Stereodivergent Synthesis through Catalytic Asymmetric Reversed

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Stereodivergent Synthesis through Catalytic Asymmetric Reversed Hydroboration Tao-tao Gao, Wen-Wen Zhang, Xin Sun, Hou-Xiang Lu, and Bi-Jie Li J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13520 • Publication Date (Web): 26 Feb 2019 Downloaded from http://pubs.acs.org on February 26, 2019

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Journal of the American Chemical Society

Stereodivergent Synthesis through Catalytic Asymmetric Reversed Hydroboration Tao-Tao Gao, Wen-Wen Zhang, Xin Sun, Hou-Xiang Lu and Bi-Jie Li* Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100084, China ABSTRACT: The control of chemo-, regio-, diastereo- and enantioselectivity is a central theme in organic synthesis. The capability to obtain the full set of stereoisomers of a molecule would significantly enhance the efficiency for the synthesis of natural product analogues and creation of chiral compound libraries for drug discovery. Despite the tremendous progress achieved in the field of asymmetric synthesis in the past decades, the precise control of both relative and absolute configurations in catalyst-controlled reactions that create multiple stereocenters remains a significant synthetic challenge. We report here the development of a catalystcontrolled hydroboration with hitherto unattainable selectivity. The Rh-catalysed hydroboration of α, β-unsaturated carbonyl compounds with pinacolborane proceeds with high level of regio-, diastereo-, and enantio-selectivities to provide hydroboration product with two vicinal stereocenters. Through the appropriate choice of substrate geometry (E or Z) and ligand enantiomer (S or R), all the possible diastereoisomers are readily accessible. The boron-containing products underwent many stereospecific transformations, thus providing a strategy for collective stereodivergent synthesis of diverse valuable chiral building blocks.

1.

Introduction Hydroboration of alkenes is a tremendously useful method in organic synthesis which is recognized by the Nobel Prize in 1979. It has been routinely practiced by organic chemists during the synthesis of small molecules, natural products, agrochemicals and bioactive compounds. In addition to the operational simplicity, the predictable selectivity of hydroboration has rendered it an extremely reliable tool for alkene functionalization.1 Hydroboration of electron-rich terminal olefins occurs with inherent anti-Markovnikov selectivity, which places the boron at the terminal position of the alkene (Scheme 1, A). In addition to minimize steric repulsion, the electron-donating substituent of the alkene can stabilize the positive charge developed in the transition state.2 Consistent with this electronic requirement, it has been observed since 1964 that hydroboration of electron-deficient alkenes, for example, α, β-unsaturated carbonyl compounds, resulted in the introduction of the hydride at the β position and the boron at the α position (Scheme 1, B).3 The α-boryl carbonyl compound formed easily underwent further hydrolysis. Consequently, in contrast to the hydroboration of electron-rich olefin, the synthetic power of the hydroboration of electrondeficient olefin has not been fully established. For more than 50 years, this selectivity has not been challenged. In the context of a program aimed at achieving challenging selectivity for useful synthetic methods,4 we wondered if we could harness the power of transition metal catalysis5 to achieve a reversed hydroboration. Specifically, we anticipated the hydroboration of α, β-unsaturated carbonyl compound would occur to deliver the hydride at the α position and the boron at the β position.6 If the regioselectivity could be reversed and the stereoselectivity could be controlled, this process would result in a powerful stereoselective method for creation of two stereocenters α and β to a carbonyl group simultaneously (Scheme 1, C). In addition, this strategy would create vast opportunity for stereodivergent synthesis.7 First, because the

catalytic hydroboration is a stereospecific process, the synaddition would enable the diastereoselectivity of the vicinal stereocenters to be precisely controlled. Second, both E and Z isomers of α, β-unsaturated carbonyl compounds are easily available. The relative configuration of the product would be readily tuned by the configuration of the substrate. Through effect catalyst control and appropriate choice of substrate geometry (E or Z), the full set of stereoisomeric products would be readily accessible through this method. The successful implement of this strategy will open a new door for the precise control of regio-, diastereo- and enantio-selectivities of alkene hydroboration. However, substantial challenges exist for the reversed catalytic hydroboration of α, β-unsaturated carbonyl compounds. First, similar to the selectivity observed in the uncatalysed hydroboration of α, β-unsaturated carbonyls, Evans and Fu discovered that rhodium-catalysed hydroboration of α, β-unsaturated carbonyl compounds afforded solely conjugated reduction product in as early as 1990.8 Thus, new catalyst must be identified to overcome this intrinsic selectivity. Second, because the reversed catalytic hydroboration generates two stereocenters in a single operation, the new catalyst must be capable of effective control of both the diastereoselectivity and enantioselectivity. While asymmetric synthesis of organoboranes with a single stereocenter could be achieved in high selectivity, catalytic hydroboration that creates two vicinal stereocenters is particularly rare.9 Although asymmetric boration of α, β-unsaturated carbonyl compound that generate a single stereocenter could be realized through catalytic protoboration using pinacol diborane and a proton source,10 this process is not stereospecific, and consequently catalyst enabled diastereocontrol is not possible.11

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Scheme 1. Catalytic Hydroborations. A. Hydroboration of Alkenes: Nobel Prize in 1979

H B

+

R



-

BR2

H B R

R

R B. Since 1964: Hydroboration of Electron-Deficient Alkene O

O

+ -

H B



O

H B R

R

O

BR2

R

R

[H+]

C. This Work (2019): Reversed Hydroboration of Electron-Deficient Alkene

O

B H

cat. H B

O

X H

O

R

H O

C H

H

R B H R

R

O

All Stereoisomers Accessible

H

Analysis of the potential pathways for catalytic reduction and hydroboration reveals the key design principle for a reversed hydroboration. For the boryl metal hydride intermediate obtained through oxidative addition of hydroborane, the way of the migratory insertion of the alkene dictates the regioselectivity (Scheme 2). Therefore, if an appropriate ligand could be identified to reverse the selectivity and control the enantioselectivity of this elementary step, an unprecedented stereoselective reversed hydroboration process would be achieved. Scheme 2. Design of a Reversed Hydroboration. O Me Amide

P

Me

Rh

P

H

H

Me

Me

P

nPr

NHEt Amide

P

O Bpin

HBpin

Reduction

Me

H Me

Rh O Bpin

O

H Bpin

HBpin (2.0 equiv) CHCl3, r.t, 12 h

Bn nPr

N H

2a

2a (%)

2b (%)

ee (%)

ligand

2a (%)

2b (%)

L1

90

20:1 dr, 95% ee

OH O Br

N H

2

Et

N H

Bn

5h, 58%, >20:1 dr, 95% ee

5k, 59%, >20:1 dr, 93% ee

Me

N H

Me

5g, 79%, >20:1 dr, 98% ee

Ph

S N H

5d, 79%, >20:1 dr, 97% ee

OH O

N H Me

Me

Me

OH O

OH O N H

Me

N H

Me

N H Me 5f, 84%, >20:1 dr, 97% ee

Me

OH O

O

5c, 55%, >20:1 dr, 93% ee

5j, 67%, >20:1 dr, 92% ee

OH O

Cl

Me

Cl

OH O

OH O Me

N H

OH O Me

AcO

Me

5b, 77%, >20:1 dr, 96% ee

NH

OH O Me

OH O

OH O

Me

Me O

N H

5p, 61%, >20:1 dr, 94% ee

Me


2.2 Substrate Scope. The catalytic system has broad substrate scope (Table 2). Because the hydroboration product and the minor reduction product are difficult to separate, the organoboronates were further oxidized to form the corresponding alcohols. Amides with alkyl and aryl substituents on the nitrogen atom or the vinylic position underwent selective β-boration. Functional groups including thiophene, indole, alkene and aryl halides were compatible with the catalytic system (3a-3p). Chemoselective hydroboration occurred preferentially at the electron-deficient alkene for substrate 1h containing alkenes with different electronic properties. Unsaturated lactams did not undergo hydroboration in the current system because of the conformational constrain. Despite significant effort directed towards the enantioselective hydroboration of 1,1-disubstituted alkene, current existing methods were mainly limited to styrene derivatives.14 In addition to 1,2-disubstituted alkene, our catalytic system is applicable to 1,1-disubstituted alkene. Catalytic hydroboration of acrylamide with α-substitution proceeded smoothly to give enantio-pure α-substituted carbonyl compounds. With a catalyst effective for installation of stereocenters at both the α and β positions, we further tested the possibility to create two vicinal stereocenters. In the presence of the rhodium catalyst and JoSPO ligand, a range of α, β-disubstituted acrylamides underwent reversed hydroboration to give the carbonyl compounds with two stereocenters in high enantioselectivities (Table 2). The absolute configuration was determined by X- ray structure of the alcohol 5m. Remarkably, complete diastereo-controls were observed in all these cases, as a result of the stereospecificity of the catalytic hydroboration process (5a-5p). Thus, the stereospecific syn-addition ensures the complete diastereoselectivity and the effective catalyst control governs the high enantioselectivity. However, the reactions of β, β-disubstituted acrylamides generated mainly reduction products, due to the large sterics for forming tertiary boronic esters. Scheme 3. Stereodivergent Hydroboration. OH O Ar Me

OH O N H

Me

(E)-1, L8

(E)-1, ent-L8

then [Ox]

then [Ox]

(S,R)-5q, 84% >20:1 dr, 96% ee

Me

Me

N H

Me

(R,S)-5q, 82% >20:1 dr, 95% ee

O Ar

Ar

N H

2.4 Diversification of Organoboranes. The boron element in the reversed hydroboration products provides an exceptional handle for further transformations (Scheme 4).15 For example, stereospecific oxidation of the organoboron generates a hydroxyl group, thus enabling all four stereoisomers of aldoltype products to be obtained. Catalytic asymmetric aldol reactions are typically either syn- or anti-selective. A catalytic method for a highly selective, stereodivergent aldol remains to be developed.16 Our highly modular and stereodivergent hydroboration-oxidation sequence provides a possible entry to this synthetic challenge.7a In addition to oxidation, the hydroboration product underwent C-C bond formation. Furthermore, the amide group could be reduced to an aldehyde which could undergo further transformations. Scheme 4. Diversification of Organoboranes. Et

then I2

Et Me

N H

Ar Me

N H

(R,R)-5q, 71% >20:1 dr, 92% ee

then [Ox]

then [Ox]

Me Ar = 4-BrC6H4

N H

Me

KHF2

6, 99% >20:1 dr, 96% ee

N H

Bn

7, 89% >20:1 dr, 97% ee

N H

Bn

8, 87% >20:1 dr

K+ BF3- O Et Me

2-fluoropyridine Triflic anhydride

TBDPSO

then HSiEt3

Et

O H

9, 72% 7:1 dr, 92% ee

Me

2.5 Functionalization of Drug-Derived Molecules. To further demonstrate the functional group tolerance of this reversed hydroboration, we applied the catalyst system to complex substrates derived from bioactive molecules (Scheme 5). Catalytic hydroboration of α, β-unsaturated amides derived from Paroxetine, Sertraline, dehydroabietylamine and Rivaroxaban afforded the hydroboration products in high diastereoselectivities. The existing stereocenters on these substrates had little impact on the diastereocontrols. These results demonstrate that the catalytic system has potential to functionalize relatively complex molecules.

OH O Ar

Et

Bn

2c, 97% ee

Bn

O

vinyl-MgBr Bpin O

1

(Z)-1, ent-L8

N H

Me

Me

(Z)-1, L8 Me

OH O

NaBO3

H Bpin

OH O

Page 4 of 9

Me

(S,S)-5q, 70% >20:1 dr, 93% ee

2.3 Stereodivergent Synthesis. Subsequently, we attempted the stereodivergent synthesis of all possible stereoisomers through our method (Scheme 3). The two anti-enantiomers could be prepared through catalytic hydroboration of E-amide using ligand L8 and ent-L8, respectively. By simply switching to Z-amide, the two syn-enantiomers could be readily accessible through a similar strategy. The four stereoisomers of 5q were obtained in good yields, with complete diastereo-controls (>20:1) and high enantioselectivities (>90% ee).


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Journal of the American Chemical Society Scheme 5. Functionalization of Drug-Derived Molecules. O N

Rh(COD)2OTf (3-5 mol%) L8 (3.6-6.0 mol%)

OH O

NaBO3

N

HBpin (2.0 equiv) CHCl3, r.t, 12 h Me OH O

Me

N

OH N

O

O

F

O O

Cl

10, 77%, >20:1 dr derived from Paroxetine psychotropic drug

Cl

11, 73%, >20:1 dr derived from Sertraline antidepressant

Me

Me

HO O

Me Me

O

NH

O N

OH N H

O

O N O 12, 74%, >20:1 dr derived from dehydroabirtylamine

13, 71%, >20:1 dr derived from intermediate of Rivaroxaban, antithrombotic

2.6 Computational Studies. The ligand has a pronounced effect on the unusual selectivity of the hydroboration process. To gain insight into the origin of the regio- as well as enantioselectivity, computational studies were conducted. As a comparison, the energy profiles of catalytic hydroboration using PPh3 and JoSPO ligands were computed. For each ligand, both pathways that lead to hydroboration and reduction products were analyzed. Extensive conformational searches were conducted for all intermediates and transition states, and the lowest energy conformers are shown (see Supporting Info for details). The catalytic hydroboration with PPh3 as a ligand starts with ligand displacement to form an amide-bound cationic rhodium complex (Fig. 1, A). Oxidative addition of pinacolborane to the rhodium center generates a five-coordinated rhodium hydride (Int-3a). After migratory insertion of the alkene into the rhodium hydride, an alkyl rhodium complex (Int-5a) is formed, in which the amide is coordinated to the metal center. Finally, C-B reductive elimination delivers the hydroboration product after dissociation. The highest energy transition state is the migratory insertion step (TS-4a). The catalytic reduction process proceeds through a similar mechanism. The key

difference is the orientation of the alkene in the alkene bound rhodium complex that undergoes migratory insertion. In transition state TS-4b, migratory insertion delivers the hydride to the β-position of the α, β-unsaturated amide. Subsequent CB reductive elimination gives rise to α-borylation product 15b, which undergoes protonolysis to form the reduction product. The highest energy transition state of the catalytic reduction process is also the migratory insertion step (TS-4b). The computation results indicate that catalytic reduction is favored over catalytic hydroboration by 1.2 kcal/mol. Experimentally, the reduction product was observed predominantly when PPh3 was used as a ligand. The catalytic reaction with JoSPO ligand follows a similar mechanism (Fig. 1, B). However, the activation energy difference between reduction and hydroboration was reversed. The migratory insertion leading to hydroboration (TS-4c) has an activation barrier of 20.5 kcal/mol while the migratory insertion leading to reduction (TS-4d) has an activation barrier of 21.8 kcal/mol. Therefore, the reversed hydroboration is favored over reduction when JoSPO was used as a ligand. This is also in agreement with the experimental observations. These computation results indicate that the activation energies of the migratory insertions dictate the regioselectivity of the catalytic reaction. The JoSPO ligand has a tremendous effect to lower the energy barrier for the migratory insertion that leads to hydroboration. Comparison of the two transition state structures (TS-4c and TS-4d) reveals the origin of this unusual ligand effect (Fig. 1, C). First, the hydroxyl group on one phosphine atom forms a hydrogen bonding with the oxygen of the pinalcolboryl group. The bond length of OH…O in TS-4c is substantially shorter than that in TS-4d (1.74 Å vs 1.83 Å). Thus, the stronger hydrogen bonding in TS-4c helps to stabilize the transition state. Second, the phenyl group on the other phosphine atom of the ligand forms an attractive CH…O interaction with the carbonyl group of the substrate (CH…O distance 2.29 Å) in TS-4c.17 In contrast, such interaction is not possible in TS-4d due to the orientation of the carbonyl group. This attractive interaction also plays a role to lower the activation free energy of TS-4c. Finally, the JoSPO ligand is positioned in a way that allows coordination of the amide to the metal center in TS-4c (Rh-O length 2.77 Å, bond order 0.14). No such coordination was observed in TS-4d. In PPh3 ligated TS-4a, the coordination of the amide to the rhodium center is significantly weaker (Rh-O length 3.02 Å, bond order 0.08). The coordination of the amide further stabilizes the transition state connected to hydroboration. Taken together, the JoSPO ligand has the unique properties to form hydrogen bonding through the hydroxyl group, to form attractive CH…O interaction through the phenyl group, and to accommodate coordination of the amide group to the metal center. It is likely that the hydrogen bonding played a major role (see SI for details of further analysis). These features of the ligand contribute to the reversal of the selectivity of the alkene migratory insertion step, allowing an unprecedented hydroboration process to be realized.



P

G(CHCl3, kcal/mol) Borylation Path Reduction Path P

Rh

HBpin

P 14 14 0.0

P

P

P

Rh =

P

Ph3P

Int-5b 18.5

NHEt H O

P H

P

Rh

Int-3b

O NHEt Bpin TS-6a

Rh

O B

P

O H

Rh

P

O

NHEt

Int-7a Bpin O

H NHEt

O Bpin Int-5b

P

H Bpin TS-4b

P

Bpin

Rh

P

TS-6a 22.4

Int-5a 16.4

Rh

H

P

O NHEt Bpin Int-5a

TS-6b 25.2

TS-4b 25.9

NHEt H O

P

H Bpin TS-2b

P

NHEt TS-4a

H Rh

TS-4a 27.1

Int-3a 23.5

Rh

P

Bpin

Int-3b 24.0

NHEt H O

1

H

Bpin Int-3a

TS-2b 25.8

P O

Rh

P

NHEt

H

P

H

P

O

Rh

TS-2a 26.4

O NHEt

Int-1 13.0

Rh

P

TS-2a

Bpin

Rh Int-1

O NHEt

H

P Me

H

P

P

H

H

A

Page 6 of 9

P P

H Rh

NHEt

Bpin

O

Me

Int-7a 3.7 Int-7b -1.3

TS-6b

O B

P

Rh

Ph3P

Et

15b -12.8 15a -13.8 O

O H

Rh

P

N 15a H

O NHEt Int-7b

Me

Et N H BPin 15b

reaction coordinate

B

H

G(CHCl3, kcal/mol)

P

Borylation Path

H

P

Reduction Path

Rh

P

O NHEt Int-1c

P

16

Int-1c 8.4

1

16 0.0

P

P

O H

H H

P

NHEt

O Rh

P NHEt

P

P Int-1d

O Rh

Bpin

P

NHEt TS-4c

H P

Rh O NHEt Bpin Int-5c

TS-4d 21.8 Int-3d 17.4

P

H Bpin

O NHEt Bpin TS-6c

TS-6c 18.5

Int-5c 12.5

NHEt H O

P

Rh

P

P

P

Rh H

P

Rh

Bpin TS-4d

Int-3d

NHEt O Bpin Int-5d

P P

H Rh Bpin

NHEt O

TS-6d

tBu

P O

P

P Rh

Fe

H NHEt Bpin O Me

O B

N H

Et

15a 15b -12.8

Int-7d -4.7

P * Rh = P

O

Int-7c 0.5

Me

P

O

Int-7c

H

P

O B Rh

P

Int-5d 12.1

NHEt H O

P

H Rh

TS-6d 19.9

TS-4c 20.5

Int-3c 17.0

NHEt H

H Bpin TS-2d

P O

Rh

Bpin Int-3c

TS-2c 17.4

Int-1d 10.4

Rh

Rh

P

TS-2d 17.7

HBpin P

TS-2c

Bpin

P

Me

H

P

Rh

H O NHEt

15a -13.8 O

O H

Rh O NHEt Int-7d

Me

Et N H BPin 15b

H

reaction coordinate

C

Me H P O tBu P Rh O HB H O O

Fe

TS-4c

Me

Me NHEt Me

P Me tBu P Rh H O B H O O

P Me tBu P Rh NHEt O HB H O OO

Fe

Fe

NHEt O

TS-4d

TS-4c'

Fig. 1. Computational studies of reversed hydroboration. A, Energy profile with PPh3 ligand. B, Energy profile with JoSPO ligand. C, Structures of key transition states. Calculations were carried out at the M06/6-311++g(d,p)/SDD//B3LYP/6-31g(d,p)/Lanl2dz level of theory.


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Journal of the American Chemical Society To further understand the origin of enantioselectivity, the energies of the transition states leading to the opposite enantiomer were computed. The lowest energy pathway has an activation barrier of 24.6 kcal/mol (TS-4c’). The energy difference between TS-4c and TS-4c’ (4.1 kcal/mol) correlates with the high enantioselectivity observed (see SI for TS-4d’ and related structures). In TS-4c’, the α, β-unsaturated amide coordinates to rhodium through the opposite enantio-face to that in TS-4c. In TS-4c’, the carbonyl group is positioned away from the metal center. Consequently, the CH…O interaction with the phenyl group on the ligand and the coordination to the metal center are not possible in this structure. The absence of these stabilization effect in TS-4c’ contributes to the higher energy of this transition state and leads to the high enantioselectivity observed. 3. Conclusion In summary, we have developed a new strategy for catalytic asymmetric hydroborations, specifically, rhodium-catalysed reversed hydroboration of α, β-unsaturated carbonyl compounds. This strategy allows the access to a hydroboration selectivity that has not been possible for many years. The effective catalyst control and the stereospecificity of hydroboration enables precise control of both diastereoselectivity and enantioselectivity, leading to stereodivergent synthesis of all possible stereoisomers. In addition, the boron group in these products undergoes a variety of stereospecific transformations. The combination of the stereodivergent catalytic hydroboration process and the subsequent stereospecific transformation of the organoboron compounds provides a platform for collective stereodivergent synthesis of diverse chiral building blocks. We anticipate this novel strategy will find ample applications in both organic synthesis and drug discovery.

ASSOCIATED CONTENT Experimental procedures, characterization of new compounds, crystallographic data (CIF) and spectroscopic data are provided in the Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author [email protected]

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (Grant No. 91856107), 111 Project (B16028) and National Program for Thousand Young Talents of China.

REFERENCES (1) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Middland, M. M. Organic Synthesis via Boranes Wiley-Interscience: New York, 1975. (2) Klein, D. Organic Chemistry, Second Edition; John Wiley & Sons, 2015. (3) (a) Brown, H. C.; Keblys, K. A. Hydroboration. XXII. The Reaction of Unsaturated Esters with Diborane and Disiamylborane. J. Am. Chem. Soc. 1964, 86, 1795; (b) Brown, H. C.; Chen, J. Hydroboration. 57. Hydroboration with 9-borabicyclo[3.3.1]nonane of alkenes containing representative functional groups. J. Org. Chem. 1981, 46, 3978; (c) Boldrini, G. P.; Mancini, F.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. A new approach to (Z)-vinyloxyboranes via 1,4 hydroboration of (E)-α,β-unsaturated ketones. Synthesis of syn aldols.

J. Chem. Soc., Chem. Commun. 1990, 1680; (d) Allais, C.; Tsai, A. S.; Nuhant, P.; Roush, W. R. Generation of Stereochemically Defined Tetrasubstituted Enolborinates by 1,4-Hydroboration of α,βUnsaturated Morpholine Carboxamides with (Diisopinocampheyl)borane. Angew. Chem. Int. Ed. 2013, 52, 12888. (4) (a) Bai, X. Y.; Zhang, W. W.; Li, Q.; Li, B. J. Highly Enantioselective Synthesis of Propargyl Amides through Rh-Catalyzed Asymmetric Hydroalkynylation of Enamides: Scope, Mechanism, and Origin of Selectivity. J. Am. Chem. Soc. 2018, 140, 506; (b) Wang, Z.X.; Bai, X.-Y.; Yao, H.-C.; Li, B.-J. Synthesis of Amides with Remote Stereocenters by Catalytic Asymmetric γ-Alkynylation of α,βUnsaturated Amides. J. Am. Chem. Soc. 2016, 138, 14872; (c) Bai, X.Y.; Wang, Z.-X.; Li, B.-J. Iridium-Catalyzed Enantioselective Hydroalkynylation of Enamides for the Synthesis of Homopropargyl Amides. Angew. Chem. Int. Ed. 2016, 55, 9007. (5) Burgess, K.; Ohlmeyer, M. J. Transition-metal promoted hydroborations of alkenes, emerging methodology for organic transformations. Chem. Rev. 1991, 91, 1179. (6) Zhou, N.; Yuan, X.-A.; Zhao, Y.; Xie, J.; Zhu, C. Synergistic Photoredox Catalysis and Organocatalysis for Inverse Hydroboration of Imines. Angew. Chem. Int. Ed. 2018, 57, 3990. (7) (a) Krautwald, S.; Carreira, E. M. Stereodivergence in Asymmetric Catalysis. J. Am. Chem. Soc. 2017, 139, 5627; (b) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Enantio- and Diastereodivergent Dual Catalysis: α-Allylation of Branched Aldehydes. Science 2013, 340, 1065; (c) Schindler, C. S.; Jacobsen, E. N. A new twist on cooperative catalysis. Science 2013, 340, 1052; (d) Shi, S.-L.; Wong, Z. L.; Buchwald, S. L. Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols. Nature 2016, 532, 353; (e) Huo, X.; He, R.; Zhang, X.; Zhang, W. An Ir/Zn Dual Catalysis for Enantio- and Diastereodivergent α-Allylation of αHydroxyketones. J. Am. Chem. Soc. 2016, 138, 11093; (f) Jiang, X.; Beiger, J. J.; Hartwig, J. F. Stereodivergent Allylic Substitutions with Aryl Acetic Acid Esters by Synergistic Iridium and Lewis Base Catalysis. J. Am. Chem. Soc. 2017, 139, 87; (g) Cruz, F. A.; Dong, V. M. Stereodivergent Coupling of Aldehydes and Alkynes via Synergistic Catalysis Using Rh and Jacobsen's Amine. J. Am. Chem. Soc. 2017, 139, 1029; (h) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. Control of Diastereoselectivity in Tandem Asymmetric Reactions Generating Nonadjacent Stereocenters with Bifunctional Catalysis by Cinchona Alkaloids. J. Am. Chem. Soc. 2007, 129, 768. (8) Evans, D. A.; Fu, G. C. Conjugate reduction of .alpha.,.beta.unsaturated carbonyl compounds by catecholborane. J. Org. Chem. 1990, 55, 5678. (9) (a) Collins, B. S. L.; Wilson, C. M.; Myers, E. L.; Aggarwal, V. K. Asymmetric Synthesis of Secondary and Tertiary Boronic Esters. Angew. Chem. Int. Ed. 2017, 56, 11700; (b) Smith, S. M.; Takacs, J. M. Amide-Directed Catalytic Asymmetric Hydroboration of Trisubstituted Alkenes. J. Am. Chem. Soc. 2010, 132, 1740. (10) (a) Schiffner, J. A.; Müther, K.; Oestreich, M. Enantioselective Conjugate Borylation. Angew. Chem. Int. Ed. 2010, 49, 1194; (b) Calow, A. D. J.; Whiting, A. Catalytic methodologies for the β-boration of conjugated electron deficient alkenes. Org. Biomol. Chem. 2012, 10, 5485; (c) Lee, J.-E.; Yun, J. Catalytic Asymmetric Boration of Acyclic α,β-Unsaturated Esters and Nitriles. Angew. Chem. Int. Ed. 2008, 47, 145; (d) Chen, I. H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. Catalytic Asymmetric Synthesis of Chiral Tertiary Organoboronic Esters through Conjugate Boration of β-Substituted Cyclic Enones. J. Am. Chem. Soc. 2009, 131, 11664; (e) O’Brien, J. M.; Lee, K.-s.; Hoveyda, A. H. Enantioselective Synthesis of Boron-Substituted Quaternary Carbons by NHC−Cu-Catalyzed Boronate Conjugate Additions to Unsaturated Carboxylic Esters, Ketones, or Thioesters. J. Am. Chem. Soc. 2010, 132, 10630; (f) Luo, Y.; Roy, I. D.; Madec, A. G. E.; Lam, H. W. Enantioselective Synthesis of Allylboronates and Allylic Alcohols by Copper-Catalyzed 1,6-Boration. Angew. Chem. Int. Ed. 2014, 53, 4186. (11) (a) He, Z.-T.; Zhao, Y.-S.; Tian, P.; Wang, C.-C.; Dong, H.-Q.; Lin, G.-Q. Copper-Catalyzed Asymmetric Hydroboration of αDehydroamino Acid Derivatives: Facile Synthesis of Chiral βHydroxy-α-amino Acids. Org. Lett. 2014, 16, 1426; (b) Kubota, K.; Hayama, K.; Iwamoto, H.; Ito, H. Enantioselective Borylative



Dearomatization of Indoles through Copper(I) Catalysis. Angew. Chem. Int. Ed. 2015, 54, 8809; (c) Chen, L.; Shen, J.-J.; Gao, Q.; Xu, S. Synthesis of cyclic chiral α-amino boronates by copper-catalyzed asymmetric dearomative borylation of indoles. Chem. Sci. 2018, 9, 5855. (12) Landert, H.; Spindler, F.; Wyss, A.; Blaser, H.-U.; Pugin, B.; Ribourduoille, Y.; Gschwend, B.; Ramalingam, B.; Pfaltz, A. Chiral Mixed Secondary Phosphine-Oxide–Phosphines: High-Performing and Easily Accessible Ligands for Asymmetric Hydrogenation. Angew. Chem. Int. Ed. 2010, 49, 6873. (13) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Substrate-directable chemical reactions. Chem. Rev. 1993, 93, 1307; (b) Smith, S. M.; Thacker, N. C.; Takacs, J. M. Efficient amide-directed catalytic asymmetric hydroboration. J. Am. Chem. Soc. 2008, 130, 3734; (c) Zultanski, S. L.; Fu, G. C. Catalytic Asymmetric γ-Alkylation of Carbonyl Compounds via Stereoconvergent Suzuki Cross-Couplings. J. Am. Chem. Soc. 2011, 133, 15362; (d) Shoba, V. M.; Thacker, N. C.; Bochat, A. J.; Takacs, J. M. Synthesis of Chiral Tertiary Boronic Esters by Oxime-Directed Catalytic Asymmetric Hydroboration. Angew. Chem. Int. Ed. 2016, 55, 1465; (e) Xi, Y.; Hartwig, J. F. Diverse Asymmetric Hydrofunctionalization of Aliphatic Internal Alkenes through Catalytic Regioselective Hydroboration. J. Am. Chem. Soc. 2016, 138, 6703; (f) Derosa, J.; Kleinmans, R.; Tran, V. T.; Karunananda, M. K.; Wisniewski, S. R.; Eastgate, M. D.; Engle, K. M. Nickel-Catalyzed 1,2-Diarylation of Simple Alkenyl Amides. J. Am. Chem. Soc. 2018, 140, 17878; (g) Liu, M.; Yang, P.; Karunananda, M. K.; Wang, Y.; Liu, P.; Engle, K. M. C(alkenyl)-H Activation via SixMembered Palladacycles: Catalytic 1,3-Diene Synthesis. J. Am. Chem. Soc. 2018, 140, 5805. (14) (a) Thomas, S. P.; Aggarwal, V. K. Asymmetric Hydroboration of 1,1-Disubstituted Alkenes. Angew. Chem. Int. Ed. 2009, 48, 1896; (b) Zhang, L.; Zuo, Z.; Wan, X.; Huang, Z. Cobalt-Catalyzed Enantioselective Hydroboration of 1,1-Disubstituted Aryl Alkenes. J. Am. Chem. Soc. 2014, 136, 15501; (c) Chen, J.; Xi, T.; Ren, X.; Cheng, B.; Guo, J.; Lu, Z. Asymmetric cobalt catalysts for hydroboration of 1,1-disubstituted alkenes. Org. Chem. Front. 2014, 1, 1306; (d) Zhang, H.; Lu, Z. Dual-Stereocontrol Asymmetric Cobalt-Catalyzed Hydroboration of Sterically Hindered Styrenes. ACS Catalysis 2016, 6, 6596; (e) Jang, W. J.; Song, S. M.; Moon, J. H.; Lee, J. Y.; Yun, J. Copper-Catalyzed Enantioselective Hydroboration of Unactivated 1,1Disubstituted Alkenes. J. Am. Chem. Soc. 2017, 139, 13660; (f) Smith, S. M.; Hoang, G. L.; Pal, R.; Khaled, M. O. B.; Pelter, L. S. W.; Zeng, X. C.; Takacs, J. M. [gamma]-Selective directed catalytic asymmetric

hydroboration of 1,1-disubstituted alkenes. Chem. Commun. 2012, 48, 12180; (g) He, J.; Shao, Q.; Wu, Q.; Yu, J.-Q. Pd(II)-Catalyzed Enantioselective C(sp3)–H Borylation. J. Am. Chem. Soc. 2017, 139, 3344; (h) Wang, C.; Ge, S. Versatile Cobalt-Catalyzed Enantioselective Entry to Boryl-Functionalized All-Carbon Quaternary Stereogenic Centers. J. Am. Chem. Soc. 2018, 140, 10687; (i) Zhang, L.-S.; Chen, G.; Wang, X.; Guo, Q.-Y.; Zhang, X.-S.; Pan, F.; Chen, K.; Shi, Z.-J. Direct Borylation of Primary C-H Bonds in Functionalized Molecules by Palladium Catalysis. Angew. Chem. Int. Ed. 2014, 53, 3899. (15) (a) Sandford, C.; Aggarwal, V. K. Stereospecific functionalizations and transformations of secondary and tertiary boronic esters. Chem. Commun. 2017, 53, 5481; (b) Matteson, D. S. Boronic Esters in Asymmetric Synthesis. J. Org. Chem. 2013, 78, 10009; (c) Mlynarski, S. N.; Schuster, C. H.; Morken, J. P. Asymmetric synthesis from terminal alkenes by cascades of diboration and crosscoupling. Nature 2013, 505, 386; (d) Hu, N.; Zhao, G.; Zhang, Y.; Liu, X.; Li, G.; Tang, W. Synthesis of Chiral α-Amino Tertiary Boronic Esters by Enantioselective Hydroboration of α-Arylenamides. J. Am. Chem. Soc. 2015, 137, 6746; (e) Zhang, L.; Lovinger, G. J.; Edelstein, E. K.; Szymaniak, A. A.; Chierchia, M. P.; Morken, J. P. Catalytic conjunctive cross-coupling enabled by metal-induced metallate rearrangement. Science 2016, 351, 70; (f) Schmidt, J.; Choi, J.; Liu, A. T.; Slusarczyk, M.; Fu, G. C. A general, modular method for the catalytic asymmetric synthesis of alkylboronate esters. Science 2016, 354, 1265; (g) Kim, J.; Ko, K.; Cho, S. H. Diastereo- and Enantioselective Synthesis of β-Aminoboronate Esters by Copper(I)Catalyzed 1,2-Addition of 1,1-Bis[(pinacolato)boryl]alkanes to Imines. Angew. Chem. Int. Ed. 2017, 56, 11584. (16) (a) Schetter, B.; Mahrwald, R. Modern aldol methods for the total synthesis of polyketides. Angew. Chem., Int. Ed. 2006, 45, 7506; (b) Trost, B. M.; Brindle, C. S. The direct catalytic asymmetric aldol reaction. Chem. Soc. Rev. 2010, 39, 1600. (17) (a) Li, Q.; Liskey, C. W.; Hartwig, J. F. Regioselective Borylation of the C–H Bonds in Alkylamines and Alkyl Ethers. Observation and Origin of High Reactivity of Primary C–H Bonds Beta to Nitrogen and Oxygen. J. Am. Chem. Soc. 2014, 136, 8755; (b) Huang, Z.; Lim, L. H.; Chen, Z.; Li, Y.; Zhou, F.; Su, H.; Zhou, J. Arene CH-O Hydrogen Bonding: A Stereocontrolling Tool in Palladium-Catalyzed Arylation and Vinylation of Ketones. Angew. Chem. Int. Ed. 2013, 52, 4906.


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Journal of the American Chemical Society

Insert Table of Contents artwork here O

Rh(I)/L (3-5 mol%) N

HBpin (2.0 equiv) CHCl3, r.t, 12 h > 90% ee

Bpin O N

O H P tBu

PPh2 Fe

All Stereoisomers Accessible


9

Stereodivergent Synthesis through Catalytic Asymmetric Reversed

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