Generation of Heteroatom Stereocenters by Enantioselective

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Review

Generation of Heteroatom Stereocenters by Enantioselective C–H Functionalization Johannes Diesel, and Nicolai Cramer ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03194 • Publication Date (Web): 30 Aug 2019 Downloaded from pubs.acs.org on August 30, 2019

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ACS Catalysis

Generation

of

Heteroatom

Stereocenters

by

Enantioselective C–H Functionalization Johannes Diesel and Nicolai Cramer*

Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC LCSA, BCH 4305, CH-1015 Lausanne, Switzerland

Abstract: C–H Functionalization has been established as an efficient way to generate molecular complexity. The formation of stereogenic carbon atoms by asymmetric C–H functionalization has seen tremendous progress over the last decade. More recently, the direct catalytic modification of C–H bonds has been powerfully applied to the formation of non-carbon stereogenic centers, which constitute a key design element of biologically active molecules and chiral ligands for asymmetric catalysis. This area was opened by a seminal report describing enantioselective C–H functionalization for the formation of a

ACS Paragon Plus Environment

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silicon stereocenter. It rapidly expanded with advances in the enantioselective formation of phosphorus(V) centers. Moreover, enantioselective routes to chiral sulfur atoms in the oxidation state IV (sulfoxides) and VI (sulfoximines) have been disclosed. Herein, we discuss methods of using selective functionalization of C–H bonds to generate a remote heteroatom stereogenic center via an inner-sphere C–H activation mechanism.

KEYWORDS C–H Functionalization, Asymmetric Catalysis, Heteroatom Stereocenters, Heterocycles, Homogenous Catalysis

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INTRODUCTION The direct functionalization of unactivated carbon–hydrogen (C–H) bonds remains a

challenge in organic synthesis and continues to give impetus for innovation in chemical reaction development. While the boundaries of what is considered an unactivated C–H bond, translating to non-addressable by established methodologies, have been continuously pushed over the last decades, the task of selectivity plays an increasingly important role.1 Assembling chiral molecules by utilizing enantioselective functionalization of C–H bonds has been established as an efficient way to generate molecular complexity.2


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ACS Catalysis

Tremendous progress has been achieved in the formation of stereogenic carbon atoms using asymmetric C–H functionalization. Besides the well-known point chirality of the tetrahedral carbon atom, several heteroatoms can display stereogenicity Challenges in applying C–H functionalization strategies used for the generation of carbon centered chirality to the synthesis of heteroatom stereocenters are associated with lower racemization barriers, in particular for nitrogen containing compounds and elongated carbon heteroatom bond lengths, as found for carbon phosphorus and carbon sulfur bonds, influencing the outcome of enantioselective transformations. Heteroatom stereogenic compounds are present in a variety of naturally occurring compounds and also in pharmaceuticals and functional materials (Figure 1).3 Silicon stereocenters are not present in nature, but stereogenic silicon atoms are introduced in materials with unique physicochemical properties.4 Furthermore, the higher homologue germanium can be stereogenic. The group five element nitrogen displays stereogenicity if the rapid Walden inversion locked, as found in Tröger's Base.5 The higher homologue phosphorus has a significantly higher inversion barrier and stereogenic phosphor atoms are part of various bioactive compounds.6 Additionally, P-stereogenic ligand scaffolds are


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extensively used in asymmetric catalysis.7 Stereogenic sulfur atoms play an important role in general metabolism8 and an increasing number of new pharmaceuticals contain sulfur stereocenters.9

Ph Me Me Ph Me Me Si

O

Si

O

Si

O

Chiral Polysiloxane

N Me

n

N Me

Trögers`s Base

MeO O

N Me S

P

Het

Me

HN N

P OMe

Heteroatom Stereocenters

N CF3

N H

DIPAMP

NH2 NMe2

N

PYK2 Inhibitor

Me

N

S

OOC NH3

N

tBu

Me P

N

N

O

S-Adenosyl Methionine OH OH

P

N tBu

Me

QuinoxP

Figure 1. Heteroatom Stereocenters in Bioactive Compounds and Fine Chemicals. Recently enantioselective C–H functionalization has emerged as new tool to assemble these intriguing chiral compounds more efficiently. This review deals with enantioselective C–H functionalizations to form heteroatom stereocenters operating via an inner-sphere type mechanism.10 One approach to obtain heteroatom-centered chirality is the desymmetrizing C–H activation of substrates with a prochiral heteroatom (Scheme 1). The functionality


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ACS Catalysis

containing the heteroatom can be used as a directing group in combination with a transition metal catalyst to achieve desymmetrization (Scheme 1a). Organoheteroatom compound 1 is converted, in an enantiodetermining C–H activation, to intermediate metallacycle

2,

containing

a

heteroatom

stereocenter.

Subsequent

inter-

or

intramolecular functionalization gives the chiral product 3. Conceptually different is the use of a prefunctionalized starting material, not relying on a directing group (Scheme 1b). Oxidative addition of a transition metal catalyst into the carbon–(pseudo)halogen bond of 4 gives intermediate 5 , which is converted in a enantiodetermining C–H activation to form metallacycle 6. Upon reductive elimination the chiral product 7 is released via formation of a five- or six membered ring.


5

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a) DG H C R

H C

Het

DG [M] L* H  Het C R C

[M]L* Enantiodetermining CH Activation

1

DG  H Het C R

Y Functionalization

2

Y C

3

b)

X C H C R

Het

4

X [M] L* [M]L* H Oxidative C Addition

C

C H C R

Het

H C

H Enantiodetermining CH Activation

C R

5

Het



[M]L* C

H Het Reductive C R Elimination

6



C C

7

Scheme 1. Desymmetrization Approaches: a) Directing Group Mediated C-H Functionalization, b) Oxidative Addition, C-H Functionalization Sequence. Additionally racemic heteroatom stereogenic starting materials can be applied in kinetic resolutions. Thereby overcoming the limitation of a symmetrically substituted starting material in the desymmetrization approach. Kinetic resolutions use chiral catalysts interacting differently with each substrate enantiomer (Scheme 2). The enantiomers (S)-8 and (R)-8 are recognized by a chiral catalyst resulting in different reaction rates for each enantiomer (Scheme 2a).11 One enantiomer reacts faster and forms the product 10 in maximum 50% yield. The remaining starting material (S)-8 is in an ideal case reisolated in enantiopure form. A parallel kinetic resolution takes advantage of different chemo-, regio- or stereoselectivity for the reaction of each enantiomer of a racemic mixture with a reaction partner (Scheme 2b).12 The enantiomers (S)-11 and (R)- 11 are in this case


6

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ACS Catalysis

converted to two different products. In the shown example, different regioselectivity is observed for each enantiomer and the products 14 and 15 can be obtained in maximum 50% yield. a) DG H C



DG R

Het R

H C

1

2

(S)-8



DG R

Het R

2

(S)-8

[M]L*

R

Het

H C

R1

Het R

2

(S)-8

Functionalization DG





Y

CH Activation DG 1

H C

1

R

1

Het



R

C

R2

R2 (R)-8 Racemic Mixture

DG

[M]

1

Het

Y



C

R2 10

9

b) DG [M] L* H  Het 1 R C C2

DG H C R 1

Het



H C2

(S)-11

12

[M]L*

DG C1 R

Het



H C2

(R)-11 Racemic Mixture

Y C2

14

Y Functionalization

CH Activation H

DG H  Het C1 R

L* [M] C1 R

DG Het

Y



C2

13

C1 R

DG Het



H C2

15

Scheme 2. Resolution Approaches for Enantioselective C–H Activation to Form Heteroatom Stereocenters: a) Kinetic Resolution, b) Parallel Kinetic Resolution. The present review covers catalytic enantioselective C–H functionalizations for the generation of heteroatom stereocenters until July 2019. We have grouped the reports by the formed stereogenic atom, which are the formation of stereogenic silicon, phosphorus


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Page 8 of 41

and sulfur atoms. C–H functionalization of heteroatom compounds, which rely on diastereoselective, auxiliary controlled transformations are beyond the scope of this review. Grouped information on this topic can be found in a review by Cui and Xu.13

2

FORMATION OF SILICON STEREOCENTERS

Silicon-containing molecules find wide application in a variety of materials. Large πconjugated systems with unique optoelectronic properties allow applications as lightemitting diodes and solar cells.4a, 14 Furthermore, silicon is also introduced in bioactive compounds and marketed drugs.15 Acting as carbon isosteres organosilicon structures express unique physicochemical properties and potential medicinal applications.16 In contrast to ubiquitous carbon stereocenters found in biomolecules, silicon-stereogenic compounds are not present in nature and the synthesis of chiral organosilanes, containing a stereocenter at silicon has been a challenge.17 Over the last decade significant progress in development of catalytic asymmetric methodologies to form silicon stereocenters has been made, but the known strategies are still limited in number and generality.18 The application of C–H functionalization strategies enabled more efficient access to silicon stereogenic compounds in a catalytic enantioselective way.


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ACS Catalysis

In 2012, Shintani, Hayashi and their co-workers reported the first catalytic enantioselective approach towards Si-stereocenters applying functionalization of C(sp2)– H bonds (Scheme 3).19 The work drew upon Shimizu's Pd(0)/Pd(II)-catalyzed approach to silicon-bridged biaryls.20 A Pd-Josiphos-type catalyst enabled the desymmetrization of triarylsilanes 16 to yield the silicon-stereogenic dibenzosiloles 17 in high chemo- and enantioselectivity. The formation of the undesired achiral dibenzosilole 18 was largely suppressed by applying chiral bidentate phosphine ligand L1. Ortho-substituted substrates gave the products with high yield and enantioselectivity (17a and 17b). Additionally a tetraaryl silane was a competent substrate delivering the product 17c in 60% yield and 89% ee. Furthermore, a pathway for the formation of the undesired dibenzosilole 18 was proposed. The oxidative addition product 19 can undergo a 1,5-Pd migration to give 20. Both 19 and 20 undergo base-assisted intramolecular C–H activation to yield different 6-membered palladacycles 20 and 21, reductive elimination delivers the products 17a and 18a.


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Proposed Pathways for Isomer Formation

R2

R2 Pd(OAc)2 (5-10 mol%) L1 (5.510.5 mol%)

R3 Si R1

Page 10 of 41

R2

R3

6499% 17:18 = 96:499:1 7598% ee

R3 +

Si

Et2NH, PhMe, 5070 °C

OTf 16

R2

R

R1

R2

R2 17

C H MeO tBu activation Si base Pd

MeO tBu Si

Si

1

18 (achiral)

Pd OTf 19

21

tBu 1,5-shift Me

Fe

MeO

PCy2 PAr2

L1 Ar = 3,5-Me-4-OMe-Ph

Scheme

3.

tBu

Ph Si

17a 17a:18a = 97:3 92%, 94% ee

Pd-Catalyzed

tBu

Ph Si

tBu MeO

17b 17b:18b = 98:2 84%, 94% ee

Intramolecular

Ph Si

MeO tBu Si

Pd

Pd

17c 17c:18c = 96:4 60%, 89% ee

C–H

C H MeO tBu activation Si base

OTf 20

Functionalization

22

Approach

to

Dibenzosiloles. Building upon these findings Shintani, Nozaki and their co-workers utilized the 1,5-Pd migration to achieve enantioselective C–H functionalization of 23. The application of a 4,4'-disubstituted BINAP ligand21 (R)-L2 and Pd(OAc)2 enabled the formation of siliconstereogenic 5,10-dihydrophenazasilines 24 in good yield and high enantioselectivity (Scheme 4).22 A variety of different aryl substituents were tolerated and the products were obtained in excellent enantioselectivity (e.g., 24a and 24b). Introducing a less bulky alkyl substituent on the silicon atom or the use of the corresponding secondary amine resulted in moderate selectivity (24c and 24d). Mechanistic investigations suggested 1,5-Pd migration as the enantiodetermining step and deprotonation/reductive elimination sequence as turnover-limiting.


10

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ACS Catalysis

R3

Pd(OAc)2 (5 mol%) (R)-L2 (5.5 mol%)

R2HN R3 Si R R1

4

P(Ph)2 P(Ph)2

Si

Et3N, DMA, 100 °C

R R1

6189% 1498% ee

OTf

4

N R2 SiMe3 (R)-L2

24

23 tBu tBu Si

24a 78%, 98% ee

tBu

Cy Si

tBu MeO

tBu

Me

tBu

tBu

N H

SiMe3

R4

R4

N H 24b 80%, 98% ee

Si

Si tBu

N H

Me

24c 76%, 61% ee

N Me

tBu

24d 86%, 75% ee

Scheme 4. Pd-Catalyzed Synthesis of 5,10-Dihydrophenazasilines via Enantioselective 1,5-Palladium Migration. Recently Cui, Xu and their co-workers reported a Pd(II)-catalyzed C–H olefination of tetrasubstituted silanes (Scheme 5).23 The application of a silicon tethered pyridine directing group24 enabled the C–H desymmetrization of prochiral silanes 25 in good enantioselectivity. Intermolecular functionalization was achieved using Pd(OAc)2 and a survey of different mono-protected amino acids proved Fmoc-Phe-OH as optimal.25 Silanes containing bulky alkyl substituents were converted with different electron-deficient olefins 26 to obtain the silicon-stereogenic products in moderate yield and good ee (e.g., 27a-c). In addition to methyl acrylate (e.g., 27a), styrenes (e.g., 27b) and acrylamides (e.g., 27c) were also suitable reaction partners. In general, substrates equipped with a quinoline directing group (e.g., 27c) were converted in higher ee.


11

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R2

R2 R

1

Si

R3

R2

N

Page 12 of 41

Pd(OAc)2 (10 mol%) Fmoc-Phe-OH (20 mol%) Cu(OAc)2 (20 mol%)

R1

O2 (1 atm), i-PrOH, 80 °C

N

3771% 7291% ee

R3

26

25

Si R2

27 Me

Ph

tBu Ph

tBu

Si

O OH

NHFmoc Fmoc-Phe-OH

Si

N

N

Si N

Me O

MeO2C

i-PrHN

O 2N 27a 41%, 82% ee

Ph

tBu

27b 46%, 74% ee

27c 42%, 91% ee

Scheme 5. Pd(II)-Catalyzed C–H Olefination of Tetrasubstituted Silanes. In 2013, Kuninobu, Takai and their co-workers disclosed the Rh-catalyzed asymmetric synthesis of spirocyclic compounds with a quaternary silicon atom in high yield and enantioselectivity (Scheme 6).26 Cyclization of bis(biphenylsilanes) 28 using [Rh(cod)Cl]2 and (R)-BINAP delivered a silicon stereogenic intermediate, which is converted in a second C–H functionalization to the axial chiral spirosilabifluorenes 29. Detailed mechanistic studies in collaboration with the Murai group included the isolation of intermediate (R)-30a in 88% ee.27 This could be converted under the same reaction conditions to the spirosilabifluorene (R)-29a without loss of ee, suggesting that the absolute configuration is determined in the first silylative cyclization. Intriguingly, the cyclization of 28a and 28b led to the same product enantiomer (R)-29a in comparable yield and ee, highlighting that, in this case, the substitution pattern of the biphenyl moieties did not affect the enantioselectivity.


12

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ACS Catalysis

R2

R1

[Rh(cod)Cl]2 (0.5 mol%) (R)-BINAP (1.2 mol%)

SiH2

R1

R2

OMe [Rh(cod)Cl]2 (0.5 mol%) (R)-BINAP (1.2 mol%)

SiH2

Si

1,4-dioxane, 70-135 °C

R1

R2

28

R1

7395% 7595% ee

OMe

R2

OMe

1,4-dioxane, 70°C (R)-29a 96%, 87% ee

28a

29

OMe Si

Isolated Intermediate MeO PPh2 PPh2 (R)-BINAP

OMe Si

H

88% ee

[Rh(cod)Cl]2 (0.5 mol%) (R)-BINAP (1.2 mol%)

OMe Si OMe

1,4-dioxane, 70°C MeO

OMe (R)-30a

SiH2

28b

(R)-29a 95%, 84% ee

Scheme 6. Rh-Catalyzed Asymmetric Synthesis of Spirosilabifluorenes. Takai, Murai and their co-workers extended this methodology for functionalization of more challenging C(sp3)–H bonds, however only with poor enantiocontrol (Scheme 7).28 In a single example twofold dehydrogenative C(sp3)–H bond silylation of silane 31a led via 32a to spirosilabiindane 33a in 75% yield and 40 % ee using [Rh(cod)Cl]2 and (R)-H8BINAP. To achieve high levels of reactivity, the application of hydrogen acceptors was necessary. Addition of 3,3-dimethyl-1-butene enabled significantly reduced reaction temperature and increased conversion and yield. Furthermore, silicon could be replaced by germanium to obtain chiral spirogermabiindane 33b. Among a variety of chiral phosphine ligands, (R)-(S)-BPPFA performed best giving the product 33b with moderate yield (68%) and low ee (5%). In this case, the addition of a hydrogen acceptor did not result in improved yields.


13

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Me Me Me XH2 Me Me Me 31

Me

Me Me

Me Me

see below

Page 14 of 41

X

X H Me Me Me 32

PPh2 PPh2



Me Me 33

(R)-H8-BINAP

Me Me [Rh(cod)Cl]2 (3 mol%) (R)-H8-BINAP (9 mol%) 3,3-dimethyl-1-butene 1,4-dioxane, 100 °C

Si  Me Me 33a 75%, 40% ee

Fe

NMe2 PPh2

PPh2 (R)-(S)-BPPFA

Me Me [Rh(cod)Cl]2 (1.5 mol%) (R)-(S)-BPPFA (4.5 mol%) 1,4-dioxane, 100 °C

Ge  Me Me 33b 68%, 5% ee

Scheme 7. Rh-Catalyzed Sequential C(sp3)–H Bond Activation. In 2017, He and co-workers reported a Rh-catalyzed tandem silacyclobutane (SCB) desymmetrization/C–H silylation and intermolecular dehydrogenative silylation to form dibenzosiloles (Scheme 8).29 SCB activation has been extensively studied previously in a variety of transition metal catalyzed transformations.30 In an enantiodetermining Si–C bond activation SCBs 34 are converted via intermediate silane 35 to form products 36 bearing a quaternary silicon stereocenter. This work represents a rare example where C– H activation is not the enantiodetermining step to achieve formation of a heteroatom stereocenter. The application of [Rh(cod)OH] and (R)-TMS-Segphos enabled the formation of dibenzosiloles 36 in good yield and high enantioselectivity. Both 2-chloroand 3-chlorothiophene were compatible arene partners, delivering 36a and 36b respectively in high enantioselectivity. Unsubstituted benzene was also converted albeit in moderate yield and selectivity (36c). Meta-substituted biaryl silanes were suitable substrates delivering 36d with 88% ee. Although the isolation of intermediate 35 failed, a


14

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ACS Catalysis

series of control experiments suggested that the SCB opening/C–H silylation occurs first with subsequent intermolecular dehydrogenative silylation to form 36. The formation of intermediate 35 is stereoselective and the subsequent dehydrogenative coupling is stereospecific and independent of the ligand chirality. [Rh(cod)OH] (10 mol%) (R)-TMS-Segphos (10 mol%)

Si H R1

R2

Ar H

Pr

R1

5478% 6593% ee

R1

R2

36 Cl

Cl

O Pr

O

PAr2 PAr2

O

Pr

S Si

S

S Si

Si

Si Me

Pr

Pr Me

Me

O

Me

Ar = 3,5-TMS-Ph (R)-TMS-Segphos

Scheme

R2

35

Cl

Ar Si

Si

p-xylene or neat Ar-H, 40 °C

34

Pr

H

8.

36a 60%, 86% ee

Tandem

36b 64%, 91% ee

Desymmetrization

36c 54%, 65% ee

of

36d 61%, 88% ee

Silacyclobutanes/Intermolecular

Dehydrogenative Silylation.

3

FORMATION OF PHOSPHORUS STEREOCENTERS

Organophosphorus compounds bearing a stereocenter at phosphorus are found in bioactive molecules and materials,31 but the main role of chiral phosphorus compounds is in the application as robust and versatile ligand scaffolds, or as organocatalysts in asymmetric catalysis.32

Typically, chiral P(III)-compounds are used as ligands in

transition-metal catalysis,7 and P(V)-compounds serve as Lewis base33 and Brønsted acid catalysts.34 While in many cases different types of chirality are placed within the backbone of the ligand, the introduction of a stereogenic center on phosphorus can be advantageous because of its closer proximity to the catalytic center.35 The comparably


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Page 16 of 41

low number of P-chiral ligands is associated with the challenges in their synthesis, often relying on a variety of resolution techniques.36 Catalytic asymmetric methods exist but are still limited in scope and efficiency.37 Recently the application of C–H functionalization technology for the synthesis of organophosphorus compounds has led to a variety of new

P-stereogenic compounds, which were previously inaccessible. In 2015, the Han group presented a Pd(II)-catalyzed desymmetrization C–H arylation strategy to access P-chiral phosphinamides (Scheme 9).38 The work is builds on the racemic transformation, previously reported by the same group.39 According to the proposed mechanism, the phosphinamide of 37 serves as directing group guiding the ortho C–H metalation. Additionally the authors observed an important role of DMF, facilitating the C–H activation event. Hypothesizing that stereoinduction is feasible if a strongly coordinating DMF-like chiral ligand is applied, a variety of amino acid derivatives were explored.25 The use of Pd(OAc)2 and L3 enabled the formation of P-stereogenic phosphinamides 39 in good yield and high enantioselectivity. Ag2CO3 serves as the oxidant while 1,4-benzoquinone (BQ) was proposed to assist reductive elimination.39 The addition of 40 equivalents of water in anhydrous DMF was crucial to improve both yield and enantioselectivity. Further studies revealed a positive influence of polar protic additives on the enantioselectivity.40 This observation was rationalized by stabilization of a transition-state through an H-bonding network provided by the additive. Metasubstituted diaryl phosphinamides 37a-c reacted smoothly and both electron-donating and electron-withdrawing groups were tolerated (39b and 39c). Furthermore, boronic


16

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ACS Catalysis

esters decorated with halogen and ester functionalities (39a and 39b) were suitable substrates for this transformation delivering the products in good yield and high ee. Pd(OAc)2 (10 mol%) L3 (20 mol%) BQ (50 mol%)

F

R O P R

CN

F N H

Ar

F

BPin

F

37

Me

O OH NHBoc L3

O P

R

N H

39a 68%, 90% ee

Br

MeO

O P

F

N H

F

39

OMe

ArF

CN

F

Ar

4874% 8798% ee

38

OtBu

O P

Ag2CO3, Li2CO3, H2O DMF, 40 °C

Me

F

R

CF3

N H

ArF

39b 63%, 92% ee

F3C

CO2Me

O P

N H

ArF

39c 48%, 87% ee

F

Scheme 9. Desymmetrizing C–H Arylation for the Synthesis of Phosphinamides. By applying an intramolecular Pd(0)/Pd(II) C–H arylation strategy Duan and co-workers achieved, in 2015, the enantioselective formation of P-chiral phosphinic amides (Scheme 10).41 Cyclization was accomplished by using N-(o-bromoaryl)-diarylphosphinic amides 40 and Pd(OAc)2 in combination with TADDOL-derived phosphoramidite L4.42 Substrates substituted with both electron-donating and electron-withdrawing groups were well tolerated delivering the products in high yield and high enantioselectivity (41a and 41b). Furthermore, phosphinic amide containing a cleavable N-PMB protecting group reacted smoothly and the corresponding product 41c was obtained in 81% yield and 91% ee. Additionally the obtained products could be converted into P-chiral biphenyl monophosphine ligands via the addition of organolithium compounds and P–N bond cleavage. Shortly after this report Liu, Ma and their co-workers reported the same


17

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Page 18 of 41

transformation, also applying Pd(OAc)2 in combination with a similar TADDOL-derived phosphoramidite L5 obtaining the P-chiral products in very high yields (up to 99%) and enantioselectivity (up to 97% ee).43 R1

O R P N

R1 see below

Br

R1

R1

40 MeO

Pd(OAc)2 (5 mol%) L4 (10 mol%) PivOH (30 mol%) K3PO4, PhMe, 80 °C

5894%, 8393% ee

F3C

O Me P N

Me

O

Me

O

O

Ph

O PMB P N

F3C

MeO 41a 88%, 89% ee

41b 91%, 91% ee

P NR2

Ph

L4 R = Me, L5 R = Et

41 O Me P N

Ph

O

Ph

R2

R2

2015, Duan

Ph

O R P N

41c 81%, 91% ee

2015, Liu & Ma Pd(OAc)2 (8 mol%) L5 (10 mol%) PivOH (40 mol%) CsCO3, hexane, 60 °C

3499%, 8897% ee

Scheme 10. Pd-Catalyzed Enantioselective C–H Arylation of Phosphinic Amides. After these two reports the Tang group reported a similar Pd(0)/Pd(II) C–H arylation strategy for the formation P-chiral biaryl phosphonates (Scheme 11).44 Various obromoaryl phosphonates 42 were cyclized to form 43 using Pd(OAc)2 and a new modification of the P-chiral monophosphorus ligand BI-DIME L6.45 The enantioselectivity of the reaction was further improved by fine-tuning the base and Ph2CHCOOK proved optimal. Both electron-poor and electron–rich phosphonates were converted to the products (43a and 43b) in good yield and enantioselectivity. In addition, condensed arenes were well tolerated, delivering the product in good yield and enantioselectivity (43c). Product 43d was converted to P-chiral phosphine oxide 44 by twofold sequential alkyllithium addition. The aryloxy substituent displacement on the phosphonate occurred


18

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ACS Catalysis

stereospecifically, and by reversing the order of addition of the alkyllithium reagent the opposite enantiomer of the phosphine oxide 44 could be obtained.

R2 Br R

O

O P O

Pd(OAc)2 (4 mol%) L6 (8 mol%)

1

R

2

Ph2CHCOOK, PhMe, 70 °C

R1 O R

O P O

1

OPh

R2

1792% 5888% ee

42

O P O

43

43d (80% ee) a) iPrLi, Et2AlCl, THF, -65 °C (72%) b) MeLi, Et2AlCl, THF, -65 °C (90%)

O P O

O

tBu

PhO

O P O

O PhO P O

O

O P O HO

L6

MeO

F

O P iPr Me

43a 83%, 84% ee

43b 85%, 88% ee

43c 81%, 87% ee

44 (80% ee)

Scheme 11. Biaryl Phosphonates Synthesis by Intramolecular Pd-Catalyzed C–H Arylation. In a related work Cui, Xu and their coworkers disclosed an enantioselective synthesis of phosphole oxides (Scheme 12).46 A combination of Pd(OAc)2 and (S,S)-Me-Duphos enabled Pd(0)/Pd(II) C–H arylation of different o-bromoaryl phosphine oxides 45. The cyclized products 46 were obtained in moderate yield and enantioselectivity. Superior results on the same transformation were reported recently by the Duan group.47 Two catalytic systems were developed and applied for the formation of both enantiomers of the corresponding dibenzophosphole oxides 46. A Pd-catalyst containing an achiral phosphine ligand (Pd(PCy3)2) and a chiral BINOL-phosphoric acid/amide mixture (L7/ L8 = 1/1) proved optimal to achieve good enantioselectivity. Dibenzophosphole oxide (S)-


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Page 20 of 41

46a was obtained in 95% yield and 88% ee. Furthermore, a nonlinear effect was observed for this catalyst system and the involvement of more than one phosphoric acid/amide in the enantioselective C–H palladation step was suggested. The second set of conditions relied on the use of Pd(OAc)2 and (R)-Segphos in combination with pivalic acid. Dibenzophosphole oxide (R)-46a was obtained in moderate yield and high enantioselectivity under these conditions. Me Br O

O

see below

P

R P

R2

1

2019, Duan

Pd(OAc)2 (5 mol%) (S,S)-Me-Duphos(10 mol%) CsCO3, xylene, 140 °C

Conditions A: Pd(PCy3)2 (3 mol%) L7 (6 mol%), L8 (6 mol%) CsCO3, xylene, 110 °C

7795%, 5690% ee

O

O

PPh2 PPh2

O O

Me (S,S)-Me-Duphos

46

2017, Cui & Xu

5578%, 2494% ee

O O P XH O

Me Me P

R 45

2



R2

R1

O

P

R2

Ph P

F

L7 X = O, L8 X = NH

Conditions B: Pd(OAc)2 (5 mol%) (R)-Segphos (15 mol%) PivOH (30 mol%) CsCO3, PhMe, 120 °C

(S)-46a 95%, 88% ee

2186%, 7496% ee

(R)-Segphos

O

Ph P

F (R)-46a 68%, 90% ee

Scheme 12. Pd-Catalyzed Enantioselective Synthesis of Dibenzophosphole oxides. In 2015, the Chang group demonstrated a dual role of a carboxylic acid additive in an Ircatalyzed enantioselective C–H amidation of diaryl phosphine oxides 47 (Scheme 13).48 The methodology drew upon their earlier report on the development of a diastereoselective auxiliary controlled transformation.49 The combination of [Cp*IrCl2]2 and AgNTf2 to generate a dicationic iridium complex, and the tartaic acid derivative L9 as chiral ligand gave the C–H amidated phosphine oxides 48 in good yields and low


20

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ACS Catalysis

enantioselectivity using tosyl azide as the amidation reagent. Mechanistic studies suggested that the chiral acid takes part in the rate-limiting and enantiodetermining concerted metalation deprotonation (CMD) step.48,

50

Subsequently Cramer and

coworkers showcased that high levels of enantiocontrol are feasible using a combination of readily modifiable CpxIr(III) complexes51 and a chiral carboxylic acid. Applying Cat-1 together with tert-leucine derived (S)-L10 gave the products 48 in high yield and very high enantioselectivity.52 An extensive investigation of chiral carboxylic acids revealed a strong cooperative effect between the Cpx ligand and phthaloyl tert-leucine (S)-L10 delivering phosphine oxide 48a in 83% yield and 92% ee. Application of the opposite enantiomer (R)-L10 resulted in significantly lower reactivity and erosion of enantioselectivity (15% yield and 20% ee for 48a) highlighting the strong matched-mismatched effect between the Cpx ligand and the chiral acid. Phosphine oxides bearing a tert-butyl substituent were converted to the C-H amidated products in excellent enantioselectivity (48b and 48c). The readily cleavable o-nosyl group could be introduced easily delivering product 48c in 92% yield and 96% ee.

R3

O P R1

R2

see below R1

47

R1

NH

R2

2017, Cramer Cat-1 (2 mol%) (S)-L10 (24 mol%) R3N3 (1.1 eq) AgNTf2 (8.5 mol%) tAmOH/dioxane, 0 °C

44-91%, 11-32% ee

12-95%, 40-98% ee

OMe

CO2H

HO2C

tBu OMe

OPiv

R1

I Cat-1

L9

48

[Cp*IrCl2]2 (2 mol%) L9 (4 mol%) TsN3 (1.1 eq) AgNTf2 (8 mol%) DCE, 60 °C

2015, Chang

OPiv

O P

Ts

NH

O P

Ts Ph

Ir

I

NPhth 2

o-Ns NH

O P

Ph

Cy

tBu

48a 83%, 92% ee

48b 95%, 98% ee

CO2H

(S)-L10

NH

O P

Ph

tBu 48c 92%, 96% ee


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Page 22 of 41

Scheme 13. Enantioselective Ir-Catalyzed C–H Amidation of Phosphine Oxides. In 2018, the Cramer group employed the CpxIr(III)/chiral carboxylic acid system to achieve C–H arylation of phosphine oxides 49, providing access to P- and axially chiral products 51 (Scheme 14).53 The use of quinone diazides 50 in an Ir-catalyzed racemic arylation was reported previously by Yang and co-workers.54 Application of the powerful combination of CpxIr(III) Cat-1 and (S)-L10 enabled the formation of P-chiral biaryl phosphine oxides in excellent yield and enantioselectivity (51a and 51b). Introduction of ortho-substituted diazides generated a stable chiral axis, delivering products with both axial and P-chirality in excellent diastereo- and enantioselectivity (51c and 51d). The protocol was also applicable for the enantioselective synthesis of purely axial chiral phosphine oxides (51e and 51f), underlining that the chiral Cpx ligand also has a bearing on the formation of the atropchiral biaryl axis. The obtained products could be reduced to the corresponding phosphines and hence serve as access to chiral monodentate MOPtype ligands.55 R3 N2

O P R

1

R

O

2

R

1

R3

49

Cl

Cl

50

Cat-1 (3 mol%) (S)-L10 (15 mol%) AgNTf2 (12 mol%)

OMe

dioxane or DCE, 15 °C 4198% 3799% ee

OH O P

OH O P

tBu

tBu

OH O P tBu

R1

R2

51b 97%, 95% ee

51c 85%, >20:1 dr, 98% ee

I Cat-1

R1

Ir

I

NPhth 2

(S)-L10

Axial Chiral

CO2Me OH O P

OH MeO

OH

O P

OMe

tBu

51d 61%, >20:1 dr, 99% ee

MeO

OMe OMe

51e 93%, 90% ee

O P

Me Me

OMe

OMe

51a 98%, 95% ee

CO2H

tBu OMe

51

Axial & P-Chiral

P-Chiral

OH O P

OMe

51f 73%, 92% ee


22

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ACS Catalysis

Scheme 14. C–H Arylation to Access P- and Axially Chiral Biaryl Phosphine Oxides. In 2017, Sun and Cramer reported a desymmetrization of phosphinamides 52 generating

P-chiral cyclic products 54 (Scheme 15).56 The first example of a Rh(III)-catalyzed enantiodetermining C–H activation, and subsequent trapping with internal alkynes 53 enabled the formation of the annulated products 54 in high enantioselectivity.57 Reducing the reversibility of the C–H activation was crucial to obtain high ee. This was achieved by adding the inorganic base K2CO3, which efficiently mitigated the reversibility of the enantiodetermining step. By applying atropchiral Cat-2 and Ag2CO3 as the stoichiometric oxidant, a variety of differently substituted diaryl phosphinamides were converted in good yield and high enantioselectivity.58 The alkyne acceptors could be readily exchanged. Diaryl (e.g., 54a) and unsymmetrical substituted alkynes (e.g., 54b and 54c) were capable substrates delivering the products with high ee. Additionally, the regioselectivity for unsymmetrical alkynes was >20:1 in all cases, outperforming the achiral Cp*Rh(III) catalyst, for which poor to modest regioselectivity was observed. Dialkyl alkynes were converted in high enantioselectivity as well, albeit with lower yield (e.g., 54d). Furthermore, highly enantiospecific reduction of the P(V)-products 54 to valuable P(III)chiral compounds was achieved under carefully optimized conditions.


23

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

CF3

R1 O P R1

N H

CF3

R2

52

R3

Page 24 of 41

Ag2CO3, K2CO3, tBuOH, 90 °C

R1

O P N

CF3 R3

3786% 8492% ee

53

CF3

R1

Cat-2 (5 mol%) (PhCO2)2 (5 mol%)

R2 54

Me O ArF P N

OMe OMe

Rh

Me

Ph Ph

Cat-2

54a 80%, 92% ee

Ph

O ArF P N

Ph

O ArF P N

Ph

O ArF P N

PMP Bu

Bu 54b 75%, 90% ee

54c 84%, 92% ee

Pr N Me

Pr 54d 55%, 92% ee

Scheme 15. Rh-Catalyzed Enantiotopic C–H Activation of Phosphinamides. Sun and Cramer further extended this methodology to alkyl, aryl phosphinic amides to obtain enantioenriched products through a kinetic resolution process (Scheme 16).59 Chiral phosphinic amides 55 were selectively converted into 57 due to a difference in cyclometalation rates (see Scheme 2a). Crucial for a sufficient rate difference of the two starting material enantiomers was the development of new trisubstituted Cpx ligands (Cat3).60 The application of Cat-3 enabled the resolution of phosphinic amides 55, delivering highly enantioenriched starting material (S)- 55 and cyclized products 57 with s-values61 up to 50. Different aryl substituents had little influence on the reaction performance delivering the products in high enantioselectivity (e.g., 55a and 57a). Longer alkyl chains decorated with a benzyl ether group (e.g., 55b and 57b) and unsymmetrically substituted alkynes (e.g., 55c and 57c) were suitable reaction partners delivering the products with high selectivity. Furthermore, product 57a was successfully applied as Lewis-base catalyst in an enantioselective reductive aldol reaction.


24

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ACS Catalysis

CF3 R2 O P R

1

CF3

N H

R3

R4

56

rac-55

CF3

CF3

Cat-3 (10 mol%) (BzO2)2 (10 mol%) Ag2CO3, K2CO3, tBuOH, 90 °C

R2 O P R1

s-value = 5-50

CF3

N H

+

R1

ArFHN tBu

OMe

Rh

Cat-3

O P

Me

Me O ArF P N Ph Ph

57a 55a 46%, 86% ee 46%, 90% ee s-factor = 42

ArFHN

O P

BnO

CF3 R

(S)-55

57

3750% 5899% ee OMe

R2 O P N R2

3655% 5492% ee

O ArF P N

OBn

3

ArFHN

Ph

Ph 57b 55b 47%, 86% ee 44%, 86% ee s-factor = 29

O P

Me

Me O ArF P N PMP Bu

57c 55c 46%, 88% ee 46%, 90% ee s-factor = 45

Scheme 16. Rh-Catalyzed Kinetic Resolution of Phosphinic Amides.

4

FORMATION OF SULFUR STEREOCENTERS

Biomolecules containing sulfur stereocenters are ubiquitous in nature and play an important role in the chemical reactions of general metabolism.8 In particular, chiral sulfonium ions, sulfoxides (both oxidation state IV) and sulfoximines (oxidation state VI) bind stereoselectively with enzymes in metabolic processes. Because of the significant bioactivity, an increasing number of marketed drugs and bioactive compounds entering clinical trials contain sulfoxides and sulfoximines in enantiopure form.9, 62 Furthermore, chiral sulfoximines can improve pharmacokinetic properties, compared to commonly introduced sulfone and sulfonamide derivatives.63 In addition, chiral sulfoxides are of high importance in stereoselective synthesis. Sulfoxides serve as efficient and versatile chiral auxiliaries for the formation of C–C and C–X bonds,64 or as chiral ligands in asymmetric catalysis.65 Traditional methods to access enantiopure organosulfur compounds include diastereoselective transformations, various resolution techniques and biocatalytic


25

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reactions.64,

66

Page 26 of 41

Methods to access compounds containing a sulfur stereocenter in a

catalytic asymmetric fashion are still limited in scope and efficiency.64, 67 Recently C–H activation technology has been applied to efficiently access chiral sulfoxides and sulfoximines. In 2018, Wang and co-workers introduced a Pd(II)-catalyzed enantioselective C–H olefination of diaryl sulfoxides (Scheme 17).68 A survey of a range of different monoprotected amino acids25 revealed Ac-Leu-OH as optimal ligand for this transformation. Desymmetrization of prochiral diaryl sulfoxides 58 gave the alkenylated products (60a 60c) in moderate yield and high enantioselectivity. Both ortho-substituted and electronpoor sulfoxides were converted with excellent enantioselectivity (60a and 60b). Aside from methyl acrylate, diethyl vinyl phosphonate was also a competent reaction partner delivering the product 60c with good ee. The yields were reflective of moderate conversion rates. Most likely due to strong coordination of the sulfoxides to palladium resulting in possible deactivation of the catalyst. The remaining starting materials were recovered without significant loss. Additionally, non-symmetric diaryl sulfoxides 58 were converted in a parallel kinetic resolution (see Scheme 2b) to deliver two products from the racemic starting materials. Diaryl sulfoxides with two different ortho substituents reacted to give products 60d and 60e in excellent enantioselectivity. Mechanistic studies confirmed that a regiodivergent parallel kinetic resolution was operative.


26

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ACS Catalysis

O S R1

R3

R2

58

O

CO2Me 60a 61%, 98% ee

R2

OH NHAc

60

O

S

F

Me O

R3

Ac-Leu-OH

Parallel Kinetic Resolution R1  R2 O

Me

S

R1

3172% 7099% ee

59

Me

S

Ag2CO3, HFIP, 75 - 100 °C

Desymmetrization R1 = R2 Me

O

Pd(OAc)2 (10 mol%) Ac-Leu-OH (30 mol%)

F

CO2Me 60b 52%, 99% ee

Me

S

O

OMe

Me

S

PO(OEt)2 60c 36%, 86% ee

O

OMe

S

CO2Me 60d 36%, 98% ee

MeO2C 60e 33%, 98% ee

Scheme 17. Pd-Catalyzed Enantioselective C–H Functionalization of Diaryl Sulfoxides. In

2018,

the

desymmetrization

of

sulfoximines

under

Rh(III)-catalyzed

C–H

Functionalization was reported independently by the Cramer group and by the Li group (Scheme 18).69 Symmetric diaryl sulfoximines 61 were converted applying diazo compounds 62 to form chiral-at-sulfur 1,2-benzothiazines 63 using different modifications of CpxRh(III) catalysts. Sun and Cramer applied their trisubstituted Cpx ligand (Cat-4) in combination with tert-leucine-derived ligand L11 to obtain the annulated products in high yield and enantioselectivity (e.g., 63a).59-60 A variety of different diazo compounds proved to be capable reaction partners for this transformation delivering the products in high ee. However,

application

of

less

reactive

diazo

compounds

led

to

decreased

enantioselectivity. As the trapping of the diazo reaction partner occurs after the enantiodetermining C–H activation, no influence on the ee was expected. Reversibility of the C–H activation step was suggested to explain the observed inferior results for less reactive diazo compounds. Li and co-workers applied another CpxRh(III) catalyst Cat-5 in combination with differently substituted benzoic acid derivatives achieving an


27

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Page 28 of 41

enantiodivergent desymmetrization of sulfoximines 61. The use of Cat-5 and 2methoxybenzoic acid gave benzothiazine (R)- 63a in very high yield and enantioselectivity. Interestingly, when applying 2,6-dimethoxybenzoic acid the opposite product enantiomer (S)-63a was obtained in moderate selectivity, which could be further improved to 86% ee by changing the solvent to tetrachloroethane. Additionally, the coupling of sulfoximines with α-diazo malonates was achieved using modified reaction conditions. tBu HN

R1

O S

O R1

R1

R3 see below

R2 N2

61

62

2018, Cramer Cat-4 (2.5 mol%) L11 (30 mol%) NaSbF6, tBuOH, 35 °C

6195%, 5892% ee

R1

OMe

O S  N

OMe Rh

R2 R

Cl

O

CO2H N

O

iPr Cl

OMe OMe Rh I

2

I

Cat-4

63

L11

Cat-5

2018, Li Ph

O S N Me CO2Et

(R)-63a 92%, 92% ee

2

3

Ph Conditions A: Cat-5 (2.5 mol%) 2-MeO-Ph-CO2H (50 mol%) AgNTf2 (20 mol%) MeOH, 25 °C 3097%, 8499% ee

O S N Me CO2Et

(R)-63a 96%, 96% ee

Ph Conditions B: Cat-5 (2.5 mol%) 2,6-MeO2-Ph-CO2H (50 mol%) AgNTf2 (20 mol%) TCE, 30 °C 6094%, 7692% ee

O S N Me CO2Et

(S)-63a 92%, 86% ee

Scheme 18. Rh-Catalyzed Enantioselective C–H Functionalization of Sulfoximines. Further extending this methodology, Brauns and Cramer recently presented the kinetic resolution of chiral sulfoximines (Scheme 19).70 Addressing the limitations of two identical aryl substituents, the kinetic resolution (see Scheme 2a) allowed for the conversion of racemic aryl alkyl substituted sulfoximines 64 to cyclic benzothiazines 66 and additionally provided with enantioenriched acyclic starting materials (S)-64. Screening of different trisubstituted CpxRh(III) catalysts and carboxylic acids revealed Cat-6 in combination with


28

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ACS Catalysis

phenylalanine-derived acid L12 as optimal, delivering the products 66 in excellent selectivity. A variety of different aryl and alkyl substituted sulfoximines 64 were tolerated and p-nitroaryl methyl sulfoximine 64a was resolved with excellent s-value61 and very high enantioselectivity for both the acyclic starting material (S)-64a and the annulated sulfoximine 66a. Additionally 64a was successfully converted to a known precursor of a proline-rich tyrosine kinase 2 (PYK2) inhibitor, currently undergoing clinical trials.9b

R1

R2 O S NH

O R

R3

4

MeOH, 40 °C

N2

R1

s-value = 38-200

65

rac-64

Cat-6 (3 mol%) L12 (10 mol%)

R2 O S NH

R1

R2 O S N R3 R 66

(S)-64 3949% 8699% ee

4

4250% 8297% ee

2+

2 [SbF6]OMe

H

OMe Rh N N N

Me

Me Bn

O

CO2H N

Me Me

Cat-6

L12

O

O S NH

O 2N

Me

O 2N

O S N Me CO2Me

(S)-64a 66a 47%, 96% ee 47%, 97% ee s-factor = >200

Scheme 19. Kinetic Resolution of Sulfoximines via Rh-Catalyzed C–H Functionalization.

5

CONCLUSIONS AND FUTURE PERSPECTIVES

The application of enantioselective C–H functionalization strategies has provided efficient access to valuable chiral heteroatom scaffolds over the past seven years. The reported structures include bioactive molecules currently in clinical trials and chiral ligand scaffolds, which could be applied in asymmetric catalysis. The majority of the methodologies were published from 2015 onwards and the formation of sulfur stereogenic centers via


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Page 30 of 41

enantioselective C–H functionalization was initiated only in 2018, highlighting the room for further developments. Approaches so far relied mainly on the desymmetrizing C(sp2)–H activation of prochiral substrates with formation of a heteroatom stereocenter in a distal position. Enantioselective C(sp3)–H activation is developing rapidly over the last years, enabling functionalization in closer proximity to the formed stereocenter.2b Application of these recent activation strategies to the formation of heteroatom stereocenters would enable access to more diverse, previously inaccessible product scaffolds. Another area of active research within enantioselective C–H functionalization is the application of 3d transitionmetal catalysts.2c,

2d

The base metal complexes can serve as worthwhile alternative

catalysts for established methodologies, but can also provide with complementary reactivity to the presented noble metal complexes. Hence, the introduction of 3d transition-metal catalysis would also provide with a greater diversity in accessible stereogenic heteroatom molecules. Given the great importance of chiral heteroatom scaffolds, in particular in drug discovery, we expect enantioselective C–H functionalization strategies to play an increasingly important role in target-oriented synthesis, to access complex structures containing chiral heteroatoms more efficiently.

6

AUTHOR INFORMATION 6.1

Corresponding Author

* E-mail: [email protected]


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ACS Catalysis

6.2

Notes

The authors declare no competing financial interest.

7

ACKNOWLEDGMENT

This work is supported by the Swiss National Science Foundation (no. 155967).

8 1.

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Table of Contents Graphic


40

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ACS Catalysis

BnO tBu tBu

OMe Si

Ph

MeO

tBu

S Me

Si

O P

Si

Cl

Pr

OMe

tBu

DG H C R

[M]L* (cat.)

H C

Het

Y

Ph

Ph

tBu

Me S O NH

Ph CF3 O P

Y C Ph O P

Si N H

Ph

N Ar

F3C

DG  H Het R C

tBu

O 2N

O P

OH O P

Ts

HN

Me

tBu O

Ph

O

CO2Et

ArF

F

OMe

S

O

S N Me

N H

CO2Me F

Ph P

BnO

Ph

PMB

P

F O

NHAr

N O P

Ph


41

Generation of Heteroatom Stereocenters by Enantioselective

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