bisphosphine ligand. However, the utility of this Trost-type ligand remains to be explored in the future.

Acknowledgments

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Table of Contents

Chapter 1. Modular Synthesis of -Aminophosphine P,N-Ligands and Their Applications in the Pd-Catalyzed Asymmetric Decarboxylative Allylation Reaction ...... 1

1 Introduction ...... 1

1.1 Overview of P,N-ligands in Asymmetric Catalysis ...... 1

1.2 Decarboxylative Allylation Reaction ...... 10

2 Objectives ...... 18

3 Results and Discussion ...... 19

3.1 Synthesis of -Substituted -Aminophosphines and Their appplications in the Pd-Catalyzed Asymmetric Decarboxylative Allylation Reaction ...... 19

3.2 Attempted Synthesis of -Disubstituted -Aminophosphines ...... 26

3.3 Attempted C–H Activation of (R)-2-Phenylglycinol ...... 31

4 Experimental ...... 36

4.1 Procedures and Compounds...... 36

4.1 1H NMR, 13C NMR and 31P NMR Spectra ...... 53

Chapter 2. Synthesis of Bifunctional Thiourea-Phosphine Organocatalysts and Their Applications in the Asymmetric Morita-Baylis-Hillman (MBH) Reaction ...... 83

1 Introduction ...... 83

1.1 Mechanism of the MBH Reaction ...... 83

1.2 The Asymmetric MBH Reaction...... 87

1.3 The Asymmetric aza-MBH Reaction ...... 91

1.4 Asymmetric Transformations Related to the MBH Reaction ...... 95

2 Objectives ...... 98

3 Results and Discussion ...... 98

4 Conclusion and Future Work ...... 105

5 Experimental ...... 106

5.1 Procedures and Compounds...... 106

5.2 1H NMR, 13C NMR and 31P NMR Spectra ...... 116

5.3 X-Ray Crystallography Data ...... 139

List of Abbreviations

(m) Medium (s) Strong (w) Weak °C Degrees Celsius Ac Acetate acac Acetylacetone Ar Aryl Boc tert-Butyloxycarbonyl Bn Benzyl Bz Benzoyl cod 1,5-Cyclooctadiene DART Direct Analysis in Real Time dba Dibenzylideneacetone DCC Dicyclohexylcarbodiimide DMAP 4-Dimethylaminopyridine DMF Diastereomeric ratio ee Enantiomeric excess er Enantiomeric ratio eq. Equivalent ESI Electro-spray ionisation Et Ethyl EWG Electron withdrawing group g Grams HRMS High resolution mass spectrometry i-Pr iso-Propyl IR Infra red L Ligand Leu Leucine M Molar m- meta m/z Mass/charge ratio Me Methyl MeCN Acetonitrile mg Milligrams MHz Mega hertz min. Minutes mL Milliliters n-Bu normal-Butyl nbd Norbornadiene NMR Nuclear magnetic resonance Nu Nucleophile o- ortho p- para PMP para-methoxyphenyl vi

TBAB Tetrabutylammonium bromide TBAB Tetrabutylammonium chloride TBS tert-Butyldimethylsilyl t-Bu tert-Butyl Tf Triflate THF Tetrahydrofuran Ts Tosyl v/v Volume per volume

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List of Tables

Table 1. Scope for secondary phosphine oxides ...... 24

Table 2. Scope for -substituted--aminophosphine oxides ...... 24

Table 3. Scope for -substituted--aminophosphines...... 25

Table 4. Screening of P,N-ligands for decarboxylative allylic alkylation ...... 26

Table 5. Decomposition products isolated in the reduction of aminophosphine oxide ...... 30

Table 6. Scope for thiourea-phosphine catalysts ...... 98

Table 7. Screening of bifunctional catalysts in the MBH reaction ...... 98

Table 8. Screening of P-chiral bifunctional catalysts in the MBH reaction ...... 102

Table 9. Screening of P-chiral C2-symmetrical bisphosphine ligand in Pd-catalyzed AAA reaction ...... 103

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List of Figures

Figure 1. X-ray crystal data Pd -allyl complex ...... 2

Figure 2. The exo-endo equilibrium of the Pd-allyl complex ...... 3

Figure 3. 31P NMR spectra of ring-opening reaction using KOtBu and NaOtBu ...... 23

Figure 4. X-ray crystal structure of thiourea-phosphine-borane 2.28a ...... 100

List of Schemes

Scheme 1. Asymmetric allylic substitution reactions of 1,3-dialkylallyl acetates using PHOX ligand ...... 2

Scheme 2. Asymmetric allylic substitution of 1,3-dimethylallyl acetate with dimethyl malonate 4

Scheme 3. Asymmetric allylic substitution of cyclic substrates with dimethyl malonate...... 4

Scheme 4. Intermolecular asymmetric Heck reaction using PHOX and BINAP ligands ...... 5

Scheme 5. Ir-catalyzed asymmetric hydrogenation of non-functionalized olefins ...... 5

Scheme 6. Asymmetric hydroboration-oxidation of arylalkenes using Rh-QUINAP ...... 5

Scheme 7. Asymmetric diboration-oxidation of olefins using Rh-QUINAP ...... 6

Scheme 8. Asymmetric three component condensation employing QUINAP and its analog ...... 6 Scheme 9. Asymmetric Kumada coupling reaction using -aminophosphine ...... 7

Scheme 10. Cu-catalyzed conjugated addition of diethylzinc to enones using iminophosphine ... 8

Scheme 11. Ru-catalyzed asymmetric tandem Michael addition/hydrogenation of cyclic enone . 8

Scheme 12. Fe-catalyzed hydrogenation of esters and N-heterocycles ...... 9

Scheme 13. Fe-catalyzed asymmetric hydrogenation of ketones and activated imines ...... 9

Scheme 14. The Tsuji reaction ...... 10

Scheme 15. Proposed catalytic cycle of the decarboxylative allylic alkylation of allyl enol carbonates and allyl β-keto esters ...... 11

Scheme 16. The initial report of enantioselective Tsuji reaction using Trost P,P-ligand and PHOX P,N-ligand ...... 11

Scheme 17. Asymmetric decarboxylative allylic alkylation using Trost ligands ...... 12

Scheme 18. Asymmetric decarboxylative allylic alkylation using PHOX 1.4 and 1.16 ...... 13 x

Scheme 19. Synthesis of chiral -fluoroketones through decarboxylative allylic alkylation ...... 14

Scheme 20. Enantioselective decarboxylative enolate alkylation cascade ...... 14

Scheme 21. Ir-catalyzed allylic alkylation of -substituted β-ketoesters ...... 15

Scheme 22. Sequential allylic alkylation catalyzed by Ir and Pd complexes ...... 16

Scheme 23. Proposed mechanism by Stoltz and Goddard for asymmetric decarboxylative allylic alkylation using PHOX ...... 17

Scheme 24. Proposed mechanism by Trost for asymmetric decarboxylative allylic alkylation using Trost ligand ...... 17

Scheme 25. Asymmetric decarboxylative allylic alkylation of cis-1.18 using Trost ligand ...... 18

Scheme 26. Asymmetric decarboxylative allylic alkylation using -aminophosphin ...... 18

Scheme 27. Modular synthesis of -aminophosphines ...... 18

Scheme 28. Conventional synthesis of chiral -aminophosphines ...... 19

Scheme 29. Previous literature reports on synthesis of chiral -aminophosphines via tosyl displacement...... 20

Scheme 30. Synthesis of chiral -aminophosphines via cyclic sulfamidates...... 21

Scheme 31. The first successful ring-opening of cyclic sulfamidate with secondary phosphine oxide ...... 22

Scheme 32. Tautomerism of secondary phosphine oxides ...... 22

Scheme 33. Competing reaction pathways in the ring-opening of cyclic sulfamidate with secondary phosphine oxide...... 23

Scheme 34. Reductive amination of P,N-ligand ...... 26

Scheme 35. Attempted ring-opening of 1,2-disubstituted cyclic sulfamidate with secondary phosphine oxide ...... 27

Scheme 36. Decomposition pathway of benzylic tosylate ...... 27

Scheme 37. Ring-opening of cyclic sulfamidates with fluoride ...... 28

Scheme 38. Ring-opening and P-alkylation of cyclic sulfamidates ...... 29

Scheme 39. Attempted synthesis of -disubstituted -aminophosphine derived from 1-amino- 2-indanol 1.42...... 31

Scheme 40. -C−H arylation of alanine ...... 32

Scheme 41. Hypothetical divergent synthesis of -substituted -aminophosphines via C–H activation ...... 33

Scheme 42. Known C–H activation of primary benzylamines ...... 34

Scheme 43. Synthesis of starting materials for C–H activation ...... 34

Scheme 44. Attempted C–H iodination using I2 ...... 35

Scheme 45. Regeneration of Pd(OAc)2 from PdI2 ...... 35

Scheme 46. Attempted C–H iodination using IOAc ...... 36

Scheme 47. The Morita-Baylis-Hillman reaction ...... 83

Scheme 48. Mechanism of MBH reaction proposed in 1980s ...... 84

Scheme 49. Kinetic study of MBH reaction by Hill and Issac ...... 84

Scheme 50. Kinetic study performed by McQuade et al...... 85

Scheme 51. Mechanism of MBH reaction revised by McQuade and Aggarwal ...... 85

Scheme 52. Asymmetric MBH reaction using a quinidine derivative as a bifunctional catalyst .87

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Scheme 53. Asymmetric MBH reaction using quinidine binaphthyl thiourea-tertiary amine 2.2 88

Scheme 54. Asymmetric MBH reaction using cyclohexyl thiourea-phosphine 2.3 ...... 88

Scheme 55. Asymmetric MBH reaction using threonine derived thiourea-phosphine 2.4 ...... 89

Scheme 56. Asymmetric MBH reaction using acid-base co-catalyst systems ...... 90

Scheme 57. Asymmetric aza-MBH reaction using quinidine derivatives ...... 91

Scheme 58. Asymmetric aza-MBH reaction using BINOL derived bifunctional catalyst ...... 92

Scheme 59. Asymmetric aza-MBH reaction using thiourea/DABCO cocatalyst system ...... 93

Scheme 60. Asymmetric aza-MBH reaction using phosphine-sulfonamide catalyst 2.12 ...... 93

Scheme 61. Enantioselective [3+2] annulation of allenoate with acrylate...... 94

Scheme 62. Mechanism of [3+2] annulation of allenoate with acrylate ...... 95

Scheme 63. Asymmetric Michael addition of oxindoles catalyzed by chiral phosphine ...... 95

Scheme 64. Mechanism of asymmetric Michael addition catalyzed by chiral phosphine ...... 96

Scheme 65. Asymmetric Michael addition reaction and aza-Henry reaction catalyzed by chiral phosphines...... 96

Scheme 66. Asymmetric MBH reaction catalyzed by amino acid based thiourea-phosphines ....97

Scheme 67. P-chiral phosphino-thiourea catalysts ...... 99

Scheme 68. Synthesis of unsymmetrical secondary phosphine oxide ...... 99

Scheme 69. Synthesis of P-chiral phosphine-thiourea catalysts ...... 101

Scheme 70. Synthesis of P-chiral C2-symmetrical bisphosphine ligands ...... 102

Scheme 71. AAA reactions using Trost ligand ...... 102

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Scheme 72. Rh-catalyzed asymmetric hydrosilylation of ketones ...... 105

xiv 1

Chapter 1

Modular Synthesis of -Aminophosphine P,N-Ligands and Their Applications in the Pd-Catalyzed Asymmetric Decarboxylative Allylation Reaction

1 Introduction

1.1 Overview of P,N-Ligands in Asymmetric Catalysis

P,N-ligands are an important class of ligands for asymmetric catalysis. P,N-ligands are highly effective in promoting a variety of metal-catalyzed enantioseletive transformations, including asymmetric allylic alkylation, asymmetric hydrogenation, and enantioselective diboration of alkenes.1 P,N-ligands contain two electronically distinct donor atoms: a “hard” nitrogen atom with -donor property and a “soft” phosphorus atom that can act as botha -donor and a - acceptor. This combination of mixed donors exerts regiocontrol when applied to the context of -allyl metal complexes where the allylic terminus trans to the phosphorus donor is preferentially attacked by the incoming nucleophile.1c The thermodynamic trans effect of P,N- ligands is reflected by the different Pd–C distances in the X-ray crystal structure (Figure 1).1a

PHOX ligands developed independently by the groups of Helmchen, Pfaltz and Williams,2 give rise to reactive palladium complexes in the asymmetric allylic substitution reactions of symmetric allylic acetates, providing up to 99% ee for 1,3-diphenylallyl acetate with dimethyl

1 a) Pfaltz, A.; Drury, W. J. Proc. Natl. Acad. Sci. USA. 2004, 101, 5723–5726. b) ern nde , E.; Guiry, P. 2 a) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure Appl. Chem. 1997, 69, 513−518. b) Pfaltz, A. Acta Chem. Scand. B 1996, 50, 189−194. c) Williams, J. M. J. Synlett 1996, 705−710.

2 malonate. However, diminishing enantioselectivities were observed for smaller alkyl groups. Interestingly, there was no selectivity for cyclohexene-2-yl acetate using this ligand (Scheme 1).3

Figure 1. X-ray crystal data Pd -allyl complex

3 Helmchen, G.; Pfaltz, A. Acc. Chem. Res.2000, 33, 336−345.

Scheme 1. Asymmetric allylic substitution reactions of 1,3-dialkylallyl acetates using PHOX ligand

Figure 2. The exo-endo equilibrium of the Pd-allyl complex

Mechanistic investigations using NMR spectroscopy revealed a rapid equilibrium between two conformers of the -allyl intermediates in a ratio of 9:1 in favor of the exo conformation (Figure 2).3 Assuming subsequent nucleophilic attack only occurs at the allylic terminus trans to the P-donor, the enantiomeric ratio of the product is determined by the exo/endo ratio. The X-ray crystal structure of the more stable exo conformer of the Pd -allyl complex suggested that the endo diastereomer is destabilized by the steric clash between the equatorial P-aryl group of the

PHOX ligand and the phenyl group of the allyl substrate.5 The energy difference between the two diastereomers diminishes as the steric demand of the allyl substituent decreases and thus results in the erosion of exo/endo ratio and the enantioselectivity. The modified ligand 1.2 gave 90% ee for 1,3-dimethylallyl acetate (Scheme 2), while 1.3 provided excellent ee for cyclic substrates (Scheme 3).3

Scheme 2. Asymmetric allylic substitution of 1,3-dimethylallyl acetate with dimethyl malonate

Scheme 3. Asymmetric allylic substitution of cyclic substrates with dimethyl malonate

In addition to their application in the asymmetric allylic substitution reactions, PHOX ligands have shown great potential in intermolecular asymmetric Heck reaction, providing significant improvement in yields and/or enantioselectivities compared to bisphosphine ligands (Scheme 4).4 Lastly, the Ir-PHOX system is uniquely effective in the asymmetric hydrogenation of non- functionalized olefins. Ir-PHOX system can be complementary to Rh- and Ru-bisphosphine catalyst systems that are selective toward functionalized olefins containing coordinating groups such as amides and carboxylic acids in close proximity to the double bond (Scheme 5).5

4 McCartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122−5150.

5 a) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402−1411. b) erendel mies i gue , M.; Andersson, P. G. Chem. Rev. 2014, 114, 2130−2169.

Scheme 4. Intermolecular asymmetric Heck reaction using PHOX and BINAP ligands

Scheme 5. Ir-catalyzed asymmetric hydrogenation of non-functionalized olefins

The axially chiral P,N-ligand, QUINAP, that was introduced concurrently with the PHOX ligands in 1993, was successfully employed in the asymmetric hydroboration-oxidation of styrene derivatives using catecholborane, achieving good to excellent enantioselectivity for a wider range of alkenes compared to the initial Rh-BINAP system (Scheme 6).1a

Scheme 6. Asymmetric hydroboration-oxidation of arylalkenes using Rh-QUINAP

In 2003, Morken’s group reported a highly enantioselective syn-addition of bis(catecholato)diboron across trans-disubstituted alkenes.6 However, the enantioselectivity was

6 Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 8702−8703.

6 less satisfactory for other classes of alkene substrates (Scheme 7). In the same year, Knochel’s group developed a powerful three-component coupling reaction between an aldehyde, a secondary amine, and an alkyne using Cu-QUINAP as the catalyst system, giving good yields and ees when dibenzylamines were coupled with a wide range of aliphatic aldehydes and alkynes (Scheme 8). More recently, another variant of QUINAP 1.8 was developed to address some of the challenging aldehyde substrates reported previously (Scheme 8). 7

Scheme 7. Asymmetric diboration-oxidation of olefins using Rh-QUINAP

Scheme 8. Asymmetric three component condensation employing QUINAP and its analog 1.8

7 a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed. 2003, 42, 5763− 5766. b) Gommermann, N.; Knochel, P. Chem. Eur. J. 2006, 12, 4380−4392. c) Cardoso, F. S. P.; Abboud, K. A.; Aponick, A. J. Am. Chem. Soc. 2013, 135, 14548−14551.

-Aminophosphines, which can be readily prepared from chiral amino acids, were first used by Hayashi and Kumada in the asymmetric Kumada coupling reaction (Scheme 9). The hemilabile property of the amine group proved to be critical for obtaining high enantioselectivity. During the enantio-discriminatig step, the dimethylamino group on the ligand is believed to dissociate from the nickel centre and bind preferentially with one of the enantiomers of Grignard reagent. Subsequent transmetallation and reductive elimination give enantio-enriched products in up to 94% ee (Scheme 9).8

Scheme 9. Asymmetric Kumada coupling reaction using -aminophosphine ligand 1.9

Iminophosphine 1.10 was shown to be a competent chiral ligand for the Cu-catalyzed conjugated addition of diethylzinc to enones (Scheme 10).9

8 a) Hayashi, T.; Fukushima, M.; Konishi, M.; Kumada, M. Tetrahedron Lett. 1980, 21, 79−82. b) Grushin, V. V. Chem. Rev. 2004, 104, 1629−1662.

9 Saitoh, A.; Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1997, 8, 3567.

Scheme 10. Cu-catalyzed conjugated addition of diethylzinc to enones using iminophosphine 1.10

Morris and coworkers developed a ruthenium hydride borohydride complex 1.11 containing - aminophosphine ligand and demonstrated its utility in the highly enantioselective tandem 10 Michael addition /H2-hydrogenation of the cyclic enone (Scheme 11).

Scheme 11. Ru-catalyzed asymmetric tandem Michael addition/hydrogenation of cyclic enone

More recently, Guan et al. and Jones et al. reported the use of an earth-abundant and nontoxic iron-based catalyst bearing a PNP-pincer ligand in the hydrogenation of esters and N- heterocycles (Scheme 12). 11

10 a) Guo, R.; Morris, R. H.; Song, D. J. Am. Chem. Soc. 2005, 127, 516−517. b) Guo, R.; Lough, A. J.; Morris, R. H.; Song, D. Organometallics 2004, 23, 5524−5529. c) Abdur-Rashid, K.; Guo, R.; Lough, A. J.; Morris, R. H.; Song. Adv. Synth. Catal. 2005, 347, 571−579.

11 Chakraborty, S.; Dai, H.; Bhattacharya, P.; Fairweather, N. T.; Gibson, M. S.; Krause, J. A.; Guan, H. J. Am. Chem. Soc. 2014, 136, 7869−7872. b) Chakraborty, S.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2014, 136, 8564−8567.

Scheme 12. Fe-catalyzed hydrogenation of esters and N-heterocycles

Morris et al. achieved good to excellent enantioselectivities in the asymmetric hydrogenation of ketones and activated imines employing an iron precatalyst 1.13 containing unsymmetrical N ’ pincer ligand (Scheme 13).12

Scheme 13. Fe-catalyzed asymmetric hydrogenation of ketones and activated imines

12 a) Lagaditis, P. O.; Sues, P. E.; Sonnenberg, J. F.; Wan, K. Y.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2014, 136, 1367−1380. b) Sonnenberg, J. F.; Lough, A. J.; Morris, R. H. Organometallics 2014, 33, 6452−6465.

In addition to their role as ligands for transition metals, -aminophosphines are receiving new attention as the building blocks for chiral bifunctional catalysts in the field of organocatalysis, which will be discussed in Chapter 2.

1.2 Decarboxylative Allylation Reaction

The decarboxylative allylic alkylation reaction, discovered by Tsuji and co-workers in the 1980s, allows the construction of all-carbon quaternary centres from allyl enol carbonates or allyl β-keto esters precursors under mild and neutral conditions (Scheme 14).13 The preparation of these α- quaternary ketones would otherwise have been difficult under basic conditions, due to the regioselectivity issue caused by two enolizable protons with very similar pKa values.

Scheme 14. The Tsuji reaction

The proposed mechanism is shown in Scheme 15. The coordination and ionization of the allyl moiety by the Pd(0) complex takes place to generate a palladium carbonate intermediate, and subsequent decarboxylation of the carbonate leads to the palladium enolate intermediate. This in

13 a) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793–1796. b) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21, 3199–3202.

11 situ generated enolate nucleophile then recombines with the palladium -allyl electrophile to give the product and regenerates the catalyst.14

Scheme 15. Proposed catalytic cycle of the decarboxylative allylic alkylation of allyl enol carbonates and allyl β-keto esters

The first enantioselective variant of the Tsuji reaction was reported independently by the Trost group and the Stoltz group employing different ligands (Scheme 16).15,16

Scheme 16. The initial report of enantioselective Tsuji reaction using Trost P,P-ligand and PHOX P,N-ligand

14 a) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381–6384. b) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140–145. 15 Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044–15045.

16 Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846–2847.

Trost was able to obtain excellent enantioselectivities for mostly benzannulated substrates using the bisphosphine ligand 1.14. The substrate scope was further expanded by the same group and the group of Murakami to include vinylogous esters and thioesters, acyclic carbonates and allyl -acetamido--keto carboxylates (Scheme 17).17

Scheme 17. Asymmetric decarboxylative allylic alkylation using Trost ligands

Stoltz et al. discovered that PHOX ligands provided excellent reactivity and high enantioselectivity for carbocyclic and heterocyclic substrates with tolerance to a wide array of

17 a) Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem. Int. Ed. 2006, 45, 3109–3112. b) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343–18357. c) Kuwano, R.; Ishida, N.; Murakami, M. Chem. Commun. 2005, 31, 3951–3952.

13 substituents and functionalities.18 The electron-deficient variant of the original PHOX ligand PHOX 1.16 was identified to significantly enhance the rate, ee or dr of the reaction and thus is key for achieving a broad substrate scope (Scheme 18).19

Scheme 18. Asymmetric decarboxylative allylic alkylation using PHOX 1.4 and 1.16

A notable expansion of the reaction scope was made by Nakamura to prepare enantio-enriched α-fluoroketones (Scheme 19).20

18 a) Hong, A.Y. ; Stoltz, B. M. Eur. J. Org. Chem. 2013, 14, 2745–2759. b) Liu, Y.; Han, S. J.; Liu, W. -B.; Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740–751.

19 Craig II, R. A.; Stoltz, B. M. Tetrahedron Lett. 2015, 56, 4670–4673. 20 Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem. Int. Ed. 2005, 44, 7248–7251.

Scheme 19. Synthesis of chiral -fluoroketones through decarboxylative allylic alkylation

Interestingly, Stoltz et al. showed that the enolate nucleophile can be trapped with a Michael acceptor before allylic alkylation, giving rise to cyclic ketones bearing adjacent quaternary and tertiary stereocenters (Scheme 20). However, excellent diastereoselectivity was achieved only for a limited number of substrates.21

Scheme 20. Enantioselective decarboxylative enolate alkylation cascade

Alternatively, ketones bearing adjacent quaternary and tertiary stereocenters can be obtained by Ir-catalyzed allylic alkylation of -substituted β-ketoesters employing phosphoramide as the

21 Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010, 2 192−196

15 chiral ligand (Scheme 21). Excellent regio‑, diastereo‑, and enantioselectivities were achieved for both the cyclic and acyclic substrates using different lithium salt additives.22

Scheme 21. Ir-catalyzed allylic alkylation of -substituted β-ketoesters

To add another level of sophistication to the system, Stoltz demonstrated that using a cleverly devised 2-(trimethylsilyl)ethyl -ketoester can lead to sequential double allylic alkylation using the Ir-phosphoramide/Pd-PHOX dual catalyst system. Treatment with fluoride triggered a cascade degradation of the 2-(trimethylsilyl)ethyl group and exposed the prochiral enolate to Pd- allyl electrophile. The consecutive allylic alkylation reaction furnished the products with excellent diastereo‑ and enantioselectivities (Scheme 22).19b

22 a) Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298–17301. b) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626–10629.

Scheme 22. Sequential allylic alkylation catalyzed by Ir and Pd complexes

The mechanism of the Pd-catalyzed decarboxylative allylic alkylation reaction of enol carbonates has been investigated by both the Stoltz and the Trost groups. Based on theoretical calculations, Stoltz and Goddard proposed that a relatively stable pentacoordinated- allylpalladium enolate complex exo-5 is formed following the decarboxylation (Scheme 23). This pentacoordinate species rearranges to the tetracoordinate -allylpalladium enolate complex (Re/Si)-8. Furthermore, the Re/Si faces of the enolate interact differently with PHOX ligand during the transition state. Therefore, the formation of (Re/Si)-8 could be the enantio- determining step, provided that the rotation barrier (currently unknown) about Pd-O bond is large enough to prevent racemization of (Re/Si)-8. (Re/Si)-8 then undergoes an uncommon pericyclic reductive rearrangement transition state that is different from the traditional three-centered reductive elimination. Hence, the final product is believed to be generated via an “inner sphere” mechanism.23

23 a) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2007, 129, 11876–11877. b) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2012, 131, 19050–19060.

Scheme 23. Proposed mechanism by Stoltz and Goddard for asymmetric decarboxylative allylic alkylation using PHOX

Trost and coworkers argued that covalently bonded palladium enolate, even if it exists, would equilibrate with the tight enolate/-allylpalladium ion-pair and an “outer sphere” SN2 attack of the enolate on the -allylpalladium complex should mostly likely be the operating mechanism (Scheme 24). To support their argument, they carried out an enantioselective Tsuiji reaction using enol carbonate cis-1.18 in the presence of a bisphosphine ligand (Scheme 25).14b The cis configuration from the starting material is preserved in the product. This result provides strong evidence for a double inversion “outer sphere” mechanism that is common for allylic alkylation of “soft” nucleophiles.

Scheme 24. Proposed mechanism by Trost for asymmetric decarboxylative allylic alkylation using Trost ligand

Scheme 25. Asymmetric decarboxylative allylic alkylation of cis-1.18 using Trost ligand

2 Objectives

Previous research in our group showed that electron-deficient -aminophosphine 1.20 displayed excellent reactivity and induced good enantioselectivity in the decarboxylative allylation of enol carbonate (Scheme 26).

Scheme 26. Asymmetric decarboxylative allylic alkylation using -aminophosphine

In order to further improve the enantioselectivity of the reaction, we aimed to generate a ligand library using a novel modular approach recently developed in our lab (Scheme 27).

Scheme 27. Modular synthesis of -aminophosphines

3 Results and Discussion

3.1 Synthesis of -Substituted -Aminophosphines and Their Applications in Decarboxylative Allylation Reaction

Traditionally, chiral -aminophosphines are prepared from chiral 1,2-aminoalcohols in four synthetic steps: Boc-protection of the primary amine, tosylation of the alcohol followed by displacement of the tosyl group with potassium diphenylphosphide, and, finally, deprotection of the Boc group (Scheme 28).24

Scheme 28. Conventional synthesis of chiral -aminophosphines

There are reports in the literature that describe the successful syntheses of these - aminophosphines from the corresponding tosylate precursors.(Scheme 29 (1) and (2))21 There are also findings where these -amino tosylates fall short of serving as precursor to the desired phosphine products (Scheme 29 (3) and (4))25 A major drawback of this approach is the formation of aziridine that cannot be re-opened by KPPh2. Changing the Boc protecting group to phthalimide only led to the formation of the another side product via neighboring group participation of the amide carbonyl group.

24 a) Saitoh, A.; Uda, T.; Morimoto, T. Tetrahedron: Asymmetry 1999, 10, 45014511. b) Quirmbach, M.; Holz, J.; Tararov, V. I.; Borner, A.Tetrahedron 2000, 56, 775780.

25 a) Anderson, J. C.; Cubbon, R. J.; Harling, J. D. Tetrahedron: Asymmetry 2001, 12, 923935. b) Christoffers, J. Helvetica Chimica Acta. 1998, 81, 845852.

Scheme 29. Previous literature reports on synthesis of chiral -aminophosphines via tosyl displacement

To get around such these previous complications, Guo et al. demonstrated that a variety of chiral 1,2-aminoalcohols can be reliably converted to stable N-Boc protected cyclic sulfamidates. The ring opening of these cyclic sulfamidates with potassium diphenylphosphide followed by the deprotection of Boc affords chiral aminophosphines in good yields (Scheme 30).26

Scheme 30. Synthesis of chiral -aminophosphines via cyclic sulfamidates

However, the reaction was only demonstrated for diphenylphosphino and BINAP-phosphepine moieties. Attempts to synthesize electron-deficient P,N-ligand by simply switching the nucleophile to bis(4-(trifluoromethyl)phenyl)phosphanide failed to deliver any desired product.27 In light of this limitation, we set out to develop a modified version of this method that would permit easy modification of the diaryl substituents on the phosphine group.

26 Guo, R.; Lu, S.; Chen, X.; Tsang, C.-W.; Jia, W.; Sui-Seng, C.; Amoroso, D.; Abdur-Rashid, K. J. Org. Chem. 2010, 75, 937940.

27 J. Su, unpublished results

Scheme 31. The first successful ring-opening of cyclic sulfamidate with secondary phosphine oxide

It was identified that the combination of potassium tert-butoxide and bis(4- (trifluoromethyl)phenyl) phosphine oxides was able to open the cyclic sulfamidate (Scheme 31).24 Efforts towards optimizing the reaction conditions revealed two other competing pathways. Firstly, it is known that penta-valent secondary phosphine oxides can tautomerize in solution to trivalent phosphinous acids under neutral condition (Scheme 32).28 Under basic conditions, the oxygen atom can potentially compete with the phosphorus atom that would otherwise give rise to the desired product (Scheme 33 (1) and (2)). 24Another side reaction is the oxidation of secondary phosphine oxides (phosphinous acids) to phosphinic acids (Scheme 33 (3)) which is hydrophilic and dissolves in the aqueous layer during workup.29

Scheme 32. Tautomerism of secondary phosphine oxides

28 Christiansen, A.; Li, C.; Garland, M.; Selent, D.; Ludwig, R.; Spannenberg, A.; Baumann, W.; Franke, R.; Börner, A. Eur. J. Org. Chem. 2010, 2010, 27332741.

29 Tsvetkov, E. N.; Bondarenko, N. A.; Malakhova, I. G. ; Kabachnik, M. I. Synthesis, 1986, 3, 198208.

Scheme 33. Competing reaction pathways in the ring-opening of cyclic sulfamidate with secondary phosphine oxide

We reasoned that the use of “hard” metal cation that associates tighter with the oxygen atom should suppress O-alkylation and favor the “soft” P-alkylation. Indeed, switching from KOtBu to NaOtBu effectively suppressed O-alkylation as shown in Figure 3.

A KOtBu NaOtBu A

Figure 3. 31P NMR spectra of ring-opening reaction using KOtBu and NaOtBu

In addition, we carried out these ring-opening reactions in degassed THF under inert atmosphere to minimize the oxidation of secondary phosphine oxides. Various secondary phosphine oxide precursors were prepared by reacting the in situ generated Grignard reagents with diethyl phosphite (Table 1). With the optimized reaction conditions, several sterically and electronically differentiated aryl groups were installed on the phosphorus atom (Table 2).

Table 1. Scope for secondary phosphine oxides

Table 2. Scope for -substituted--aminophosphine oxides

The -aminophosphine oxides were then successfully reduced using diphenylsilane at 140 °C (Table 3).30 Due to the air-sensitive nature of organophosphines, the final P,N-ligands are purified through flash column chromatography using degassed eluent under argon.

Table 3. Scope for -substituted--aminophosphines

Electron-deficient P,N-ligands 1.32 and 1.36 were tested in the decarboxylative allylation reaction of enol carbonate (Table 4). Both ligands promoted the reaction to full conversion. However, the ee values were lower than what has been achieved using 1.20. To answer whether or not functionalizing the primary amine group would improve the enantioselectivity, ligand 1.38 was prepared by reductive amination of ligand 1.27 followed by reduction of 1.37 (Scheme 34). Unfortunately, ligand 1.38 did not display any catalytic activity. Considering the fact that electron-withdrawing groups such as 4-trifluoromethylphenyl group on the phosphine has been found to be optimal for these decarboxylative allylation reactions, we turned our attention toward optimizing the enantioselectivity of the reaction further by introducing a second chirality centre onto the carbon backbone of the P,N-ligand.

30 McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2010, 51, 55505554.

Table 4. Screening of P,N-ligands for decarboxylative allylic alkylation

Scheme 34. Reductive amination of P,N-ligand

3.2 Attempted Synthesis of ,-Disubstituted -Aminophosphines

Unfortunately, attempts to open 1,2-disubstituted cyclic sulfamidate 1.39 with our previously optimized condition only resulted in full recovery of the starting material. Switching the base back to KOtBu gave only O-alkylated side product (Scheme 35). The second phenyl substituent most likely blocks the electrophilic carbon from the incoming phosphorus nucleophile. As a result of this, only the smaller oxygen nucleophile can approach and thus open up the ring.

Scheme 35. Attempted ring-opening of 1,2-disubstituted cyclic sulfamidate with secondary phosphine oxide

We were then prompted to reconsider the possibility of using an open-chain, conformationally less rigid electrophile that could permit easier access for the incoming phosphorus nucleophile through carbon-carbon bond rotation. However, the isolation of the benzylic tosylate intermediate was not possible according to Guo et al., due to neighboring group participation of the Boc group, which rapidly displaces the tosyl group to form oxazolidinone as the only product (Scheme 36).23

Scheme 36. Decomposition pathway of benzylic tosylate

We considered whether we could install a less labile leaving group so that the intermediate would be more resistant against the intramolecular cyclization of the Boc group, but at the same time be adequately reactive towards intermolecular SN2 attack of the secondary phosphine oxide nucleophile. Commonly employed leaving groups such as chloride and bromide naturally came to mind. Although the required benzylic chloride and bromide had not been known in the literature, the ring-opening of cyclic sulfamidates with a fluoride is precedented as a means to prepare 18F-labeled compounds for imaging through Positron Emission Tomography (PET) (Scheme 37). 31

Scheme 37. Ring-opening of cyclic sulfamidates with fluoride

Knowing this, we decided to try opening the cyclic sulfamidate with tetra-n-butylammonium chloride and bromide. Gratifyingly, the reactions proceeded to full conversion after stirring at room temperature overnight and the products were isolated in 87 and 33 % yield, respectively (Scheme 38). Next, to test whether the halides could be displaced by a phosphorus nucleophile, the two intermediates were treated with secondary phosphine oxides under basic conditions. We found that while the benzylic chloride was unreactive, the benzylic bromide afforded the product in 40% yield. After deprotection of the Boc group, however, all efforts to reduce the aminophosphine oxide 1.41 to the aminophosphine failed (Table 5). Heating 1.41 neat with diphenylsilane at 140 °C resulted in the liberation of secondary phosphine oxide 1.21 through C– 32 P bond cleavage. Treatment of 1.41 with BH3▪SMe at 70 °C, led to the cleavage of C–C bond.

The use of 1,1,3,3-tetramethyldisiloxane (TMDS) with catalytic amount of Ti(OiPr)4 also

31 VanDort, M. E.; Jung, Y.-W.; Sherman, P. S.; Kilbourn, M. R.; Wieland, D. M. J. Med. Chem. 1995, 38, 810815.

32 Hérault, D.; Nguyen, D. H.; Nuela, D.; Buono, G. Chem. Soc. Rev. 2015, 44, 25082528.

29 resulted in C–C bond cleavage.33 It seems that the phosphine oxide starting material is prone to decomposition in the presence of a Lewis acid.

Scheme 38. Ring-opening and P-alkylation of cyclic sulfamidates

33 M. Berthod, A. Favre-Réguillon, J. Mohamad, G. Mignani, G. Docherty, M. Lemaire, Synlett, 2007, 15451548.

Table 5. Decomposition products isolated in the reduction of aminophosphine oxide

Another synthetic target that we examined was derived from 1-amino-2-indanol 1.42 (Scheme 39). The tosylate intermediate 1.43 was expected to be stable from ring-closure because the tosyl group and the Boc group are locked in a cis configuration. The two known decomposition pathways - aziridination and oxazolidinone formation - require the neighboring group to approach from the opposite side. Surprisingly, treatment of tosylate 1.43 with secondary phosphine oxide and base only resulted in the full recovery of the starting material. Switching to a more reactive triflate group afforded the product 1.45 in modest yield. The attempt to remove the Boc group with trifluoroacetic acid led to P–C bond cleavage, suggesting that the product is unstable towards acidic conditions. Instead, stirring 1.45 with zinc bromide overnight successfully hydrolyzed the Boc group and furnished the product 1.46 in good purity after work up. It should be noted that, eluting the crude product through a silica gel column resulted in complete decomposition of 1.46. Unfortunately, the desired phosphine product was not observed

31 by 31P spectroscopy even with attempted reduction of the crude phosphine oxide mixture using either diphenylsilane or BH3.

Scheme 39. Attempted synthesis of -disubstituted -aminophosphine derived from 1-amino- 2-indanol 1.42

3.3 Attempted C–H activation of (R)-2-phenylglycinol

Given the daunting synthetic challenge of -disubstituted -aminophosphines, we turned our attention back to the ligand scaffold bearing a single chiral centre. By this time, we had almost exhausted the small pool of commercially available chiral 1,2-aminoalcohols that could be relevant to our research. We were therefore drawn to the idea of modifying the existing chiral backbone through C–H activation. The power of this approach was demonstrated recently by Yu and his collaborators in Bristol-Myers Squibb, where simple alanine was transformed into a diverse range of non-natural amino acids through sequential sp3 C–H arylation. The resulting

32 amino acids were readily reduced to amino alcohols which were used to make novel BOX and PyBOX ligands (Scheme 40).34

Scheme 40. -C−H arylation of alanine

For our system, we hypothesized using the primary amine to direct sp2 ortho-functionalization of 2-phenylglycinol (Scheme 41). If successful, the resulting novel amino alcohols could be transformed into P,N-ligands using our established methodology.

34 Chen, G.; Shigenari, T.; Jain, P.; Zhang, Z.; Jin, Z.; He, J.; Li, S.; Mapelli, C.; Miller, M. M.; Poss, M. A.; Scola, P. M.; Yeung, K.; Yu, J. Q. J. Am. Chem. Soc. 2015, 137, 33383351.

Scheme 41. Hypothetical divergent synthesis of -substituted -aminophosphines via C–H activation

Although ortho-palladation of N,N-dialkylbenzylamines is well-known, the first synthetically relevant C–H activation using primary benzylamine as the directing group was not reported until 2006 (Scheme 42).35 Under rather harsh reaction conditions, the ortho-diarylation of benzylamines possessing only simple hydrocarbon backbones was realized and the products were isolated as trifluoroacetamides in decent yields. More recently, Yu and coworkers reported an enantioselective C–H iodination of benzyamines via kinetic resolution employing I2 as the sole oxidant (Scheme 42).36 The C–H activation of one of the enantiomers is selectively accelerated by the addition of matched ligand – either L or D mono-protected amino acid. The drawback of this approach was the generation of a 1:1 mixture of mono- and di-iodinated products. However, this limitation may not necessarily be a pitfall for an initial screening as it effectively increases the chemical space covered by the ligand library.

35 Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 52115213. 36 Chu, L.; Xiao, K. J.; Yu, J. Q. Science. 2014, 346, 451455.

Scheme 42. Known C–H activation of primary benzylamines

With this hypothesis in mind, we decided to try the C–H iodination of enantiopure (R)-2- phenylglycinol using the matched D-amino acid ligand. The synthesis of the starting materials is presented in Scheme 40. The amino-alcohol 1.47 was sequentially protected with a triflyl and a tert-butyldimethylsilyl group in 61% yield over two steps. D-leucine 1.50 was treated with benzoyl chloride in aqueous sodium hydroxide to give N-Bz-(D)-Leu 1.51 in 75% isolated yield.

Scheme 43. Synthesis of starting materials for C–H activation

The C–H iodination reaction was set up using the conditions as reported by Yu and coworkers. However, the reaction came to a halt at low conversion after stirring vigorously at room temperature for 48 hours. The ratio of starting material, the mono- and diiodinated product ratio was found to be around 2:1:0.25 by integration of the 1H NMR spectrum (Scheme 44). The

35 turnover number of the palladium catalyst was calculated to be around 4. Several attempts to improve the conversion, including increasing the temperature, varying the palladium-to-ligand ratio, and adjusting the solvent ratio, proved fruitless. The only way to improve the conversion was by increasing the palladium loading. Based on these results, we suspected that the inactive

PdI2 formed after two catalytic cycles was not being effectively converted back to the reactive

Pd(OAc)2 by CsOAc, Na2CO3 and DMSO, a combination of reagents that was previously shown to regenerate the active catalyst in a different reaction (Scheme 45).37

Scheme 44. Attempted C–H iodination using I2

Scheme 45. Regeneration of Pd(OAc)2 from PdI2

We wondered whether we could prevent the formation of PdI2 in the first place by using IOAc as the oxidant. IOAc, generated by mixing I2 with AgOAc or PhI(OAc)2, had been employed by Yu

37 Wang, X.; Hu, Y.; Bonacorsi, S.; Hong, Y.; Burrell, R.; Yu, J. Q. J. Am. Chem. Soc. 2013, 135, 1032610329.

36 and coworkers as the C–H iodination reagent before they discovered the conditions (Scheme 45) 38 that enabled them to adopt the much more practical I2 for C–H iodination. The result we obtained from the use of IOAc is presented in Scheme 46. We observed predominantly the diiodinated product along with a negligible amount of mono-iodinated product, and the turnover number was improved to around 7. However, full conversion of the starting material was not attained even with a 20 mol% Pd loading. From a practical perspective, no further C–H iodination reaction was attempted beyond this point.

Scheme 46. Attempted C–H iodination using IOAc

4 Experimental

4.1 Procedures and Compounds

General procedure for preparing diaryl secondary phosphine oxides 1.21–1.24.

Bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.21)

Mg turnings (0.56 g, 23 mmol) were activated with iodine in diethyl ether (12 mL) and 1-bromo- 4-(trifluoromethyl)benzene (5 g, 22 mmol) was added at 0 °C. The mixture was stirred under gentle reflux for 90 min. Diethyl phosphite (1.02 g, 7.4 mmol) was then added dropwise at 0 ºC.

38 Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem. Int. Ed. 2005, 44, 21122115.

The reaction mixture was stirred at room temperature for 14 h. 2N Hydrochloric acid (12 mL) was added dropwise at 0 ºC and the mixture was stirred at 23 ºC for 5 min. Extraction with diethyl ether followed by purification by column chromatography (Hexanes /EtOAc, 3:1 v/v) afforded phosphine oxide 1 (1.5 g, 61%) as a yellow solid.

1 13 H NMR (300 MHz, CDCl3) δ 8 20 (d, J (P-H) = 492 Hz, 1H), 7.96 – 7.74 (m, 10H). C NMR

(101 MHz, CDCl3) δ 134 84 (dd J = 33.0, 3.0 Hz), 134.82 (d, J = 100.0 Hz), 131.19 (d, J = 12.0 31 Hz), 126.04 (dq, J = 13.2, 3.8 Hz), 123.30 (dd, J = 272.9, 1.1 Hz). P NMR (121 MHz, CDCl3) δ 17.81.

Di-o-tolylphosphine oxide (1.22)

Synthesized according to general procedure using 1-bromo-2-methylbenzene (5.68 g, 33.2 mmol), Mg turning (834 mg, 34.3 mmol) and diethyl phosphite (1.53 g, 11 mmol). Purified by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:4 v/v) to afford 1.22 (1.38 g, 55%) as a white solid.

1 H NMR (400 MHz, CDCl3) δ 8 19 (d J = 477.6 Hz, 1H), 7.70 (m, 2H), 7.45 (m, 2H), 7.31 (m, 13 2H), 7.23 (m, 1H), 2.36 (s, 6H). C NMR (101 MHz, CDCl3) δ 141 08 (d J = 9.9 Hz), 132.52 (d, J = 2.7 Hz), 132.42 (d, J = 11.8 Hz), 131.22 (d, J = 10.3 Hz), 129.29 (d, J = 100.2 Hz), 31 126.04 (d, J = 12.8 Hz), 20.15 (d, J = 7.0 Hz). P NMR (121 MHz, CDCl3) δ 17 64

Bis(4-methoxyphenyl)phosphine oxide (1.23)

Synthesized according to general procedure using 1-bromo-4-methoxybenzene (5.98 g, 32.0 mmol), Mg turning (802 mg, 33.0 mmol) and diethyl phosphite (1.47 g, 10.7 mmol). Purified by flash chromatography on silica gel (100% EtOAc) to afford 1.23 (1.08 g, 39%) as a white solid.

1 H NMR (400 MHz, CDCl3) δ 8 01 (d = 478 0 H 1H) 7 71 – 7.52 (m, 4H), 7.07 – 6.94 (m, 13 4H), 3.83 (s, 6H). C NMR (101 MHz, CDCl3) δ 162 92 (d J = 2.9 Hz), 132.67 (d, J = 13.0 Hz), 31 122.92 (d, J = 108.0 Hz), 114.46 (d, J = 13.9 Hz), 55.39. P NMR (121 MHz, CDCl3) δ 20 50

Diphenylphosphine oxide (1.24)

Synthesized according to general procedure using bromobenzene (5.98 g, 38.1 mmol), Mg turning (957 mg, 39.4 mmol) and diethyl phosphite (1.75 g, 12.7 mmol). Purified by flash chromatography on silica gel (100% EtOAc) to afford 1.24 (1.48 g, 57%) as a white solid.

1 H NMR (300 MHz, CDCl3) δ 8 08 (d J = 480.2 Hz, 1H), 7.71 (m, 4H), 7.63 – 7.45 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 131 26 (d J = 10.4 Hz), 130.74 (d, J = 11.4 Hz), 128.94 (d, J = 31 12.9 Hz), 128.29 (d, J = 13.3 Hz). P NMR (121 MHz, CDCl3) δ 21 38

General procedure for preparing cyclic sulfamidates 1.25, 1.26, 1.39. tert-Butyl (S)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.25)

A solution of (Boc)2O (520 mg, 2.4 mmol) in THF (4 mL) was added to a mixture of (S)-2- amino-3-methyl-1-butanol (220 mg, 2.1 mmol) and sodium carbonate (0.5 g, 4.7 mmol) in

THF/H2O (1/1, 8 mL) at 0 ºC. The mixture was stirred at room temperature for 3 h. Water was added to the mixture and was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated to afford the crude product in quantitative yield as a colorless viscous liquid, which was used in the next step without purification.

Pyridine (1 g, 10 mmol) was added dropwise to a solution of N-Boc-protected (S)-2-amino-3- methyl-1-butanol (426mg, 2.10 mmol) and SOCl2 (621 mg, 5.2 mmol) in MeCN (6 mL) at -40 ºC. The reaction mixture was allowed to warm up and stirred at room temperature for 3 h. Water was added to quench the reaction at 0 ºC. The aqueous layer was extracted with ethyl acetate.

The organic phase was dried over anhydrous MgSO4 and concentrated to afford an orange color oil. The residual was azeotroped three times with toluene and was dried on high vacuum to remove pyridine. The crude product was used for the next step without purification.

RuCl3∙3H2O (30 mg, 0.146 mmol) was added to a solution of cyclic sulfamidite (0.45 g) in

CH3CN/H2O (1:1, 10 mL) at 0 ºC. NaIO4 (0.67 g, 3.13 mmol) was added in one portion. The reaction was stirred at room temperature for 14 h. The aqueous layer was extracted with diethyl ether. The combined organic layer was washed with brine, dried over MgSO4 and concentrated.

The residual was re-dissolved in CH2Cl2 and was filtered through a short plug of silica to remove Ru catalyst. The solvent was removed in vacuo to afford the final product (293mg, 53% over three steps) as a white or slightly yellow crystalline solid.

1 H NMR (400 MHz, CDCl3) δ 4 57 (dd J = 9.5, 6.4 Hz, 1H), 4.39 (dd, J = 9.5, 1.8 Hz, 1H), 4.19 (ddd, J = 6.4, 5.2, 1.8 Hz, 1H), 2.27 (pd, J = 6.9, 5.2 Hz, 1H), 1.55 (s, 9H), 1.02 (d, J = 6.9 Hz, 13 3H), 0.97 (d, J = 7.0 Hz, 3H). C NMR (101 MHz, CDCl3) δ 149 10 85 34 67 02 62 01, 30.04, 27.89, 18.00, 16.46. tert-Butyl (R)-4-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.26)

Synthesized according to general procedure using (R)-2-amino-2-phenylethan-1-ol (364 mg, 2.65 mmol). The final product 1.26 (380 mg, 48% over three steps) was obtained as a white crystalline solid.

1 H NMR (300 MHz, CDCl3) δ 7 56 – 7.34 (m, 5H), 5.44 – 5.19 (dd, J = 6.7, 4.2 Hz, 1H), 4.87 (dd, J = 9.2, 6.7 Hz, 1H), 4.41 (dd, J = 9.2, 4.2 Hz, 1H), 1.43 (s, 9H). 13C NMR (101 MHz,

CDCl3) δ 148 28 136 95, 129.26, 129.15, 126.17, 85.59, 71.79, 60.77, 27.83. tert-Butyl (4R,5S)-4,5-diphenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.39)

Synthesized according to general procedure using (1S,2R)-2-amino-1,2-diphenylethan-1-ol (521 mg, 2.44 mmol). The final product 1.39 (666 mg, 72% over three steps) was obtained as a white crystalline solid.

1 H NMR (399 MHz, CDCl3) δ 7 16 (m 6H) 7 10 – 7.01 (m, 2H), 6.96 – 6.88 (m, 2H), 6.16 (d, J 13 = 5.6 Hz, 1H), 5.42 (d, J = 5.6 Hz, 1H), 1.49 (s, 9H). C NMR (101 MHz, CDCl3) δ 148 24 133.53, 130.57, 129.31, 128.53, 128.42, 128.37, 128.27, 127.21, 126.27, 85.67, 83.36, 66.60, 27.89.

General procedure for preparing aminophosphine oxides 1.27–1.31.

(S)-(2-Amino-3-methylbutyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.27)

Bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.21 (186 mg, 0.55 mmol) was added to a solution of sodium tert-butoxide (53 mg, 0.55 mmol) in degassed THF (5 mL) under inert atmosphere. The mixture was stirred for 5 min. tert-Butyl (S)-4-isopropyl-1,2,3-oxathiazolidine- 3-carboxylate 2,2-dioxide 1.25 solid (146 mg, 0.55 mmol) was added and the reaction mixture

was stirred at 60 for 3 h. The reaction was quenched with 2N H2SO4 (4 mL) at room

41 temperature and the mixture was stirred for another 20 min. Extraction with diethyl ether followed by purification by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:4 v/v). Trifluoroacetic acid (1.1 mL, 14.3 mmol) was added to a solution of the purified product in dry

CH2Cl2 (5 mL) at 0 °C. The reaction was allowed to warm up and stirred at room temperature for

3 h. Saturated Na2CO3 was added dropwise to the solution at 0 °C. The aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4 and concentrated to afford the final product 1.27 (160 mg, 69%) as colorless oil.

1 H NMR (300 MHz, CDCl3) δ 7 98 – 7.82 (m, 4H), 7.79 – 7.68 (m, 4H), 3.07 (m, 1H), 2.67 – 2.18 (m, 2H), 1.91 (s, 2H), 1.67 (m, 1H), 0.88 (app dd, J = 6.8, 5.6 Hz, 6H). 13C NMR (101

MHz, CDCl3) δ 137 69 (d J = 95.4 Hz), 136.53 (d, J = 96.3 Hz), 134.48 – 134.00 (m), 134.00 – 133.58 (m), 131.36 (d, J = 9.5 Hz), 131.03 (d, J = 9.8 Hz), 126.26 – 125.46 (m), 124.78, 122.06, 52.01 (d, J = 4.6 Hz), 34.71 (d, J = 12.7 Hz), 33.75 (d, J = 72.9 Hz), 18.29, 17.51. 31P NMR -1 (121 MHz, CDCl3) δ 30 79 IR (neat, cm ): 3044 (w), 2961 (w), 1684 (w), 1400 (m), 1317 (s), 1183 (m), 1163 (s), 1117 (s), 1100 (s), 1060 (s), 1017 (s), 840 (m), 790 (m), 764 (m), 708 (s), 20 + 670 (m). Optical rotation: []D (c 1.15, CHCl3) = +26.8. HRMS (DART-TOF) m/z: [M + H] calcd for C19H21F6NOP 424.12649; found 424.12666.

(S)-(2-Amino-3-methylbutyl)di-o-tolylphosphine oxide (1.28)

Synthesized according to general procedure using di-o-tolylphosphine oxide 1.22 (115 mg, 0.5 mmol), sodium tert-butoxide (48 mg, 0.5 mmol) and tert-Butyl (S)-4-isopropyl-1,2,3- oxathiazolidine-3-carboxylate 2,2-dioxide 1.25 (133 mg, 0.5 mmol). The intermediate was purified by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:3 v/v) before treatment of trifluoroacetic acid. The final product 1.28 (67 mg, 42%) was isolated as a colorless oil.

1 H NMR (300 MHz, CDCl3) δ 7 81 (ddd J = 12.5, 7.7, 1.5 Hz, 1H), 7.64 (ddd, J = 12.9, 7.7, 1.4 Hz, 1H), 7.46 – 7.34 (m, 2H), 7.34 – 7.24 (m, 2H), 7.24 – 7.12 (m, 2H), 3.21 – 2.89 (m, 1H), 2.49 – 2.45 (m, 2H), 2.46 – 2.34 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 1.79 – 1.61 (m, 1H), 0.87

13 (app t, 6H). C NMR (101 MHz, CDCl3) δ 141 68 (d J = 8.4 Hz), 141.21 (d, J = 8.8 Hz), 132.43 (d, J = 9.6 Hz), 132.05 (d, J = 96.4 Hz), 132.01 , 131.91 , 131.89 , 131.87 , 131.30 (d, J = 11.1 Hz), 130.65 (d, J = 95.3 Hz), 125.79 (d, J = 6.6 Hz), 125.68 (d, J = 7.0 Hz), 52.16 (d, J = 4.0 Hz), 34.52 (d, J = 12.8 Hz), 32.37 (d, J = 71.9 Hz), 21.26 (d, J = 4.0 Hz), 21.15 (d, J = 4.4 31 -1 Hz), 18.22, 17.88. P NMR (121 MHz, CDCl3) δ 35 29 IR (neat, cm ): 2957 (m), 2871 (w), 1593 (m), 1568 (m), 1452 (s), 1385 (m), 1283 (m), 1174 (s), 1138 (s), 1084 (w), 1071 (w), 927 20 (m), 805 (m), 751 (s), 730 (s), 688 (m). Optical rotation: []D (c 1.45, CHCl3) = +68.7. + HRMS (DART-TOF) m/z: [M + H] calcd for C19H27F6NOP 316.18303, found 316.18342.

(S)-(2-Amino-3-methylbutyl)bis(4-methoxyphenyl)phosphine oxide (1.29)

Synthesized according to general procedure using bis(4-methoxyphenyl)phosphine oxide 1.23 (105 mg, 0.4 mmol), sodium tert-butoxide (39 mg, 0.4 mmol) and tert-Butyl (S)-4-isopropyl- 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 1.25 (106 mg, 0.4 mmol). The intermediate was purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:50 v/v) before treatment of trifluoroacetic acid. The final product 1.29 (34 mg, 25%) was isolated as a colorless oil.

1 H NMR (399 MHz, CDCl3) δ 7 69 – 7.54 (m, 4H), 6.93 (m, 4H), 3.80 (s, 3H), 3.77 (s, 3H), 3.00 (dddd, J = 11.7, 9.6, 4.9, 2.6 Hz, 1H), 2.69 (s, 3H), 2.36 – 2.09 (m, 2H), 1.65 (pd, J = 6.8, 4.8 Hz, 13 1H), 0.83 (app t, J = 6.7 Hz, 6H). C NMR (100 MHz, CDCl3) δ 162 28 (d J = 2.8 Hz), 162.23 (d, J = 2.9 Hz), 132.73 (d, J = 10.5 Hz), 132.30 (d, J = 10.8 Hz), 125.41 (d, J = 105.3 Hz), 123.37 (d, J = 104.8 Hz), 55.31 (d, J = 1.6 Hz), 55.27 (d, J = 1.7 Hz), 52.00 (d, J = 4.3 Hz), 31 34.41 (d, J = 12.7 Hz), 33.91 (d, J = 72.8 Hz), 18.16, 17.74. P NMR (121 MHz, CDCl3) δ 33.14. IR (neat, cm-1): 2956 (m), 2839 (w), 1596 (s), 1570 (m), 1503 (s), 1463 (m), 1408 (m), 1292 (s), 1253 (s), 1173 (s), 1119 (s), 1026 (s), 930 (m), 829 (s), 802 (s), 762 (m), 729 (m), 660 20 + (m). Optical rotation: []D (c 3.5, CHCl3) = +36.1. HRMS (DART-TOF) m/z: [M + H] calcd for C19H27NO3P 348.17285, found 348.17327.

(S)-(2-Amino-3-methylbutyl)diphenylphosphine oxide (1.30)

Synthesized according to general procedure using diphenylphosphine oxide 1.24 (162 mg, 0.8 mmol), sodium tert-butoxide (77 mg, 0.8 mmol) and tert-Butyl (S)-4-isopropyl-1,2,3- oxathiazolidine-3-carboxylate 2,2-dioxide 1.25 (212 mg, 0.8 mmol). The intermediate was purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:50 v/v) before treatment of trifluoroacetic acid. The final product 1.30 (123 mg, 54%) was isolated as a colorless oil.

1 H NMR (400 MHz, CDCl3) δ 7 73 (m 4H) 7 57 – 7.35 (m, 6H), 3.04 (dddd, J = 12.0, 10.0, 4.9, 2.3 Hz, 1H), 2.48 (br s, 2H), 2.37 (ddd, J = 15.0, 9.2, 2.3 Hz, 1H), 2.26 (ddd, J = 15.0, 12.0, 10.0 13 Hz, 1H), 1.66 (m, 1H), 0.85 (app t, J = 7.1 Hz, 6H). C NMR (101 MHz, CDCl3) δ 134.00 (d, J = 98.7 Hz), 132.33 (d, J = 98.3 Hz), 131.77 (app t, J = 2.8 Hz), 130.93 (d, J = 9.1 Hz), 130.47 (d, J = 9.3 Hz), 128.75 (d, J = 1.5 Hz), 128.63 (d, J = 1.6 Hz), 51.95 (d, J = 4.3 Hz), 34.57 (d, J = 31 12.7 Hz), 33.79 (d, J = 71.9 Hz), 18.20 , 17.66 . P NMR (162 MHz, CDCl3) δ 32 83 IR (neat, cm-1): 2958 (m), 2871 (w), 1401 (m), 1591 (w), 1465 (w), 1437 (s), 1387 (s), 1179 (s), 1119 (s), 20 1028 (m), 997 (m), 930 (m), 744 (s), 719 (s). Optical rotation: []D (c 1.3, CHCl3) = +41.7. + HRMS (DART-TOF) m/z: [M + H] calcd for C17H23NOP 288.15173, found 288.15217.

(R)-(2-Amino-2-phenylethyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.31)

Synthesized according to general procedure using bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.21 (244 mg, 0.72 mmol), potassium tert-butoxide (81 mg, 0.72 mmol) and tert-Butyl (R)-4- phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 1.26 (180 mg, 0.6 mmol). The intermediate was purified by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:9 v/v) before

44 treatment of trifluoroacetic acid. The final product 1.31 (100 mg, 35%) was isolated as a white solid.

1 H NMR (300 MHz, CDCl3) δ 7 93 – 7.77 (m, 4H), 7.77 – 7.65 (m, 4H), 7.39 – 7.11 (m, 5H), 4.51 (ddd, J = 10.5, 9.0, 4.0 Hz, 1H), 2.90 – 2.60 (m, 2H), 1.94 (s, 2H). 13C NMR (101 MHz,

CDCl3) δ 144 99 (s) 144 87 (s) 131 29 (d), 130.93 (d), 128.76, 127.78, 126.10, 125.71 (dt, J = 31 11.9, 3.8 Hz), 51.27 (d, J = 3.4 Hz), 39.52 (d, J = 69.9 Hz). P NMR (121 MHz, CDCl3) δ 28 52 IR (neat, cm-1): 2900 (w), 1496 (w), 1456 (w), 1400 (m), 1321 (s), 1165 (s), 1120 (s), 1100 (s), 1061 (s), 1017 (s), 835 (m), 789 (m), 768 (m), 742 (m), 708 (m), 696 (s). Optical rotation: 20 + []D (c 0.3, CHCl3) = –18.7. HRMS (DART-TOF) m/z: [M + H] calcd for C22H19F6NOP 458.11084, found 458.11092.

General procedures for preparing aminophosphines 1.32–1.36 through silane reduction

(S)-1-(Bis(4-(trifluoromethyl)phenyl)phosphanyl)-3-methylbutan-2-amine (1.32)

Diphenylsilane (0.29 g, 1.58 mmol) was added into a 2 dram vial containing (S)-(2-amino-3- methylbutyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.27 (96 mg, 0.23 mmol). The reaction was heated at 140 under inert atmosphere for 14 h. The reaction was allowed to cool down to room temperature and the crude mixture was directly loaded onto silica gel column. The eluent was degassed in advance through sparging with argon for 20 min. The crude product was purified through silica gel flash column chromatography using 50:1 v/v CH2Cl2/MeOH under a positive pressure of argon. The final product 1.32 (53 mg, 57%) was isolated as a colorless oil.

1 H NMR (300 MHz, CDCl3) δ 7 78 – 7.41 (m, 8H), 2.63 (m, 1H), 2.33 (m, 1H), 2.04 (m, 1H), 13 1.72 (m, 1H), 0.90 (app dd, J = 7.9, 6.8 Hz, 6H). C NMR (101 MHz, CDCl3) δ 143 81 (d J = 15.5 Hz), 142.57 (d, J = 16.8 Hz), 133.50 (d, J = 19.8 Hz), 132.64 (d, J = 18.4 Hz), 131.23 (d, J = 32.4 Hz), 130.69 (d, J = 32.6 Hz), 125.89 – 124.91 (m), 54.19 (d, J = 13.1 Hz), 34.58 (d, J =

7.4 Hz), 34.37 (d, J = 12.3 Hz), 18.85, 17.05. 31P NMR (121 MHz, Chloroform-d) δ -20.39. + HRMS (DART-TOF) m/z: [M + H] calcd for C19H21F6NP 408.13158, found 408.13147.

(S)-1-(Di-o-tolylphosphanyl)-3-methylbutan-2-amine (1.33)

Synthesized according to general procedure using diphenylsilane (0.26 g, 1.4 mmol) and (S)-(2- amino-3-methylbutyl)di-o-tolylphosphine oxide 1.28 (63 mg, 0.20 mmol). Purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:50 v/v) to afford 1.33 (36 mg, 61%) was isolated as a colorless oil.

1 H NMR (400 MHz, CDCl3) δ 7 25 – 7.10 (m, 8H), 2.81 – 2.63 (m, 1H), 2.45 (s, 3H), 2.43 (s, 3H), 2.25 (ddd, J = 13.8, 4.4, 1.6 Hz, 1H), 1.94 (ddd, J = 13.8, 9.2, 2.9 Hz, 1H), 1.83 (m, 1H), 13 0.95 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). C NMR (101 MHz, CDCl3) δ 142 74 (d J = 25.7 Hz), 142.00 (d, J = 25.6 Hz), 137.18 (d, J = 12.3 Hz), 136.38 (d, J = 13.4 Hz), 131.22 (d, J = 7.7 Hz), 130.12 (d, J = 2.2 Hz), 130.07 (d, J = 2.0 Hz), 128.44 (d, J = 11.7 Hz), 126.07 (d, J = 0.8 Hz), 126.04(d, J = 0.8 Hz), 54.05 (d, J = 14.0 Hz), 34.28 (d, J = 7.4 Hz), 33.37 (d, J = 12.1 31 Hz), 21.40 (d, J = 7.7 Hz), 21.18 (d, J = 7.4 Hz), 19.02 , 17.04. P NMR (162 MHz, CDCl3) δ - 44.02. IR (neat, cm-1): 3055 (w), 2956 (m), 1589 (w), 1466 (m), 1451 (m), 1378 (m), 1270 (w), 20 1200 (w), 1130 (m), 1032 (m), 910 (w), 747 (s), 719 (m). Optical rotation: []D (c 1.25, + CHCl3) = +82.4. HRMS (DART-TOF) m/z: [M + H] calcd for C19H27NP 300.18811, found 300.18886.

(S)-1-(Bis(4-methoxyphenyl)phosphanyl)-3-methylbutan-2-amine (1.34)

Synthesized according to general procedure using diphenylsilane (0.30 g, 1.61 mmol) and (S)-(2- amino-3-methylbutyl)bis(4-methoxyphenyl)phosphine oxide 1.29 (79 mg, 0.23 mmol). Purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:30 v/v) to afford 1.34 (30 mg, 40%) was isolated as a colorless oil.

1 H NMR (300 MHz, CDCl3) δ 7 44 – 7.31 (m, 4H), 6.93 – 6.80 (m, 4H), 3.80 (s, 3H), 3.78 (s, 3H), 2.66 (m, 1H), 2.25 (m, 1H), 1.99 (m, 1H), 1.75 (m, 1H), 1.26 (br s, 2H), 0.91 (d, J = 9.1 Hz, 13 3H), 0.88 (d, J = 9.0 Hz, 3H). C NMR (101 MHz, CDCl3) δ 160 28, 159.93, 134.50 (d, J = 20.6 Hz), 133.78 (d, J = 19.5 Hz), 130.20 (d, J = 9.3 Hz), 129.07 (d, J = 10.4 Hz), 114.20 (d, J = 4.7 Hz), 114.12 (d, J = 4.1 Hz), 55.18, 54.22, 54.08, 35.06 (d, J = 11.1 Hz), 34.19 (d, J = 7.6 Hz), 31 -1 18.90, 17.17. P NMR (121 MHz, CDCl3) δ -25.59. IR (neat, cm ): 2956 (m), 2835 (w), 1593 (s), 1568 (m), 1497 (s), 1462 (m), 1441 (m), 1401 (w), 1282 (s), 1245 (s), 1176 (s), 1094 (s), 20 1030 (s), 910 (w), 825 (s), 797 (m), 732 (m). Optical rotation: []D (c 2.65, CHCl3) = +71.4. + HRMS (DART-TOF) m/z: [M + H] calcd for C19H27NO2P 332.17794, found 332.17812.

(S)-1-(Diphenylphosphanyl)-3-methylbutan-2-amine (1.35)

Synthesized according to general procedure using diphenylsilane (0.36 g, 1.95 mmol) and (S)-(2- amino-3-methylbutyl)diphenylphosphine oxide 1.30 (80 mg, 0.28 mmol). Purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:30 v/v) to afford 1.35 (35 mg, 46%) was isolated as a yellow oil.

1 H NMR (400 MHz, CDCl3) δ 7 48 – 7.20 (m, 10H), 2.60 (m, 1H), 2.25 (m, 1H), 1.94 (m, 1H), 13 1.68 (m, 1H), 0.82 (app dd, 6H). C NMR (101 MHz, CDCl3) δ 133 31 133 12 132 57 132 38 128.88, 128.54, 128.48, 128.46, 128.40, 128.38, 54.27, 54.13, 34.53, 34.41, 34.17, 34.09, 18.89, 31 17.11. P NMR (162 MHz, CDCl3) δ -21.62.

(R)-2-(Bis(4-(trifluoromethyl)phenyl)phosphanyl)-1-phenylethan-1-amine (1.36)

Synthesized according to general procedure using diphenylsilane (0.69 g, 3.72 mmol) and (R)-(2- amino-2-phenylethyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.31 (243 mg, 0.53 mmol).

Purified by flash chromatography on silica gel (MeOH /CH2Cl2, 1:50 v/v) to afford 1.36 (119 mg, 51%) was isolated as a slightly yellow solid.

1 H NMR (300 MHz, CDCl3) δ 7 63 – 7.55 (m, 4H), 7.55 – 7.44 (m, 4H), 7.41 – 7.16 (m, 5H), 13 4.03 (m, 1H), 2.67 – 2.41 (m, 2H), 1.82 (s, 2H). C NMR (100 MHz, CDCl3) δ 133 31 (d J = 19.6 Hz), 132.81 (d, J = 18.9 Hz), 128.68 (s), 127.53(s), 126.05(s), 125.32 (m), 53.87 (d, J = 31 -1 16.5 Hz), 39.43 (d, J = 14.7 Hz). P NMR (121 MHz, CDCl3) δ -21.05. IR (neat, cm ): 2935 (w), 2870 (w), 1606 (m), 1454 (w), 1398 (m), 1321 (s), 1165 (s), 1119 (s), 1104 (s), 1059 (s), 20 1015 (s), 952 (m), 879 (m), 828 (s), 769 (m), 724 (m), 699 (s). Optical rotation: []D (c 0.8, + CHCl3) = -26.0. HRMS (DART-TOF) m/z: [M + H] calcd for C22H19F6NP 442.11593, found 442.11624.

(S)-N-(1-(bis(4-(trifluoromethyl)phenyl)phosphanyl)-3-methylbutan-2-yl)cyclohexanamine (1.38)

Cyclohexanone (46 mg, 0.47 mmol), sodium triacetoxyborohydride (125 mg, 0.59 mmol) and acetic acid (4.8 mg, 0.08 mmol) were added sequentially to a solution of (S)-(2-amino-3- methylbutyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.27 (168 mg, 0.39 mmol) in CH2Cl2

(2 mL). The reaction was stirred at room temperature for 2 h. Saturated Na2CO3 was added to the reaction. The aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over anhydrous MgSO4, concentrated and purified through flash column chromatography on

silica gel (MeOH /CH2Cl2, 1:50 v/v) to afford 1.37 as a white solid (169 mg, 82%). 1.37 was reduced with diphenylsilane (0.41 g, 2.23 mmol) using the general procedure to afford 1.38 (116 mg, 75%) as a colorless oil after column (MeOH /CH2Cl2, 1:50 v/v).

1 H NMR (400 MHz, CDCl3) δ 7 65 – 7.54 (m, 6H), 7.54 – 7.47 (m, 2H), 2.63 – 2.48 (m, 1H), 2.35 (tt, J = 10.1, 3.3 Hz, 1H), 2.25 (ddd, J = 13.8, 4.7, 2.0 Hz, 1H), 2.03 (ddd, J = 14.0, 8.6, 1.9 Hz, 1H), 1.99 – 1.89 (m, 1H), 1.70 – 1.58 (m, 4H), 1.59 – 1.44 (m, 1H), 1.22 – 1.04 (m, 3H), 1.04 – 0.90 (m, 2H), 0.89 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz,

CDCl3) δ 144 39 (d = 16 6 H ) 143 24 (d = 16 9 H ) 133 44 (d = 19 4 H ) 132 79 (d = 18.4 Hz), 131.25 (d, J = 42.9 Hz), 130.98 (d, J = 32.4 Hz), 130.55 (d, J = 32.5 Hz), 130.28 (d, J = 43.0 Hz), 125.79 – 124.60 (m), 56.42 (d, J = 12.8 Hz), 53.84, 34.31, 33.64, 30.80 (d, J = 13.0 Hz), 30.54 (d, J = 7.2 Hz), 26.07, 24.99 (d, J = 4.8 Hz), 18.41, 16.95. 31P NMR (162 MHz,

CDCl3) δ -20.14. tert-Butyl ((1R,2R)-2-bromo-1,2-diphenylethyl)carbamate (1.40)

Method A.

Tetra-n-butylammonium bromide (129 mg, 0.4 mmol) was added to a solution of tert-butyl (4R,5S)-4,5-diphenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 1.39 (75 mg, 0.2 mmol) in

THF (1.5 mL). The reaction was stirred at room temperature for 10 h. 2N H2SO4 (1 mL) was added to the solution and stirred for 20 min. Extraction with diethyl ether followed by purification by column chromatography (Hexanes /EtOAc, 9:1 v/v) afforded 1.40 (22 mg, 30%) as a white solid.

Method B.

18-Crown-6 (590 mg, 2.23 mmol) was added to a suspension of potassium bromide (664 mg, 5.58 mmol) and tert-butyl (4R,5S)-4,5-diphenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 1.39 (419 mg, 1.12 mmol) in THF (6 mL). The reaction was stirred at 60 °C for 5 h. Water was added to the reaction and the aqueous layer was extracted with diethyl ether. The combined

organic layer was dried over anhydrous MgSO4, concentrated in vacuo to afford 1.40 (289 mg, 70%) as a white solid. The product was used in the next step without purification.

1 H NMR (400 MHz, CDCl3) δ 7 42 – 7.34 (m, 2H), 7.33 – 7.24 (m, 6H), 7.24 – 7.18 (m, 2H), 13 5.54 (d, J = 8.6 Hz, 1H), 5.24 (br, 2H), 1.43 (s, 9H). C NMR (100 MHz, CDCl3) δ 154 97 138.89, 128.79, 128.50, 128.42, 128.35, 128.28, 128.13, 127.70, 126.92, 80.05, 60.24, 28.35. + HRMS (ESI-TOF) m/z: [M + Na] calcd for C19H22BrNNaO2 398.0726, found 398.0722.

((1S,2R)-2-Amino-1,2-diphenylethyl)bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.41)

Bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.21 (253 mg, 0.75 mmol) was added to a solution of sodium tert-butoxide (72 mg, 0.75 mmol) in degassed THF (5 mL) under inert atmosphere. The mixture was stirred for 5 min. tert-Butyl ((1R,2R)-2-bromo-1,2- diphenylethyl)carbamate 1.40 solid (281 mg, 0.75 mmol) was added and the reaction mixture was stirred at 60 °C for 3 h. The reaction was quenched with 2N H2SO4 (5 mL) at room temperature and the mixture was stirred for another 20 min. The aqueous layer was extracted with diethyl ether. The combined organic layer was dried over anhydrous MgSO4, concentrated in vacuo to afford a white solid (460 mg). Trifluoroacetic acid (1.48 mL, 19.4 mmol) was added to a solution of the crude product in dry CH2Cl2 (10 mL) at 0 °C . The reaction was allowed to warm up and stirred at room temperature for 3 h. Saturated Na2CO3 was added dropwise to the solution at 0 °C . Extraction with CH2Cl2 followed by purification by flash chromatography on silica gel (MeOH /CH2Cl2, 1:40 v/v) afford the final product 1.41 (140 mg, 35%) as a white solid.

1 H NMR (300 MHz, CDCl3) δ 7 81 (dd J = 10.6, 8.1 Hz, 2H), 7.63 – 7.51 (m, 4H), 7.42 (dd, J = 8.4, 2.5 Hz, 2H), 7.38 – 7.30 (m, 2H), 7.17 (dd, J = 4.9, 1.9 Hz, 3H), 7.12 – 7.06 (m, 2H), 7.02 (m, 3H), 4.85 (t, J = 6.6 Hz, 1H), 3.78 (t, J = 6.4 Hz, 1H), 1.71 (s, 2H). 13C NMR (100 MHz,

CDCl3) δ 141 86 (d J = 6.9 Hz), 137.14 (d, J = 22.2 Hz), 136.20 (d, J = 18.3 Hz), 133.57 –

132.45 (m), 131.15 (d, J = 9.0 Hz), 130.94 (d, J = 8.8 Hz), 130.66 (d, J = 7.0 Hz), 128.53 (d, J = 1.3 Hz), 128.12 , 127.82 , 127.75 (d, J = 1.9 Hz), 127.41 , 125.47 – 125.11 (m), 125.10 – 124.70 31 -1 (m), 56.16 , 54.46 (d, J = 69.2 Hz). P NMR (121 MHz, CDCl3) δ 29 26 IR (neat, cm ): 3065 (w), 3025 (w), 1401 (m), 1321 (s), 1169 (s), 1123 (s), 1062 (s), 1369 (w), 1018 (m), 837 (m), 791 20 (m), 756 (m), 710 (s), 670 (s). Optical rotation: []D (c 0.79, CHCl3) = +13.9. HRMS (ESI- + TOF) m/z: [M + H] calcd for C28H23F6NOP 534.1416, found 534.1420.

(1R,2S)-1-((tert-Butoxycarbonyl)amino)-indan-2-yl trifluoromethanesulfonate (1.44)

A solution of (Boc)2O (321 mg, 1.47 mmol) in THF (2 mL) was added to a mixture of (1R,2S)- (+)-cis-1-amino-2-indanol 1.42 (200 mg, 1.34 mmol) and sodium carbonate (0.31 g, 2.9 mmol) in THF/H2O (1/1, 4 mL) at 0 ºC. The mixture was stirred at room temperature for 3 h. Water was added to the mixture and was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated to afford the crude product in quantitative yield as a white solid, which was used in the next step without purification. Trifluoromethanesulfonic anhydride (56 mg, 0.2 mmol) was added dropwise to a solution of pyridine (19 mg, 0.24 mmol) and N-Boc protected (1R,2S)-(+)-cis-1-amino-2-indanol (50 mg,

0.2 mmol) in dry CH2Cl2 (1 mL) at –40 ºC. The reaction was stirred at –40 ºC for 1 h. Saturated

NH4Cl was added to quench the reaction. The aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over anhydrous MgSO4, and concentrated to afford the product 1.44 (67mg, 89%) as a yellow or orange solid.

1 H NMR (300 MHz, CDCl3) δ 7 31 (m 4H) 5 67 (br s 1H) 5 46 (dd J = 9.3, 4.5 Hz, 1H), 5.04 19 (d, J = 9.3 Hz, 1H), 3.45 – 3.14 (m, 2H), 1.51 (s, 9H). F NMR (282 MHz, CDCl3) δ -75.13.

((1R,2R)-1-Amino-indan-2-yl)bis(4-(trifluoromethyl)phenyl)phosphine oxide (1.45)

Bis(4-(trifluoromethyl)phenyl)phosphine oxide 1.21 (494 mg, 1.46 mmol) was added to a solution of sodium tert-butoxide (140 mg, 1.46 mmol) in degassed THF (8 mL) under inert atmosphere. The mixture was stirred for 5 min. (1R,2S)-1-((tert-Butoxycarbonyl)amino)-indan- 2-yl trifluoromethanesulfonate 1.44 solid (556 mg, 1.46 mmol) was added and the reaction mixture was stirred at 60 ºC for 3 h. The reaction was quenched with 2N H2SO4 (8 mL) at room temperature and the mixture was stirred for another 10 min. Extraction with diethyl ether followed by purification by flash chromatography on silica gel (EtOAc /CH2Cl2, 1:9 v/v) afford the final product 1.45 (216 mg, 26%) as a white solid.

1 H NMR (300 MHz, CDCl3) δ 7 82 (t J = 9.1 Hz, 2H), 7.76 – 7.64 (m, 4H), 7.61 (dd, J = 8.5, 2.7 Hz, 2H), 7.30 – 7.20 (m, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.07 (t, J = 8.5 Hz, 2H), 5.84 (d, J = 6.2 Hz, 1H), 3.04 – 2.68 (m, 3H), 2.07 (dt, J = 17.4, 9.0 Hz, 1H), 1.55 – 1.39 (m, 2H), 1.25 (s, 31 + 9H). P NMR (121 MHz, CDCl3) δ 32 83 HRMS (ESI-TOF) m/z: [M + H] calcd for

C28H27F6NO3P 570.1627, found 570.1614.

(R)-N-(2-((tert-Butyldimethylsilyl)oxy)-1-phenylethyl)-1,1,1-trifluoromethanesulfonamide (1.49)

To a stirred solution of the (R)-2-amino-2-phenylethan-1-ol (685 mg, 5 mmol) in CH2Cl2 (10 mL) was added triethylamine (556 mg, 5.5 mmol) at -78 °C under inert atmosphere. After stirring for 10 min at -78 °C, trifluoromethanesulfonic anhydride (1.41 g, 5 mmol) was added dropwise and the mixture was stirred for 1 h at that temperature before being quenched by water (20 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined

organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated to give the trifluoromethanesulfonamide without purification.

To a 50 mL round bottle was added the crude product from the previous step, tert- butyldimethylsilyl chloride (825 mg, 5.5 mmol), DMAP (60 mg, 0.5 mmol) and CH2Cl2 (12 mL).

The mixture was cooled to 0 °C and Et3N (560 mg, 5.5 mmol) was added dropwise. The solution was warmed to room temperature and stirred for 12 h. Then the reaction was quenched with water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (EtOAc/hexanes, 1:20 v/v) to afford 1.49 (1.19 g, 62% over 2 steps) as a colorless oil.

1 H NMR (300 MHz, CDCl3) δ 7 43 – 7.27 (m, 5H), 5.91 (d, J = 6.5 Hz, 1H), 4.72 (m, 1H), 3.97 (dd, J = 10.4, 4.2 Hz, 1H), 3.79 (dd, J = 10.4, 4.7 Hz, 1H), 0.86 (s, 9H), -0.03 (s, 3H), -0.04 (s, 3H).

Benzoyl-D-leucine (1.51)

Benzoyl chloride (281 mg, 2 mmol) was added dropwise to a suspension of D-leucine (262 mg, 2 mmol) in aqueous 2N NaOH (5 mL) at 0 °C . The reaction was stirred at room temperature for 3h. Then the reaction was acidified with 1N HCl until pH<2. Extraction with EtOAc followed by column chromatography on silica gel (MeOH/ CH2Cl2, 1:50 v/v) afforded product 1. 51 (176 mg, 75%) as a white solid.

1 H NMR (399 MHz, CDCl3) δ 10 79 (br s, 1H), 7.77 (d, J = 7.3 Hz, 2H), 7.48 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 6.88 (d, J = 8.0 Hz, 1H), 4.82 (td, J = 8.1, 4.2 Hz, 1H), 2.02 – 1.57 (m, 2H), 0.96 (d, J = 2.1 Hz, 3H), 0.95 (d, J = 2.2 Hz, 3H).

4.2 1H NMR, 13C NMR and 31P NMR Spectra

Chapter 2

Synthesis of Bifunctional Thiourea-Phosphine Organocatalysts and Their Applications in the Asymmetric Morita-Baylis-Hillman (MBH) Reaction

1 Introduction

1.1 Mechanism of the Morita-Baylis-Hillman (MBH) Reaction

The Morita-Baylis-Hillman (MBH) reaction is a carbon-carbon bond forming reaction between an aldehyde and an activated alkene catalyzed by tertiary amines or phosphines.39 If an activated imine is used instead of an aldehyde, the reaction is commonly referred to as the aza-Morita- Baylis-Hillman (aza-MBH) reaction (Scheme 47).

Scheme 47. The Morita-Baylis-Hillman reaction

The mechanism of a tertiary amine-catalyzed MBH reaction is presented in Scheme 48.40 The conjugate addition of tertiary amine A to the Michael acceptor generates the zwitterionic

39 a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815. b) Morita, K. Japan Patent, 6803364, 1968. b) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972.

40 Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed. 1983, 22, 795.

84 ammonium-enolate intermediate B, which then attacks the incoming aldehyde and forms intermediate C. Intramolecular proton transfer and subsequent elimination affords the product and regenerates the tertiary amine catalyst A.

Scheme 48. Mechanism of MBH reaction proposed in 1980s

The aldol addition step was proposed to be the rate-determining step by Hill and Issac. They observed that the rate of reaction was first order in acetaldehyde, acrylonitrile and DABCO, and the kinetic isotope effect (KIE) at the -position of the acrylonitrile was low (Scheme 49).41

Scheme 49. Kinetic study of MBH reaction by Hill and Issac

However, this theory has been challenged by McQuade et al. and Aggarwal et al., who proposed that the proton transfer step is rate limiting based on both kinetic and theoretical studies.

41 J. S. Hill, N. S. Isaacs, J. Phys. Org. Chem. 1990, 3, 285288.

McQuade observed a large normal KIE for the -position of methyl acrylate and a large inverse KIE for the aldehyde proton (Scheme 50). In addition, the reaction was found to be second-order in aldehyde and first-order in DABCO and acrylate in all tested solvents (DMSO, DMF, MeCN, 42 THF, CHCl3).

Scheme 50. Kinetic study performed by McQuade et al.

McQuade therefore proposed that the mechanism involves the formation of a hemiacetal adduct with a second equivalent of aldehyde and the -proton is abstracted in the rate determining step via a six-membered transition state (Scheme 51).40

42 a) Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147150. b) Price, K. E.; Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org. Chem. 2005, 70, 39803987.

Scheme 51. Mechanism of MBH reaction revised by McQuade and Aggarwal

Aggarwal et al. suggested that protic additives can act as proton shuffles to accelerate the - deprotonation (Scheme 51).43 The proton transfer step is rate limiting only at the beginning of the reaction (<20% conversion). Once the allylic alcohol product, which can act as a proton shuffle, has built up to a certain extent, the aldol addition step becomes the rate-determining step. They observed that the normal acrylate is consumed faster than the -deuterated acrylate in up to 20% conversion.41a In a subsequent computational study, Aggarwal and Harvey confirmed that under aprotic conditions, the formation of hemiacetal and the proton transfer via a cyclic transition state proposed by McQuade is the most likely operating mechanism. In the presence of methanol however, a slightly lower energy pathway in which the alcohol serves as a shuttle to transfer the proton from carbon to oxygen was found.41b Most recently, Singleton refuted the proton-shuttle mechanism and questioned the usefulness of computational study in predicting the thermodynamics and kinetics of MBH reactions. A two-step acid-base mechanism involving proton transfer to and from protic solvent was fully supported by their experiments. Their study also suggested the involvement of competitive rate-limiting steps in the methanol mediated

43 a) Aggarwal, V. K.; Fulford, S. Y.; Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2005, 44, 17061708. b) Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2007, 129, 1551315525.

MBH reactions. The proton transfer of the elimination step was found to be rate-limiting at 25 °C, while the aldol addition became the primary rate-limiting step at low temperatures.44

1.2 The Asymmetric Morita-Baylis-Hillman (MBH) Reaction

Since the seminal discovery of a highly enantioselective MBH reaction using a bifunctional catalyst derived from quinidine in 1999, several acid-base cocatalysts and bifunctional catalyst systems have been developed to improve the efficiency and expand the scope of the initial reaction. In the following sections, progress in the asymmetric MBH and aza-MBH reactions will be presented separately for clarity purposes, although there is considerable overlap between research in both fields, as the catalyst systems initially developed for MBH reaction often found successful application later in the aza-MBH reaction and vice versa. Each catalyst system will be presented in the chronological order of its discovery.

In 1999, Hatakeyama et al. discovered that a hydroxylated chiral amine, -isocupreidine (ICD) 2.1, confered considerable rate acceleration and asymmetric induction in the MBH reaction. Excellent enantioselectivities were achieved using hexafluoroisopropyl acrylate with several aromatic and aliphatic aldehydes despite modest yields (Scheme 52).45 The phenolic hydroxyl group was believed to stabilize oxyanion intermediate through hydrogen bonding, which not only accelerates the aldol reaction, but also creates an asymmetric environment together with the chiral amine scaffold to enable enantioseletive addition to the aldehyde.

44 Plata, R. E.; Singleton, D. A. J. Am. Chem. Soc. 2015, 137, 3811−3826

45 Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 1021910220.

Scheme 52. Asymmetric MBH reaction using a quinidine derivative as a bifunctional catalyst

Guided by this principle, Wang and coworkers designed the binaphthyl thiourea-tertiary amine catalyst 2.2 that is effective for the MBH reaction of cyclohexenone and aliphatic aldehydes. Lower yields and enantioselectivities were obtained when aromatic aldehydes were used, however (Scheme 53).46

Scheme 53. Asymmetric MBH reaction using quinidine binaphthyl thiourea-tertiary amine 2.2

Another thiourea-phosphine catalyst 2.3 bearing a 1,2-cyclohexane backbone developed by Wu et al. performed well with methyl vinyl ketone as the activated alkene. Considerable rate acceleration was achieved with 2.3, where most reactions were completed within one hour (Scheme 54).47

46 Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 42934296.

47 Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y. J.; Wu, X. Y. Tetrahedron Lett. 2008, 49, 62626264.

Scheme 54. Asymmetric MBH reaction using cyclohexyl thiourea-phosphine 2.3

Finally, a class of threonine derived thiourea-phosphine catalysts reported by Lu et al. expanded the substrate scope to include simple acrylates. Excellent yields and very good ee’s were achieved in the reactions of acrylates with electron-deficient aromatic aldehydes. The use of benzaldehyde required longer reaction time and resulted in a lower yield without much erosion of enantioselectivity (Scheme 55).48

Scheme 55. Asymmetric MBH reaction using threonine derived thiourea-phosphine 2.4

48 Han, X.; Wang, Y.; Zhong, F.; Lu, Y. Org. Biomol. Chem. 2011, 9, 67346740.

Parallel to the research in bifunctional catalysis, the development of acid-base cocatalysis also led to several breakthroughs in asymmetric MBH reaction.49 Schaus pioneered the use of a BINOL-derived chiral Brønsted acid 2.5 as the catalyst along with triethylphosphine as the nucleophilic promoter for MBH reaction of cyclohexenone with aldehydes. Excellent yields and enantioselectivities were achieved only for aliphatic aldehydes.47a A complimentary cocatalyst system discovered by Connell employing u’s chiral MA catalyst 2.6 and magnesium iodide as Lewis acid exhibited high yields and enantioselectivities in reactions of cyclopentenone with aromatic aldehydes.47b Ito demonstrated for the first time that high enantioselectivities could be obtained in the reactions of cyclohexenone with both aromatic and aliphatic aldehydes using a bis-thiourea 2.7/DABCO cocatalyst system (Scheme 56).47c

49 a) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 1209412095. b) Bugarin, A.; Connell, B. T. Chem. Commun. 2010, 46, 26442646. c) Nakayama, Y.; Gotanda, G.; Ito, K. Tetrahedron Lett. 2011, 52, 62346237.

Scheme 56. Asymmetric MBH reaction using acid-base co-catalyst systems

1.3 The Asymmetric aza-Morita-Baylis-Hillman (aza-MBH) Reaction

Shi and coworkers demonstrated that quinidine derivative ICD 2.1 was effective in the asymmetric aza-MBH reaction of N-(benzylidene)-4-methylbenzenesulfonamide with methyl vinyl ketone and methyl acrylate.50 In 2008, Zhu and Masson showed that using a new variant of quinidine derivative ICD 2.8 high yields and enantioselectivities were realized for aryl and alkyl imines with naphthyl acrylate (Scheme 57).51

50 Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 45074510.

51 Abermil, N.; Masson, G.; Zhu, J. J. Am. Chem. Soc. 2008, 130, 12596–12597.

Scheme 57. Asymmetric aza-MBH reaction using quinidine derivatives

Shi reported that in the presence of a BINOL-derived phosphine catalyst 2.8, the aza-MBH reaction of N-sulfonylated imines with methyl vinyl ketone could be obtained in high yields and enantioselectivities at low temperature. Using a modified catalyst 2.9, the same reaction could be carried out at room temperature in shorter times. Although the catalyst was less effective for acrylates, high yield and enantioselectivity were achieved for acrolein.52 Sasai independently reported an equally effective BINOL-derived catalyst 2.10 containing a tertiary amine and a pyridyl group, which gave even higher yields and enantioselectivities for certain substrates (Scheme 58).53

52 Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 37903800. 53 Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680–3681.

Scheme 58. Asymmetric aza-MBH reaction using BINOL derived bifunctional catalyst

Jacobsen et al. reported that for the first time excellent enantioselectivity could be achieved with methyl acrylates using a chiral thiourea catalyst 2.11 in combination with stoichiometric amount of DABCO. However, the product yields were only modest (< 50%) (Scheme 59).54

54 Raheem, I. T.; Jacobsen, E. N. Adv. Synth. Catal. 2005, 347, 17011708.

Scheme 59. Asymmetric aza-MBH reaction using thiourea/DABCO cocatalyst system

Lu et al. discovered a threonine-derived phosphine-sulfonamide catalyst 2.12 was effective for promoting the asymmetric aza-MBH reaction of 2-naphthyl acrylate with activated imines. The desired aza-MBH adducts were obtained in high yields and with excellent enantioselectivities (Scheme 60).55

Scheme 60. Asymmetric aza-MBH reaction using phosphine-sulfonamide catalyst 2.12

55 Zhong, F.; Wang, Y.; Han, X.; Huang, K. -W.; Lu, Y. Org. Lett. 2011, 13, 13101313.

1.4 Asymmetric Transformations Related to the Morita-Baylis-Hillman (MBH) Reaction

The application of bifunctional organocatalysts is not limited to asymmetric MBH/aza-MBH reactions. Given the particular relevance of amino acid-derived phosphine catalysts to our research, a brief survey of their utility outside MBH/aza-MBH reactions is presented in the following section. The reactions listed below are related mechanistically to the MBH reaction.

Lu and coworkers prepared a series of five-membered carbocycles with a chiral quaternary centre through highly enantioselective [3+2] annulations of an allenoate and an -substituted acrylate using a novel dipeptide derived phosphine catalyst 2.13. They further demonstrated the synthetic value of the cycloaddition product by converting it in three steps into a cytotoxic agent containing a spirooxindole core (Scheme 61).56

Scheme 61. Enantioselective [3+2] annulation of allenoate with acrylate

The proposed mechanism is shown in Scheme 62. The phosphonium enolate intermediate A attacks the less hindered terminus of the activated alkene B. The catalyst 2.13 presumably positions B in a particular orientation relative to the A through favourable hydrogen-bonding

56 Han, X.; Wang, Y.; Zhong, F.; Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726–1729.

96 interactions so that enolate A preferentially adds to one face of the olefin. Subsequent proton transfer and elimination yield the product and regenerate the catalyst as in the MBH reaction.

Scheme 62. Mechanism of [3+2] annulation of allenoate with acrylate

Lu reported the first asymmetric Michael addition mediated by the chiral phosphine 2.14 (Scheme 63). They envisioned that the in situ generated phosphonium enolate A could act as a base to deprotonate the pronucleophile and form a tight ion pair between enolate nucleophile B and chiral phosphonium C. Efficient chirality transfer during the Michael addition step affords the enantio-enriched adduct D, which then abstracts a proton from the pronucleophile to generate the final product E and completes the catalytic cycle (Scheme 64).57

Scheme 63. Asymmetric Michael addition of oxindoles catalyzed by chiral phosphine

57 Zhong, F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.; Lu, Y. Angew. Chem., Int. Ed. 2013, 52, 943– 947.

Scheme 64. Mechanism of asymmetric Michael addition catalyzed by chiral phosphine

A similar idea was explored by Zhao and coworkers in the asymmetric Mannich and aza-Henry reactions. They employed catalytic amount of both the thiourea-phosphine and methyl acrylate, which combine to form a zwitterionic base in situ which then abstracts the proton from the pronucleophile. Excellent chirality transfer was achieved from the phosphonium-nucleophile ion pair to the final Mannich or aza-Henry adduct (Scheme 65).58

Scheme 65. Asymmetric Michael addition reaction and aza-Henry reaction catalyzed by chiral phosphines

58 Wang, H.-Y. ; Zhang, K.; Zheng, C.-W.; Chai, Z.; Cao, D.-D.; Zhang, J.-X.; Zhao, G. Angew. Chem. Int. Ed., 2015, 54, 1775–1779.

2 Objectives

Amino acid-derived bifunctional phosphine-thiourea catalysts were found to be very efficient in promoting asymmetric MBH reaction of acrylates with aromatic aldehydes. Valine-based catalyst 2.17 displayed high reactivity and enantioselectivity, although the best catalyst was found to be the threonine-derived 2.4 (Scheme 66).43

Scheme 66. Asymmetric MBH reaction catalyzed by amino acid based thiourea-phosphines

So far, the refinement of these catalysts has been limited to modification of the carbon backbone as well as the thiourea component. We were interested to investigate whether tuning the electronic property of the phosphine moiety could impart any improvement on the reactivity and enantioselectivity of the catalyst. Thus, a small library of ligands analogous to 2.17 with different diaryl substituents on the phosphorus atom were prepared and tested in the asymmetric MBH reaction.

3 Results and Discussion

Previously prepared P,N-ligands were coupled with 4-nitrophenyl isothiocyanate to afford thiourea-phosphine catalysts 2.172.20 in good yields (Table 6).

Table 6. Scope for thiourea-phosphine catalysts

These bifunctional organocatalysts were tested in the MBH reaction of 4-nitrobenzaldehyde with methyl acrylate. Unfortunately, no improvement of enantioselectivity was achieved by variation of P-aryl substituent in these thiourea-phosphines. Electron-rich catalyst 2.18 gave an identical ee as the unmodified catalyst 2.17. The use of another electron-rich catalyst 2.19 led to both lower yield and ee. Electron deficient catalyst 2.20 was unable to promote the reaction, presumably due to the diminished nucleophilicity of the phosphine (Table 7).

Table 7. Screening of bifunctional catalysts in the MBH reaction

100

Around the same time, a novel P-stereogenic thiourea-phosphine catalyst 2.21 made in our lab gave an improved enantioselectivity of 86% ee (Scheme 67).24 Encouraged by this result, we decided to make another P-chiral catalyst 2.29, by replacing one of the aryl groups on the phosphorus atom with a linear alkyl chain. As a result, the steric properties of the two substituents would be further differentiated, which might impose higher level of enantio- discrimination in the reaction. In addition, the aliphatic substituent should increase the nucleophilicity of the catalyst, which can potentially promote reactions of less reactive substrates that are otherwise sluggish with diarylphosphino-thiourea catalysts. Of course, we recognized the synthetic challenges associated with making electron-rich P-chiral phosphines, mainly due to their air sensitivity and the tendency for them to racemize at higher temperatures.

Scheme 67. P-chiral phosphino-thiourea catalysts

Addition of triethyl phosphite 2.22 to in situ generated phenyl Grignard reagent followed by hydrolysis of the resulting phosphonite intermediate under acidic conditions afforded phenyl-H- phosphinate 2.23. Treatment with n-butyllithium displaced the ethoxy group and generated the unsymmetrical secondary phosphine oxide 2.24 (Scheme 68).

Scheme 68. Synthesis of unsymmetrical secondary phosphine oxide

Ring opening of the cyclic sulfamidate with 2.24 in the presence of NaOtBu afforded a 1:1 diastereomeric mixture of the products 2.25 in modest yield (Scheme 69). Separation of the diastereomers proved to be very difficult. Using 1% THF:diethyl ether as the eluent, only a small fraction of the less polar diastereomer could be isolated in pure form. We then carried the mixture of diastereomers forward, hoping that the separation could be accomplished through

101 recrystallization of the HCl salts of 2.26. Unfortunately, several recrystallization attempts in different solvent systems only resulted in the formation of oil droplets instead of crystalline solids. The ineffective crystallization can most likely be attributed to the flexible n-butyl chain. The diastereomeric mixture of 2.26 was then reduced and protected in situ as the phosphine- borane complex 2.27. Gratifyingly, we were able to separate the diastereomers at this stage using flash column chromatography on silica gel. The less polar diastereomer 2.27a was then coupled with 4-nitrophenyl isothiocyanate to afford crystalline thiourea 2.28a. We managed to grow a single crystal of 2.28a through liquid-liquid diffusion. Diethyl ether was slowly added into a solution of 2.28a in dichloromethane, forming a bilayer solvent mixture. Slow diffusion of the two solvents induces the precipitation of the solute and an X-ray quality crystal of 2.28a was obtained after standing at room temperature for 24 hours. The relative configuration of the P- chirality centre was determined by X-ray crystallography. Interestingly, the N-H hydrogens are in a disordered conformation in the crystal structure, suggesting that the thiourea group does not contribute to the crystal packing through hydrogen bonding interactions (Figure 4).

Figure 4. X-ray crystal structure of thiourea-phosphine-borane 2.28a

Attempts to deprotect the phosphine-borane compounds 2.28a/2.28b using 2.5 equivalents of DABCO resulted in full recovery of the starting material after heating at 40 ˚C for 6 hours. Considering that both raising the temperature and prolonged heating might risk racemizing or

102 oxidizing the P-chiral phosphine product, a large excess of DABCO (30 equivalents) was used to drive the equilibrium towards DABCO-BH3 adduct in order to liberate the phosphine. The reaction went to completion after 6 hours and the crude reaction mixture was directly subjected to column chromatography to minimize exposure to air. The final product 2.29a/2.29b was isolated in 50% yield.

Scheme 69. Synthesis of P-chiral phosphine-thiourea catalysts

The two diastereomeric P-chiral catalysts 2.29a and 2.29b were then tested in the MBH reaction. To our disappointment, however, both catalysts displayed low activity along with significantly lower enantioselectivities (Table 8). These suggest that diarylphosphino-thiourea is probably optimal for this particular MBH reaction. Based on this, a P-chiral catalyst bearing a phenyl group and a 2-naphthyl group could be a promising target to make in the future.

103

Table 8. Screening of P-chiral bifunctional catalysts in the MBH reaction

Given the relative scarcity of P-chiral ligands in asymmetric catalysis, the methodology our laboratory has developed to access P-chiral aminophosphines is still of significant value. We intended to use our P-chiral aminophosphine in the modular synthesis of C2-symmetrical bisphosphine ligands by coupling two equivalents of the aminophosphine with one equivalent of a dicarboxylic acid or a diacyl chloride. The resulting Trost-type ligand could be applied to asymmetric allylic alkylation (AAA) reactions. P-chiral building block 2.27a/2.27b was coupled with isophthaloyl dichloride and the resulting phosphine-borane complex 2.30a/2.30b was successfully deprotected using HBF4•OEt2 (Scheme 70).

Scheme 70. Synthesis of P-chiral C2-symmetrical bisphosphine ligands

The final bisphosphine ligands 2.31a and 2.31b were tested in the AAA reaction of 1,3- diphenylallyl acetate with diethyl malonate. The catalysts induced good levels of

104 enantioselectivity but displayed low catalytic activity (Table 9). Nevertheless, 1,3-diphenylallyl acetate is known to be a challenging substrate for the Trost ligand 2.32, giving the alkylation product in only 9% yield with 53% ee (Scheme 71).59 The same ligand performs much better for smaller 1,3-dimethylallyl acetate and cyclic substrates. It would be interesting to test our ligands on these types of substrates.

Table 9. Screening of P-chiral C2-symmetrical bisphosphine ligand in Pd-catalyzed AAA reaction

Scheme 71. AAA reactions using Trost ligand

59 Trost, B. M.; Kruegger, A. C.; Bunt, R. C.; Zambrano, J. J. Am. Chem. Soc. 1996, 118, 6520-6521.

105

4 Conclusion and Future Work

A small library of -aminophosphines bearing different chiral carbon backbones and different diaryl substituents on the phosphine group was prepared through ring-opening of cyclic sulfamidates with secondary phosphine oxides. The electron-deficient -substituted P,N-ligands were tested in the asymmetric decarboxylative allylation reaction. Although the new ligands derived from (S)-valinol and (R)-phenylglycinol demonstrated excellent catalytic activity, they were less enantioselective than the original ligand derived from (S)-tert-valinol. Attempts to prepare ,-disubstituented P,N-ligands derived from (1S,2R)-2-amino-1,2-diphenylethanol and (1R,2S)-1-amino-2-indanol failed at the final reduction step. As for future work, it would be worthwhile to examine the use of secondary phosphine-borane and butyllithium in the opening of cyclic sulfamidates and displacement of halides or sulfonates. The deprotection of aminophosphine-borane complex can be achieved under much milder condition than the reduction of corresponding aminophosphine oxide.

A series of phosphine-thiourea bifunctional catalysts derived from -aminophosphines were prepared and applied in the asymmetric MBH reaction. Attempts to improve the enantioselectivity of the original catalyst by tuning the electronic properties of the phosphine moiety were fruitless. The P-chiral catalyst bearing a phenyl group and an n-butyl group displayed lower activity and enantioselectivity. These results suggest that electronically unmodified diarylphosphino-thiourea is probably optimal for this particular MBH reaction. A future direction will be to incorporate two sterically differentiated diaryl groups, such as one phenyl group and one 2-naphthyl group, on the phosphorous donor of the P-chiral catalyst.

The P-chiral aminophosphines were employed as building blocks in the modular synthesis of C2- symmteric bisphophine ligands. The performance of these ligands in the Pd-catalyzed AAA reaction remains to be explored for 1,3-dimethylallyl acetate and cyclic substrates. Morimoto reported the use of ligand in the Rh-catalyzed asymmetric hydrosilylation of ketones (Scheme 72).9 It would be interesting to see if our P-chiral catalyst can impart any improvement on the activity and enantioselectivity of the same reaction. Finally, P-chiral P,N-ligands could be used to construct PNP’ pincer ligands which could form active metal complexes for the asymmetric hydrogenations of ketones and imines.

106

Scheme 72. Rh-catalyzed asymmetric hydrosilylation of ketones

5 Experimental

5.1 Procedures and Compounds

General procedures for preparing thiourea-phosphines 2.17-2.20, 2.29a, 2.29b

(S)-1-(1-(Diphenylphosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea (2.17)

4-Nitrophenyl isothiocyanate (26 mg, 0.14 mmol) was added to a solution of (S)-1-

(diphenylphosphanyl)-3-methylbutan-2-amine 1.35 (35 mg, 0.13 mmol) in degassed CH2Cl2 (2 mL) under argon. The reaction was stirred at room temperature for 14 h. The reaction mixture was directly loaded onto silica gel. The eluent was degassed in advance through sparging with argon for 20 min. The crude product was purified through silica gel flash column chromatography (Hexanes/EtOAc, 5:1 v/v) under a positive pressure of argon. The final product (48 mg, 82%) was isolated as a yellow solid.

1 H NMR (300 MHz, CDCl3) δ 8 65 (br s 1H) 8 21 – 8.07 (m, 2H), 7.50 – 7.39 (m, 4H), 7.38 – 7.27 (m, 8H), 6.43 (br s, 1H), 4.61 (br s, 1H), 2.51 (m, 1H), 2.31 (m, 1H), 2.18 (m, 1H), 0.95 (s, 13 3H), 0.92 (s, 3H). C NMR (101 MHz, CDCl3) δ 179 47 144 12 143 16 133 02 132 83 132.78, 132.59, 129.14, 129.00, 128.74, 128.67, 125.42, 122.17, 58.87, 58.72, 32.08, 30.77, 31 18.59. P NMR (121 MHz, CDCl3) δ -24.40.

107

(S)-1-(1-(di-o-tolylphosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea (2.18)

Synthesized according to general procedure using 4-nitrophenyl isothiocyanate (16 mg, 0.09 mmol) and (S)-1-(di-o-tolylphosphanyl)-3-methylbutan-2-amine 1.33 (25 mg, 0.08 mmol). Purification through silica gel flash column chromatography (Hexanes/EtOAc, 5:1 v/v) afforded the product (29 mg, 73%) as a yellow solid. 1 H NMR (399 MHz, CDCl3) δ 8 50 (br s 1H) 8 21 – 8.09 (d, 2H), 7.33 (m, 4H), 7.25 – 7.06 (m, 6H), 6.32 (br s, 1H), 4.57 (s, 1H), 2.41 (s, 6H), 2.37 – 2.33 (m, 1H), 2.32 – 2.26 (m, 1H), 2.24 – 31 -1 2.15 (m, 1H), 0.95 (s, 1H), 0.93 (s, 1H). P NMR (162 MHz, CDCl3) δ -46.86. IR (neat, cm ): 2959 (w), 1595 (m), 1505 (s), 1468 (s), 1450 (m), 1422 (m), 1325 (s), 1300 (s), 1255 (s), 1174  (s), 1111 (s), 1032 (w), 909 (w), 850 (m), 746 (s), 717 (s). Optical rotation: [D (cCHCl3) = +18.3

(S)-1-(1-(bis(4-methoxyphenyl)phosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea (2.3)

Synthesized according to general procedure using 4-nitrophenyl isothiocyanate (28 mg, 0.16 mmol) and (S)-1-(bis(4-methoxyphenyl)phosphanyl)-3-methylbutan-2-amine 1.34 (53 mg, 0.16 mmol). Purification through silica gel flash column chromatography (Hexanes/EtOAc, 2:1 v/v) afforded the product (55 mg, 67%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8 45 (s 1H) 8 23 – 8.03 (m, 2H), 7.46 – 7.22 (m, 6H), 6.90 – 6.75 (m, 4H), 6.36 (s, 1H), 4.61 (s, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 2.43 (ddd, J = 14.3, 4.5, 2.4 13 Hz, 1H), 2.27 – 2.11 (m, 2H), 0.94 (d, J = 6.8 Hz, 6H). C NMR (101 MHz, CDCl3) δ 160 41 160.31 , 144.01 , 134.24 (d, J = 20.8 Hz), 133.98 (d, J = 20.6 Hz), 125.38 , 121.86 , 114.37 (d, J

108

= 7.7 Hz), 59.02 (d, J = 13.2 Hz), 55.18 , 32.08 , 30.99 , 18.70 , 18.58. 31P NMR (121 MHz, -1 cdcl3) δ -28.39. IR (neat, cm ): 3294 (w), 2959 (w), 2836 (w), 1593 (s), 1568 (m), 1496 (s), 1462 (m), 1441 (m), 1326 (s), 1300 (s), 1283 (s), 1243 (s), 1175 (s), 1109 (s), 1094 (s), 1026 (s),  909 (m), 850 (m), 823 (s), 797 (s), 724 (s). Optical rotation: [D (cCHCl3) = +31.7. + HRMS (ESI-TOF) m/z: [M + H] calcd for C26H31N3O4PS 512.1767, found 512.1775.

(S)-1-(1-(bis(4-(trifluoromethyl)phenyl)phosphanyl)-3-methylbutan-2-yl)-3-(4- nitrophenyl)thiourea (2.4)

Synthesized according to general procedure using 4-nitrophenyl isothiocyanate (24 mg, 0.13 mmol) and (S)-1-(bis(4-(trifluoromethyl)phenyl)phosphanyl)-3-methylbutan-2-amine 1.32 (50 mg, 0.12 mmol). Purification through silica gel flash column chromatography (Hexanes/EtOAc, 9:1 v/v) afforded the product (43 mg, 61%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8 20 – 8.12 (m, 2H), 8.10 (s, 1H), 7.68 – 7.61 (m, 2H), 7.57 (m, 2H), 7.52 – 7.40 (m, 6H), 3.19 (tdd, J = 9.5, 5.9, 3.4 Hz, 1H), 2.66 (ddd, J = 14.0, 9.5, 1.0 Hz, 1H), 2.47 (ddd, J = 14.0, 3.4, 1.1 Hz, 1H), 2.08 – 1.91 (m, 1H), 0.97 (d, J = 6.8 Hz, 3H), 0.92 (d, 13 J = 6.7 Hz, 3H). C NMR (100 MHz, CDCl3) δ 148 99 140 96 133 23 (d J = 10.4 Hz), 133.04 (d, J = 10.4 Hz), 128.72 , 125.33 (dd, J = 7.0, 3.6 Hz), 125.17 – 124.81 (m), 123.62 , 75.35 (d, J = 13.3 Hz), 34.30 (d, J = 9.2 Hz), 32.28 (d, J = 12.8 Hz), 19.44 , 18.56 . 31P NMR -1 (162 MHz, CDCl3) δ -19.05. IR (neat, cm ): 2963 (w), 2873 (w), 1644 (w), 1603 (m), 1522 (m), 1396 (m), 1345 (m), 1320 (s), 1163 (s), 1121 (s), 1059 (s), 1015 (s), 951 (m), 827 (s), 748 (m),  + 695 (m). Optical rotation: [D (cCHCl3) = +110.0. HRMS (ESI-TOF) m/z: [M + H] calcd for C26H25F6N3O2PS 588.1304, found 588.1294.

Butyl(phenyl)phosphine oxide (2.9)

109 n-Butyllithium (0.84 mL, 2.1 mmol) was added dropwise into a solution of ethyl phenylphosphinate 2.8 (170 mg, 1.0 mmol) in dry pentane (5 mL) at 78 ºC. The reaction was stirred at this temperature for 5 h. Saturated NH4Cl was added to quench the reaction. Extraction with CH2Cl2 followed by flash column chromatography on silica gel (CH2Cl2/MeOH, 40:1 v/v) afforded the product (109 mg, 60%) as colorless oil.

1 H NMR (400 MHz, CDCl3) δ 7 49 (m 2H) 7 26 (d J = 463.3 Hz, 1H), 7.38 – 7.22 (m, 3H), 1.78 (m, 2H), 1.47 – 1.30 (m, 2H), 1.27 – 1.07 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H). 31P NMR (162 13 MHz, CDCl3) δ 27 46 C NMR (101 MHz, CDCl3) δ 132 16 (d J = 2.9 Hz), 130.98 (d, J = 96.0 Hz), 129.63 (d, J = 10.9 Hz), 128.68 (d, J = 12.2 Hz), 29.83 (d, J = 68.0 Hz), 23.48 (d, J = 14.6 Hz), 23.31 (d, J = 3.8 Hz), 13.38.

(S)-1-(Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-amine (2.12)

Butyl(phenyl)phosphine oxide 2.9 (320 mg, 1.75 mmol) was added to a solution of potassium tert-butoxide (196 mg, 1.75 mmol) in degassed THF (8 mL) under inert atmosphere. The mixture was stirred for 5 min. tert-Butyl (S)-4-isopropyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide 1.25 solid (464 mg, 1.75 mmol) was added and the reaction mixture was stirred at 60 ºC for 3 h.

The reaction was quenched with 2N H2SO4 (8 mL) at room temperature and the mixture was stirred for another 20 min. Extraction with diethyl ether followed by purification by flash chromatography on silica gel (EtOAc /CHCl3, 1:3 v/v) afforded diastereo-mixture 2.10 (200 mg, 31%) as a white solid. Trifluoroacetic acid (1.96 g, 17.2 mmol) was added to a solution of 2.10

(244 mg, 0.66 mmol) in dry CH2Cl2 (5 mL) at 0 ºC. The reaction was allowed to warm up and stirred at room temperature for 3 h. Saturated Na2CO3 was added dropwise to the solution at 0

ºC. The aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over

MgSO4 and concentrated to afford the diastereo-mixture 2.11 (168 mg, 95%) as colorless oil.

BH3▪SMe was added to a solution of 2.11 (168 mg, 0.63 mmol) in dry THF (10 mL). The reaction was stirred at 70 ºC for 14 h. Saturated NH4Cl was added to quench the reaction.

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Extraction with CH2Cl2 followed by flash column chromatography on silica gel (CH2Cl2/MeOH, 50:1 v/v) afforded 2.12a (65 mg, 38%) and 2.12b (65 mg, 38%) as colorless oil.

(S)-1-((R)-Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-amine (2.12a)

1 H NMR (400 MHz, CDCl3) δ 7 79 (m 2H) 7 57 – 7.44 (m, 3H), 3.01 (m, 1H), 2.02 (m, 1H), 1.96 – 1.79 (m, 3H), 1.66 (m, 1H), 1.58 – 1.48 (m, 1H), 1.42 (br, 2H), 1.40 – 1.23 (m, 3H), 0.91 13 (d, J = 2.9 Hz, 3H), 0.90 (J = 2.9 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3) δ 131 96 (d J = 8.8 Hz), 131.30 (d, J = 2.5 Hz), 128.86 (d, J = 9.6 Hz), 52.53 (d, J = 0.9 Hz), 34.91 (d, J = 10.5 Hz), 31.51 (d, J = 35.0 Hz), 26.11 (d, J = 37.0 Hz), 24.88 (d, J = 1.1 Hz), 31 24.20 (d, J = 13.6 Hz), 18.45, 17.40, 13.55. P NMR (121 MHz, CDCl3) δ 12 83 (d J = 89.6 Hz).

(S)-1-((S)-Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-amine (2.12b)

1 H NMR (300 MHz, CDCl3) δ 7 73 (m 2H) 7 48 (m 3H) 2 79 (tdd J = 11.9, 5.3, 2.7 Hz, 1H), 2.28 (br, 2H), 2.08 (td, J = 14.5, 2.5 Hz, 1H), 1.90 (m, 2H), 1.84 – 1.73 (m, 1H), 1.64 – 1.43 (m, 2H), 1.41 – 1.19 (m, 3H), 0.98 – 0.80 (m, 6H), 0.76 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,

CDCl3) δ 132 06 (d J = 8.6 Hz), 131.34 (d, J = 2.5 Hz), 128.79 (d, J = 9.6 Hz), 52.28 , 34.31 , 30.95 (d, J = 35.3 Hz), 26.63 (d, J = 36.9 Hz), 24.87 (d, J = 1.2 Hz), 24.15 (d, J = 13.9 Hz), 31 18.19 , 17.27 , 13.52. P NMR (121 MHz, CDCl3) δ 13 15 (br d J = 83.1 Hz).

1-((S)-1-((R)-Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-yl)-3-(4- nitrophenyl)thiourea (2.13a)

111

Synthesized according to the general procedure using 4-nitrophenyl isothiocyanate (20 mg, 0.113 mmol) and 2.12a (30 mg, 0.113 mmol). Purification through silica gel flash column chromatography (Hexanes/EtOAc, 2:1 v/v) afforded the product (42 mg, 84%) as a yellow solid.

1 H NMR (400 MHz, CDCl3) δ 8 41 (br s 1H) 8 19 (d J = 9.0 Hz, 2H), 7.75 (m, 2H), 7.67 – 7.41 (m, 5H), 6.83 (br s, 1H), 4.71 (br s, 1H), 2.25 (m, 2H), 2.07 – 1.84 (m, 3H), 1.57 – 1.38 (m, 1H), 1.33 (q, J = 7.2 Hz, 2H), 1.20 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.84 (t, J = 7.2 Hz, 3H), 13 0.80 – 0.66 (m, 3H). C NMR (101 MHz, CDCl3) δ 179 61 144 17 131 97 (d J = 8.9 Hz), 131.73, 129.06 (d, J = 9.7 Hz), 125.08, 122.66, 57.05, 31.98, 28.20 (d, J = 33.0 Hz), 25.21 (d, J 31 = 37.5 Hz), 24.69, 24.08 (d, J = 14.0 Hz), 18.92, 18.44, 13.53. P NMR (162 MHz, CDCl3) δ 9.95.

1-((S)-1-((S)-Butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-yl)-3-(4- nitrophenyl)thiourea (2.13b)

Synthesized according to the general procedure using 4-nitrophenyl isothiocyanate (10 mg, 0.057 mmol) and 2.12b (15 mg, 0.057 mmol). Purification through silica gel flash column chromatography (Hexanes/EtOAc, 2:1 v/v) afforded the product (22 mg, 88%) as a yellow solid.

1-((S)-1-((R)-Butyl(phenyl)phosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea (2.14a)

112

Degassed toluene (0.5 mL) was added into a Schlenk tube containing 2.13a (13 mg, 0.029 mmol) and DABCO (98 mg, 0.87 mmol) under argon. The reaction was stirred at 40 ºC for 6 h. The crude mixture was directly loaded onto silica gel and was purified through flash column chromatography using degassed CH2Cl2 as eluent under a positive pressure of argon. The final product (6 mg, 50%) was isolated as a yellow solid.

1H NMR (400 MHz, Chloroform-d) δ 8 20 (m, 3H), 7.55 (m, 2H), 7.48 – 7.29 (m, 5H), 6.28 (d, J = 9.1 Hz, 1H), 4.66 (s, 1H), 2.23 – 1.91 (m, 3H), 1.88 – 1.70 (m, 2H), 1.48 – 1.29 (m, 2H), 1.11 – 0.71 (m, 9H). 13C NMR (101 MHz, Chloroform-d) δ 144 28 132 59 (d J = 19.5 Hz), 129.39 , 128.65 (d, J = 7.2 Hz), 125.56 , 122.18 , 59.03 (d, J = 14.9 Hz), 32.56 , 30.94 , 28.18 (d, J = 9.7 Hz), 27.86 (d, J = 12.9 Hz), 24.20 (d, J = 12.1 Hz), 18.53 , 13.75. 31P NMR (162 MHz, + CDCl3) δ -31.93. MS (DART-TOF) m/z: [M + H] calcd for C22H31N3O2PS 432.2, found 432.2.

1-((S)-1-((S)-Butyl(phenyl)phosphanyl)-3-methylbutan-2-yl)-3-(4-nitrophenyl)thiourea (2.14b)

Degassed toluene (0.5 mL) was added into a Schlenk tube containing 2.13b (22 mg, 0.049 mmol) and DABCO (166 mg, 1.48 mmol) under argon. The reaction was stirred at 40 ºC for 6 h. The crude mixture was directly loaded onto silica gel and was purified through flash column chromatography using degassed CH2Cl2 as eluent under a positive pressure of argon. The final product (10 mg, 50%) was isolated as a yellow solid.

1H NMR (400 MHz, Chloroform-d) δ 8 25 (s 2H) 8 24 – 8.15 (m, 2H), 7.53 (m, 3H), 7.44 – 7.27 (m, 4H), 6.19 (s, 1H), 4.41 (s, 1H), 2.29 – 2.06 (m, 2H), 1.88 (ddd, J = 14.4, 8.1, 3.6 Hz, 1H), 1.74 (m, 2H), 1.47 – 1.21 (m, 4H), 0.96 (d, J = 6.7, 3H), 0.92 – 0.78 (m, 6H). 13C NMR (101 MHz, Chloroform-d) δ 144 18 132 68 (d J = 19.6 Hz), 129.39, 129.05 (d, J = 1.9 Hz), 128.94 , 128.62 (d, J = 7.4 Hz), 125.49 , 122.12 , 58.93 , 31.62 , 30.58 , 28.22 (d, J = 9.3 Hz), 31 28.14 (d, J = 13.9 Hz), 24.24 (d, J = 12.5 Hz), 18.74, 18.61, 13.77. P NMR (162 MHz, CDCl3)

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+ δ -34.01. HRMS (DART-TOF) m/z: [M + H] calcd for C22H31N3O2PS 432.18852, found 432.18746.

N1,N3-Bis((S)-1-((R)-butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-yl)isophthalamide (2.15a)

Et3N (9.6 mg, 0.095 mmol) was added into a solution of 2.12a (24 mg, 0.090 mmol) and

Isophthaloyl dichloride (9 mg, 0.045 mmol) in dry CH2Cl2. The reaction was stirred at room temperature for 14 h. Then the reaction mixture was directly loaded onto silica gel without workup. Purification through flash column chromatography on silica gel (MeOH/CH2Cl2, 1:50 v/v) afforded the final product 2.15a (22 mg, 74%) was isolated as a white solid.

1 H NMR (400 MHz, CDCl3) δ 8 00 (t J = 1.8 Hz, 1H), 7.85 (dd, J = 7.7, 1.7 Hz, 2H), 7.78 (m, 4H), 7.48 – 7.35 (m, 7H), 6.54 (d, J = 8.9 Hz, 2H), 4.35 – 4.12 (m, 2H), 2.42 (ddd, J = 15.0, 11.2, 8.8 Hz, 2H), 2.19 – 2.07 (m, 2H), 2.06 – 1.83 (m, 6H), 1.55 – 1.41 (m, 2H), 1.35 – 1.16 (m, 6H), 0.91 (d, J = 6.7 Hz, 6H), 0.81 (t, J = 7.2 Hz, 6H), 0.77 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz,

CDCl3) δ 165 56 134 00 132 08 (d J = 8.8 Hz), 131.41 (d, J = 2.5 Hz), 130.45 , 128.90 (d, J = 9.6 Hz), 128.43 (d, J = 52.1 Hz), 124.71 , 52.06 (d, J = 2.4 Hz), 32.64 (d, J = 7.2 Hz), 28.99 (d, J = 33.7 Hz), 25.32 (d, J = 37.3 Hz), 24.76, 24.13 (d, J = 14.0 Hz), 18.83, 18.62, 13.50. 31P NMR + (162 MHz, CDCl3) δ 11 30 HRMS (DART-TOF) m/z: [M – H2 + H] calcd for C38H59B2N2O2P2 659.42379, found 659.42462.

N1,N3-Bis((S)-1-((S)-butyl(phenyl)phosphanyl-borane)-3-methylbutan-2-yl)isophthalamide (2.15b)

114

Et3N (6 mg, 0.06 mmol) was added into a solution of 2.12b (15 mg, 0.056 mmol) and

Isophthaloyl dichloride (6 mg, 0.028 mmol) in dry CH2Cl2. The reaction was stirred at room temperature for 14 h. Then the reaction mixture was directly loaded onto silica gel without workup. Purification through flash column chromatography on silica gel (MeOH/CH2Cl2, 1:50 v/v) afforded the final product 2.15b (13 mg, 72%) was isolated as a white solid.

1 H NMR (400 MHz, CDCl3) δ 7 87 (m 2H) 7 85 (d J = 1.7 Hz, 1H), 7.65 (m, 4H), 7.47 – 7.41 (m, 2H), 7.40 – 7.30 (m, 5H), 6.30 (d, J = 8.5 Hz, 2H), 4.03 (m, 2H), 2.37 – 2.17 (m, 4H), 2.09 (m, 2H), 2.03 – 1.91 (m, 4H), 1.61 – 1.47 (m, 2H), 1.46 – 1.28 (m, 6H), 0.95 (d, J = 6.8 Hz, 6H), 13 0.93 – 0.87 (m, 12H). C NMR (101 MHz, CDCl3) δ 165 52 133 85, 131.89 (d, J = 8.8 Hz), 131.40 (d, J = 2.5 Hz), 130.56, 128.87 (d, J = 9.9 Hz), 127.40 (d, J = 52.4 Hz), 124.91, 51.24 (d, J = 3.3 Hz), 32.86 (d, J = 7.6 Hz), 27.83 (d, J = 34.1 Hz), 25.54 (d, J = 37.1 Hz), 24.82 , 24.25 (d, 31 J = 13.9 Hz), 18.49, 18.15, 13.58. P NMR (162 MHz, CDCl3) δ 11 39 HRMS (DART-TOF) + m/z: [M – H2 + H] calcd for C38H59B2N2O2P2 659.42379, found 659.42585.

N1,N3-Bis((S)-1-((R)-butyl(phenyl)phosphanyl)-3-methylbutan-2-yl)isophthalamide (2.16a)

HBF4• Et2 (24 mg, 0.15 mmol) was added into a solution of 2.15a (10 mg, 0.015 mmol) in degassed CH2Cl2. The reaction was stirred at room temperature for 14 h. The reaction was quenched with degassed sodium bicarbonate. The aqueous layer was extracted with CH2Cl2. The combined organic layer was directly loaded onto silica gel. Purification through flash column

115

chromatography (MeOH/CH2Cl2, 1:50 v/v) afforded the final product 2.16a (7.5 mg, 80%) as a white solid.

1 H NMR (400 MHz, CDCl3) δ 7 94 – 7.90 (m, 1H), 7.62 (dd, J = 7.7, 1.8 Hz, 2H), 7.58 – 7.50 (m, 4H), 7.35 (t, J = 7.8 Hz, 1H), 7.32 – 7.27 (m, 6H), 5.94 (d, J = 9.1 Hz, 2H), 4.21 (m, 2H), 2.03 – 1.93 (m, 6H), 1.78 – 1.67 (m, 4H), 1.41 – 1.16 (m, 8H), 0.96 (d, J = 6.8 Hz, 6H), 0.89 (d, 13 J = 6.8 Hz, 6H), 0.82 (t, J = 7.1 Hz, 6H). C NMR (101 MHz, CDCl3) δ 165 83 138 60 (d J = 15.0 Hz), 134.88 , 132.65 (d, J = 20.0 Hz), 129.55 , 129.08 , 128.59 , 128.58 , 128.52 , 53.30 (d, J = 12.3 Hz), 32.90 (d, J = 7.4 Hz), 31.82 (d, J = 14.4 Hz), 28.28 (d, J = 10.9 Hz), 27.95 (d, J = 31 13.4 Hz), 24.24 (d, J = 12.0 Hz), 18.86, 18.05, 13.75. P NMR (162 MHz, CDCl3) δ -31.26. + HRMS (DART-TOF) m/z: [M + H] calcd for C38H55N2O2P2 633.37388, found 633.37428.

N1,N3-Bis((S)-1-((S)-butyl(phenyl)phosphanyl)-3-methylbutan-2-yl)isophthalamide (2.16b)

HBF4• Et2 (54 mg, 0.33 mmol) was added into a solution of 2.15b (22 mg, 0.033 mmol) in degassed CH2Cl2. The reaction was stirred at room temperature for 14 h. The reaction was quenched with degassed sodium bicarbonate. The aqueous layer was extracted with CH2Cl2. The combined organic layer was directly loaded onto silica gel. Purification through flash column chromatography (MeOH/CH2Cl2, 1:50 v/v) afforded the final product 2.16b (18 mg, 86%) as a white solid.

1H NMR (300 MHz, Chloroform-d) δ 7 93 (m 1H) 7 64 (dd J = 7.7, 1.8 Hz, 2H), 7.54 (td, J = 7.5, 2.1 Hz, 4H), 7.38 (t, J = 7.7 Hz, 1H), 7.34 – 7.27 (m, 6H), 5.95 (d, J = 9.0 Hz, 2H), 4.23 – 3.85 (m, 2H), 2.19 – 1.97 (m, 4H), 1.90 (m, 2H), 1.82 – 1.63 (m, 4H), 1.46 – 1.22 (m, 8H), 0.96 (d, J = 6.7 Hz, 6H), 0.92 – 0.82 (m, 12H). 13C NMR (101 MHz, Chloroform-d) δ 165 85 138.06 (d, J = 15.1 Hz), 134.99 , 132.68 (d, J = 19.7 Hz), 129.34 (d, J = 37.0 Hz), 128.58 , 128.58 (d, J = 7.2 Hz), 125.16 , 52.98 (d, J = 10.6 Hz), 32.33 (d, J = 7.3 Hz), 32.09 (d, J = 14.7 Hz), 28.22 (d, J = 14.6 Hz), 28.07 (d, J = 9.9 Hz), 24.30 (d, J = 12.4 Hz), 19.06, 18.17, 13.77.

116

31 + P NMR (121 MHz, cdcl3) δ -33.16. HRMS (DART-TOF) m/z: [M + H] calcd for

C38H55N2O2P2 633.37388, found 633.37324.

5.2 1H NMR, 13C NMR and 31P NMR spectra

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

5.3 X-Ray Crystallography Data

Table 1. Crystal data and structure refinement for d15113.

Identification code d15113

Empirical formula C22 H33 B N3 O2 P S

Formula weight 445.35

Temperature 147(2) K

Wavelength 1.54178 Å

Crystal system Orthorhombic

Space group P21212

140

Unit cell dimensions a = 15.0286(5) Å = 90°.

b = 22.2881(8) Å = 90°.

c = 7.3704(3) Å  = 90°.

Volume 2468.78(16) Å3

Z 4

Density (calculated) 1.198 Mg/m3

Absorption coefficient 1.947 mm-1

F(000) 952

Crystal size 0.200 x 0.200 x 0.100 mm3

Theta range for data collection 3.547 to 67.154°.

Index ranges -17<=h<=17, -26<=k<=26, -8<=l<=8

Reflections collected 42609

Independent reflections 4363 [R(int) = 0.0344]

Completeness to theta = 67.154° 99.2 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.7529 and 0.6642

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 4363 / 5 / 310

Goodness-of-fit on F2 1.049

Final R indices [I>2sigma(I)] R1 = 0.0252, wR2 = 0.0666

R indices (all data) R1 = 0.0257, wR2 = 0.0670

Absolute structure parameter 0.011(16)

141

Extinction coefficient n/a

Largest diff. peak and hole 0.317 and -0.196 e.Å-3

142

Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for d15113. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

______

x y z U(eq)

______

S(1) 5812(1) 2783(1) 1363(1) 25(1)

P(1) 8737(1) 2918(1) 3102(1) 22(1)

O(1) 3852(1) 4802(1) -6095(3) 58(1)

O(2) 3358(1) 4969(1) -3376(3) 60(1)

N(1) 6521(1) 3192(1) -1750(2) 25(1)

N(2) 7361(1) 2525(1) -238(2) 23(1)

N(3) 3865(1) 4720(1) -4450(4) 42(1)

C(1) 6595(1) 2839(1) -253(3) 20(1)

C(2) 7655(1) 2097(1) 1136(3) 24(1)

C(3) 7584(2) 1444(1) 437(3) 32(1)

C(4) 8145(2) 1330(1) -1238(4) 42(1)

C(5) 6613(2) 1273(1) 99(4) 46(1)

C(6) 8612(1) 2244(1) 1720(3) 25(1)

C(7) 9928(1) 2972(1) 3506(3) 29(1)

C(8) 10159(2) 3601(2) 4200(6) 35(1)

C(9) 11110(2) 3633(2) 4881(5) 44(1)

C(10) 11379(3) 4280(2) 5324(8) 71(2)

143

C(7A) 9928(1) 2972(1) 3506(3) 29(1)

C(8A) 10326(6) 3459(3) 4719(10) 30(2)

C(9A) 10178(5) 4098(3) 4092(9) 35(2)

C(10A) 10747(6) 4546(3) 5160(12) 52(2)

C(11) 8460(1) 3552(1) 1680(3) 25(1)

C(12) 8924(2) 3650(1) 69(3) 33(1)

C(13) 8721(2) 4144(1) -988(3) 43(1)

C(14) 8060(2) 4535(1) -471(4) 47(1)

C(15) 7598(2) 4439(1) 1116(4) 46(1)

C(16) 7796(2) 3950(1) 2202(3) 34(1)

C(17) 5832(1) 3569(1) -2331(3) 22(1)

C(18) 5331(1) 3926(1) -1161(3) 25(1)

C(19) 4674(1) 4296(1) -1860(3) 29(1)

C(20) 4540(1) 4314(1) -3709(3) 30(1)

C(21) 5039(2) 3973(1) -4901(3) 31(1)

C(22) 5685(1) 3598(1) -4196(3) 26(1)

B(1) 8092(2) 2856(1) 5333(3) 32(1)

______

144

Table 3. Bond lengths [Å] and angles [°] for d15113.

______

S(1)-C(1) 1.6791(19)

P(1)-C(11) 1.807(2)

P(1)-C(7A) 1.819(2)

P(1)-C(7) 1.819(2)

P(1)-C(6) 1.824(2)

P(1)-B(1) 1.914(2)

O(1)-N(3) 1.226(3)

O(2)-N(3) 1.231(3)

N(1)-C(1) 1.360(3)

N(1)-C(17) 1.402(3)

N(1)-H(1N) 0.77(3)

N(2)-C(1) 1.347(3)

N(2)-C(2) 1.461(3)

N(2)-H(2N) 0.82(3)

N(3)-C(20) 1.464(3)

C(2)-C(6) 1.536(3)

C(2)-C(3) 1.547(3)

C(2)-H(2A) 1.0000

C(3)-C(4) 1.517(4)

C(3)-C(5) 1.528(3)

145

C(3)-H(3A) 1.0000

C(4)-H(4A) 0.9800

C(4)-H(4B) 0.9800

C(4)-H(4C) 0.9800

C(5)-H(5A) 0.9800

C(5)-H(5B) 0.9800

C(5)-H(5C) 0.9800

C(6)-H(6A) 0.9900

C(6)-H(6B) 0.9900

C(7)-C(8) 1.532(4)

C(7)-H(7A) 0.9900

C(7)-H(7B) 0.9900

C(8)-C(9) 1.517(5)

C(8)-H(8A) 0.9900

C(8)-H(8B) 0.9900

C(9)-C(10) 1.532(6)

C(9)-H(9A) 0.9900

C(9)-H(9B) 0.9900

C(10)-H(10A) 0.9800

C(10)-H(10B) 0.9800

C(10)-H(10C) 0.9800

C(7A)-C(8A) 1.528(6)

146

C(7A)-H(7A1) 0.9900

C(7A)-H(7A2) 0.9900

C(8A)-C(9A) 1.514(6)

C(8A)-H(8AA) 0.9900

C(8A)-H(8AB) 0.9900

C(9A)-C(10A) 1.533(7)

C(9A)-H(9AA) 0.9900

C(9A)-H(9AB) 0.9900

C(10A)-H(10D) 0.9800

C(10A)-H(10E) 0.9800

C(10A)-H(10F) 0.9800

C(11)-C(16) 1.389(3)

C(11)-C(12) 1.394(3)

C(12)-C(13) 1.382(4)

C(12)-H(12A) 0.9500

C(13)-C(14) 1.375(4)

C(13)-H(13A) 0.9500

C(14)-C(15) 1.377(4)

C(14)-H(14A) 0.9500

C(15)-C(16) 1.385(4)

C(15)-H(15A) 0.9500

C(16)-H(16A) 0.9500

147

C(17)-C(22) 1.394(3)

C(17)-C(18) 1.394(3)

C(18)-C(19) 1.384(3)

C(18)-H(18A) 0.9500

C(19)-C(20) 1.379(4)

C(19)-H(19A) 0.9500

C(20)-C(21) 1.383(3)

C(21)-C(22) 1.383(3)

C(21)-H(21A) 0.9500

C(22)-H(22A) 0.9500

B(1)-H(1) 1.07(3)

B(1)-H(2) 1.16(3)

B(1)-H(3) 1.06(3)

C(11)-P(1)-C(7A) 105.65(10)

C(11)-P(1)-C(7) 105.65(10)

C(11)-P(1)-C(6) 107.23(9)

C(7A)-P(1)-C(6) 104.31(9)

C(7)-P(1)-C(6) 104.31(9)

C(11)-P(1)-B(1) 115.99(11)

C(7A)-P(1)-B(1) 111.24(11)

C(7)-P(1)-B(1) 111.24(11)

148

C(6)-P(1)-B(1) 111.61(11)

C(1)-N(1)-C(17) 130.93(18)

C(1)-N(1)-H(1N) 117(2)

C(17)-N(1)-H(1N) 112(2)

C(1)-N(2)-C(2) 127.15(17)

C(1)-N(2)-H(2N) 115.8(15)

C(2)-N(2)-H(2N) 117.1(15)

O(1)-N(3)-O(2) 123.9(2)

O(1)-N(3)-C(20) 118.2(2)

O(2)-N(3)-C(20) 117.9(2)

N(2)-C(1)-N(1) 112.11(17)

N(2)-C(1)-S(1) 123.71(15)

N(1)-C(1)-S(1) 124.16(15)

N(2)-C(2)-C(6) 109.74(16)

N(2)-C(2)-C(3) 111.27(17)

C(6)-C(2)-C(3) 111.09(16)

N(2)-C(2)-H(2A) 108.2

C(6)-C(2)-H(2A) 108.2

C(3)-C(2)-H(2A) 108.2

C(4)-C(3)-C(5) 110.9(2)

C(4)-C(3)-C(2) 112.93(19)

C(5)-C(3)-C(2) 110.79(18)

149

C(4)-C(3)-H(3A) 107.3

C(5)-C(3)-H(3A) 107.3

C(2)-C(3)-H(3A) 107.3

C(3)-C(4)-H(4A) 109.5

C(3)-C(4)-H(4B) 109.5

H(4A)-C(4)-H(4B) 109.5

C(3)-C(4)-H(4C) 109.5

H(4A)-C(4)-H(4C) 109.5

H(4B)-C(4)-H(4C) 109.5

C(3)-C(5)-H(5A) 109.5

C(3)-C(5)-H(5B) 109.5

H(5A)-C(5)-H(5B) 109.5

C(3)-C(5)-H(5C) 109.5

H(5A)-C(5)-H(5C) 109.5

H(5B)-C(5)-H(5C) 109.5

C(2)-C(6)-P(1) 115.38(13)

C(2)-C(6)-H(6A) 108.4

P(1)-C(6)-H(6A) 108.4

C(2)-C(6)-H(6B) 108.4

P(1)-C(6)-H(6B) 108.4

H(6A)-C(6)-H(6B) 107.5

C(8)-C(7)-P(1) 109.76(18)

150

C(8)-C(7)-H(7A) 109.7

P(1)-C(7)-H(7A) 109.7

C(8)-C(7)-H(7B) 109.7

P(1)-C(7)-H(7B) 109.7

H(7A)-C(7)-H(7B) 108.2

C(9)-C(8)-C(7) 111.6(3)

C(9)-C(8)-H(8A) 109.3

C(7)-C(8)-H(8A) 109.3

C(9)-C(8)-H(8B) 109.3

C(7)-C(8)-H(8B) 109.3

H(8A)-C(8)-H(8B) 108.0

C(8)-C(9)-C(10) 111.4(4)

C(8)-C(9)-H(9A) 109.3

C(10)-C(9)-H(9A) 109.3

C(8)-C(9)-H(9B) 109.3

C(10)-C(9)-H(9B) 109.3

H(9A)-C(9)-H(9B) 108.0

C(9)-C(10)-H(10A) 109.5

C(9)-C(10)-H(10B) 109.5

H(10A)-C(10)-H(10B) 109.5

C(9)-C(10)-H(10C) 109.5

H(10A)-C(10)-H(10C) 109.5

151

H(10B)-C(10)-H(10C) 109.5

C(8A)-C(7A)-P(1) 121.9(4)

C(8A)-C(7A)-H(7A1) 106.9

P(1)-C(7A)-H(7A1) 106.9

C(8A)-C(7A)-H(7A2) 106.9

P(1)-C(7A)-H(7A2) 106.9

H(7A1)-C(7A)-H(7A2) 106.7

C(9A)-C(8A)-C(7A) 115.6(5)

C(9A)-C(8A)-H(8AA) 108.4

C(7A)-C(8A)-H(8AA) 108.4

C(9A)-C(8A)-H(8AB) 108.4

C(7A)-C(8A)-H(8AB) 108.4

H(8AA)-C(8A)-H(8AB) 107.4

C(8A)-C(9A)-C(10A) 112.0(5)

C(8A)-C(9A)-H(9AA) 109.2

C(10A)-C(9A)-H(9AA) 109.2

C(8A)-C(9A)-H(9AB) 109.2

C(10A)-C(9A)-H(9AB) 109.2

H(9AA)-C(9A)-H(9AB) 107.9

C(9A)-C(10A)-H(10D) 109.5

C(9A)-C(10A)-H(10E) 109.5

H(10D)-C(10A)-H(10E) 109.5

152

C(9A)-C(10A)-H(10F) 109.5

H(10D)-C(10A)-H(10F) 109.5

H(10E)-C(10A)-H(10F) 109.5

C(16)-C(11)-C(12) 119.6(2)

C(16)-C(11)-P(1) 120.24(17)

C(12)-C(11)-P(1) 120.14(16)

C(13)-C(12)-C(11) 119.7(2)

C(13)-C(12)-H(12A) 120.2

C(11)-C(12)-H(12A) 120.2

C(14)-C(13)-C(12) 120.5(2)

C(14)-C(13)-H(13A) 119.7

C(12)-C(13)-H(13A) 119.7

C(13)-C(14)-C(15) 120.0(2)

C(13)-C(14)-H(14A) 120.0

C(15)-C(14)-H(14A) 120.0

C(14)-C(15)-C(16) 120.3(2)

C(14)-C(15)-H(15A) 119.8

C(16)-C(15)-H(15A) 119.8

C(15)-C(16)-C(11) 119.8(2)

C(15)-C(16)-H(16A) 120.1

C(11)-C(16)-H(16A) 120.1

C(22)-C(17)-C(18) 119.94(19)

153

C(22)-C(17)-N(1) 116.43(18)

C(18)-C(17)-N(1) 123.57(18)

C(19)-C(18)-C(17) 119.6(2)

C(19)-C(18)-H(18A) 120.2

C(17)-C(18)-H(18A) 120.2

C(20)-C(19)-C(18) 119.4(2)

C(20)-C(19)-H(19A) 120.3

C(18)-C(19)-H(19A) 120.3

C(19)-C(20)-C(21) 122.1(2)

C(19)-C(20)-N(3) 119.3(2)

C(21)-C(20)-N(3) 118.6(2)

C(22)-C(21)-C(20) 118.3(2)

C(22)-C(21)-H(21A) 120.8

C(20)-C(21)-H(21A) 120.8

C(21)-C(22)-C(17) 120.6(2)

C(21)-C(22)-H(22A) 119.7

C(17)-C(22)-H(22A) 119.7

P(1)-B(1)-H(1) 108.5(18)

P(1)-B(1)-H(2) 102.9(16)

H(1)-B(1)-H(2) 112(2)

P(1)-B(1)-H(3) 108.8(16)

H(1)-B(1)-H(3) 114(2)

154

H(2)-B(1)-H(3) 110(2)

______

Symmetry transformations used to generate equivalent atoms:

155

Table 4. Anisotropic displacement parameters (Å2x 103) for d15113. The anisotropic displacement factor exponent takes the form: -22[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

______

U11 U22 U33 U23 U13 U12

______

S(1) 21(1) 33(1) 22(1) 4(1) 4(1) 2(1)

P(1) 21(1) 26(1) 20(1) -1(1) 2(1) 3(1)

O(1) 68(1) 41(1) 66(1) -1(1) -40(1) 13(1)

O(2) 33(1) 48(1) 98(2) 5(1) 0(1) 17(1)

N(1) 22(1) 31(1) 21(1) 4(1) 6(1) 8(1)

N(2) 21(1) 27(1) 21(1) 2(1) 3(1) 4(1)

N(3) 31(1) 25(1) 71(2) 2(1) -18(1) -2(1)

C(1) 20(1) 20(1) 21(1) -3(1) -2(1) -1(1)

C(2) 24(1) 24(1) 24(1) 4(1) -1(1) 4(1)

C(3) 36(1) 25(1) 36(1) 1(1) -10(1) 5(1)

C(4) 49(1) 35(1) 42(1) -12(1) -12(1) 13(1)

C(5) 46(2) 28(1) 65(2) 1(1) -21(1) -4(1)

C(6) 23(1) 27(1) 24(1) 0(1) 0(1) 4(1)

C(7) 24(1) 31(1) 32(1) -1(1) -1(1) 2(1)

C(8) 28(2) 41(3) 35(2) -4(2) -2(2) -2(2)

C(9) 32(2) 64(3) 35(2) -2(2) -6(2) -10(2)

C(10) 61(3) 83(4) 68(3) 8(3) -20(3) -43(3)

156

C(7A) 24(1) 31(1) 32(1) -1(1) -1(1) 2(1)

C(9A) 43(4) 24(4) 36(4) -7(3) 4(3) -1(3)

C(11) 25(1) 25(1) 24(1) -3(1) -2(1) 1(1)

C(12) 41(1) 32(1) 27(1) -1(1) 3(1) 1(1)

C(13) 66(2) 36(1) 28(1) 2(1) -1(1) -7(1)

C(14) 70(2) 27(1) 44(2) 7(1) -16(1) 1(1)

C(15) 50(2) 29(1) 60(2) -2(1) -6(1) 12(1)

C(16) 32(1) 30(1) 39(1) -3(1) 2(1) 3(1)

C(17) 20(1) 20(1) 26(1) 4(1) 1(1) 0(1)

C(18) 26(1) 21(1) 29(1) 1(1) 4(1) -2(1)

C(19) 22(1) 20(1) 44(1) 0(1) 6(1) -1(1)

C(20) 21(1) 19(1) 48(1) 4(1) -6(1) -1(1)

C(21) 33(1) 26(1) 32(1) 4(1) -8(1) -2(1)

C(22) 27(1) 26(1) 25(1) 0(1) 1(1) 2(1)

B(1) 31(1) 45(2) 21(1) -2(1) 10(1) 2(1)

______

157

Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for d15113.

______

x y z U(eq)

______

H(1N) 6872(19) 3144(12) -2500(40) 36(8)

H(2N) 7696(15) 2584(10) -1100(30) 17(5)

H(2A) 7260 2139 2220 29

H(3A) 7813 1175 1419 39

H(4A) 8764 1442 -990 63

H(4B) 8117 904 -1557 63

H(4C) 7917 1571 -2249 63

H(5A) 6264 1350 1197 69

H(5B) 6377 1514 -905 69

H(5C) 6576 847 -212 69

H(6A) 8981 2290 616 29

H(6B) 8850 1899 2411 29

H(7A) 10110 2668 4414 35

H(7B) 10255 2891 2366 35

H(8A) 10076 3895 3208 41

H(8B) 9748 3709 5197 41

158

H(9A) 11515 3470 3945 53

H(9B) 11171 3383 5984 53

H(10A) 11995 4287 5759 106

H(10B) 11329 4527 4228 106

H(10C) 10985 4440 6266 106

H(7A1) 10120 2581 4012 35

H(7A2) 10216 3011 2304 35

H(8AA) 10071 3415 5951 36

H(8AB) 10975 3388 4816 36

H(9AA) 9541 4202 4241 42

H(9AB) 10325 4129 2786 42

H(10D) 10632 4953 4715 78

H(10E) 10595 4523 6451 78

H(10F) 11378 4449 4997 78

H(12A) 9377 3380 -300 40

H(13A) 9040 4213 -2080 52

H(14A) 7922 4871 -1210 56

H(15A) 7141 4709 1467 56

H(16A) 7479 3886 3301 40

H(18A) 5439 3916 109 30

H(19A) 4320 4534 -1073 34

H(21A) 4940 3995 -6173 37

159

H(22A) 6032 3357 -4990 31

H(1) 7420(20) 2717(14) 5030(50) 53(8)

H(2) 8480(20) 2492(15) 6120(50) 60(9)

H(3) 8133(19) 3270(13) 6020(40) 45(8)

______

160

Table 6. Torsion angles [°] for d15113.

______

C(2)-N(2)-C(1)-N(1) -178.97(18)

C(2)-N(2)-C(1)-S(1) -0.7(3)

C(17)-N(1)-C(1)-N(2) 177.5(2)

C(17)-N(1)-C(1)-S(1) -0.8(3)

C(1)-N(2)-C(2)-C(6) -130.5(2)

C(1)-N(2)-C(2)-C(3) 106.2(2)

N(2)-C(2)-C(3)-C(4) 60.1(2)

C(6)-C(2)-C(3)-C(4) -62.5(2)

N(2)-C(2)-C(3)-C(5) -65.0(2)

C(6)-C(2)-C(3)-C(5) 172.4(2)

N(2)-C(2)-C(6)-P(1) 71.85(19)

C(3)-C(2)-C(6)-P(1) -164.69(14)

C(11)-P(1)-C(6)-C(2) -66.98(16)

C(7A)-P(1)-C(6)-C(2) -178.73(15)

C(7)-P(1)-C(6)-C(2) -178.73(15)

B(1)-P(1)-C(6)-C(2) 61.06(18)

C(11)-P(1)-C(7)-C(8) 51.8(2)

C(6)-P(1)-C(7)-C(8) 164.7(2)

B(1)-P(1)-C(7)-C(8) -74.9(2)

P(1)-C(7)-C(8)-C(9) 169.6(3)

161

C(7)-C(8)-C(9)-C(10) 172.0(4)

C(11)-P(1)-C(7A)-C(8A) 70.9(4)

C(6)-P(1)-C(7A)-C(8A) -176.3(3)

B(1)-P(1)-C(7A)-C(8A) -55.8(4)

P(1)-C(7A)-C(8A)-C(9A) -61.9(7)

C(7A)-C(8A)-C(9A)-C(10A) -168.7(6)

C(7A)-P(1)-C(11)-C(16) -125.50(18)

C(7)-P(1)-C(11)-C(16) -125.50(18)

C(6)-P(1)-C(11)-C(16) 123.67(17)

B(1)-P(1)-C(11)-C(16) -1.8(2)

C(7A)-P(1)-C(11)-C(12) 53.23(19)

C(7)-P(1)-C(11)-C(12) 53.23(19)

C(6)-P(1)-C(11)-C(12) -57.59(19)

B(1)-P(1)-C(11)-C(12) 176.96(17)

C(16)-C(11)-C(12)-C(13) 0.2(3)

P(1)-C(11)-C(12)-C(13) -178.53(19)

C(11)-C(12)-C(13)-C(14) -0.6(4)

C(12)-C(13)-C(14)-C(15) 0.4(4)

C(13)-C(14)-C(15)-C(16) 0.1(4)

C(14)-C(15)-C(16)-C(11) -0.5(4)

C(12)-C(11)-C(16)-C(15) 0.3(3)

P(1)-C(11)-C(16)-C(15) 179.06(19)

162

C(1)-N(1)-C(17)-C(22) -144.1(2)

C(1)-N(1)-C(17)-C(18) 38.8(3)

C(22)-C(17)-C(18)-C(19) 1.6(3)

N(1)-C(17)-C(18)-C(19) 178.60(18)

C(17)-C(18)-C(19)-C(20) -1.4(3)

C(18)-C(19)-C(20)-C(21) 0.2(3)

C(18)-C(19)-C(20)-N(3) -178.00(17)

O(1)-N(3)-C(20)-C(19) 168.4(2)

O(2)-N(3)-C(20)-C(19) -9.8(3)

O(1)-N(3)-C(20)-C(21) -9.9(3)

O(2)-N(3)-C(20)-C(21) 171.9(2)

C(19)-C(20)-C(21)-C(22) 0.7(3)

N(3)-C(20)-C(21)-C(22) 178.94(18)

C(20)-C(21)-C(22)-C(17) -0.4(3)

C(18)-C(17)-C(22)-C(21) -0.7(3)

N(1)-C(17)-C(22)-C(21) -177.89(19)

______

Symmetry transformations used to generate equivalent atoms:

163