Rhodium-Catalyzed Enantioconvergent Isomerization of Homoallylic

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Rhodium-Catalyzed Enantioconvergent Isomerization of Homoallylic and Bishomoallylic Secondary Alcohols Rui-Zhi Huang, Kai Kiat Lau, Zhao-Feng Li, Tang-Lin Liu, and Yu Zhao J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07007 • Publication Date (Web): 15 Oct 2018 Downloaded from http://pubs.acs.org on October 15, 2018

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Journal of the American Chemical Society

Rhodium-Catalyzed Enantioconvergent Isomerization of Homoallylic and Bishomoallylic Secondary Alcohols Rui-Zhi Huang,† Kai Kiat Lau,† Zhaofeng Li,‡ Tang-Lin Liu,*, †,‡ and Yu Zhao*,† †Department ‡

of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore 117543 School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China

Me

OH R1

R2

R1

R2

R2

up to 95% up to 95% ee

catalytic [Rh], catalytic base

or

R1

O

or

stereoconvergent isomerization; no stoichiometric reagent or waste

Me R2

R1

OH

O


() Practical procedure to access chiral ketones with a  or -stereocenter Concomitant oxidative kinetic resolution of homoallylic alcohol substrates ligand-controlled alkene or redox isomerization of bishomoallylic alcohols

ABSTRACT: We present herein an unprecedented enantioselective isomerization of homoallylic and bishomoallylic secondary alcohols, catalyzed by a commercially available rhodium-complex and a base. This catalytic redox-neutral process provides an effective access to chiral ketones in high efficiency and enantioselectivity, without the use of any stoichiometric reagent or generation of any waste. For the reaction of homoallylic alcohols, this system achieved not only a stereoconvergent access to chiral ketones bearing a β–stereocenter (up to 95%, 86% ee), but also a concomitant oxidative kinetic resolution of the alcohol substrates (S >20). In the case of bishomoallylic alcohols, an intriguing ligand-induced divergent reactivity was observed. A terminal-to-internal alkene isomerization promoted by Rh/L7 followed by redox isomerization using Rh/BINAP system produced chiral ketones bearing a γstereocenter with high yield and enantioselectivity. Mechanistic studies provided strong support for the redox-isomerization pathway with chain walking of the key alkyl-Rh intermediate.

INTRODUCTION To achieve sustainable chemical synthesis, the atom, step and redox economy of a new synthetic method represent key parameters for the measure of its efficiency.1 Consequently, cascade isomerization reactions are highly attractive due to their redox-neutral, atom-economical nature, and their ability of converting readily available materials to more complex target molecules. The catalytic isomerization of allylic alcohols, particularly, has proven to be a powerful tool to deliver synthetically valuable carbonyl compounds with a highly efficient procedure.2 Various transition metal catalysts have been developed for this transformation.3 Highly enantioselective isomerization of β-substituted primary allylic alcohols has also been documented in the literature.4,5 In a related effort to readily access novel, complex structures, the development of remote functionalization of alkenes has witnessed great advancement in recent years.6,7 These processes involve transition metal-catalyzed alkene functionalization followed by a long-range isomerization through a chainwalking pathway. With the achievement of stereocontrol, these transformations provide unique advantage of establishing stereogenic centers that are distant from the resultant functionality.

Combining the power of the two strategies, the isomerization of remote alkenyl alcohols has also attracted much attention in recent years. However, only a few successful catalytic systems were reported in the literature for such a challenging process. While early success with ruthenium catalysis was disclosed by the Grotjahn group,8 the Mazet group has introduced a couple of Pd-catalyzed systems for a general and highly efficient longrange isomerization of alkenyl alcohols of different substitution patterns.9 Importantly, a few examples of enantioselective isomerization of primary homoallylic alcohols with moderate to good enantioselectivity was also documented in these work (Scheme 1a). To the best of our knowledge, the isomerization of remote alkenyl secondary alcohols with enantiocontrol remains elusive in the literature. Two key challenges need to be addressed in order to achieve efficient and stereoselective isomerization of functionalized secondary alcohols. Firstly, the reactivity of these compounds are much lower than their primary alcohol counterpart, making the achievement of both reactivity and selectivity extremely difficult. Secondly, it is preferable to use the readily available racemic substrates,10 thus a stereoconvergent transformation needs to be realized instead of a simple kinetic resolution.11

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Scheme 1. Catalytic enantioselective isomerization of alkenyl alcohols a) Mazet's enantioselective isomerization of primary homoallylic alcohols O

O R

R

OH Me

O Me up to 88% ee

5 mol% [Pd]/Binapine or [Pd]/i-Pr-DUPHOS

or

or

NaBARF, cyclohexene

Ph

Ph

OH

O Cy 36%, 62% ee

Cy

parameters was performed. The use of TBME as the solvent was beneficial leading to a full conversion to 2a, however, at the cost of reduced enantioselectivity (entry 9). Different inorganic and organic bases were evaluated, from which the usage of DABCO produced 2a in 72% yield and 84% ee (entry 10). The recovered 1a was also found to be highly enantioenriched (98% ee). With a prolonged reaction time of 48 h, a high yield of 88% and high ee of 84% for 2a were finally achieved with this stereoconvergent isomerization reaction (entry 11). Table 1. Optimization of homoallylic alcohol isomerizationa Ph

R

OH * Ar

() homoallylic alcohols

Me R

O

up to 95%, 86% ee

+

Ar

R

up to 48%, 98% ee

2 * R

OH () bishomoallylic alcohols

50 °C

Me 2 * R

R1 ()

[Rh]/(R)-BINAP base

OH

homoallylic alcohols 80-95%

100 °C

Me R2

R1 O


Our group has focused on the development of catalytic enantioselective redox-neutral transformations for efficient chemical synthesis. In particular, we are interested in stereoconvergent transformations that convert readily available racemic alcohols to valuable enantioenriched products.12 Very recently, we introduced the first enantioselective isomerization of secondary allylic alcohols to deliver chiral ketones bearing a tertiary α-stereogenic center.13 Such a process is capable of converting readily available, racemic alcohols to the synthetically valuable chiral ketones in a stereoconvergent fashion. Herein, we present the first catalytic enantioselective isomerization of remote alkenyl secondary alcohols to deliver chiral ketones bearing a β or γ-stereocenter in high yields and enantioselectivity (Scheme 1b). This Rh-catalyzed process utilizes commercially available catalysts and a simple procedure, and operates on both homoallylic and bishomoallylic secondary alcohols. For the former case, an intriguing pathway of oxidative kinetic resolution followed by enantioselective alkene reduction is established. While for the bishomoallylic alcohols, a significant ligand effect is identified, resulting in an efficient alkene isomerization followed by isomerization of the alkenyl alcohols.

RESULTS AND DISUSSION Isomerization of homoallylic alcohols We initiated our studies by using homoallylic alcohol 1a as the model substrate and commercial Rh complex and Ag2CO3 as the catalysts (Table 1).13 Preliminary screening quickly established that slightly elevated temperature of 50 °C was necessary to achieve reasonable reactivity. Through systematic screening of chiral ligands (as exemplified in entries 1-8), the JosiPhos analog L7 proved to be optimal for enantioselectivity of 2a, albeit with a low yield (entry 7). It is interesting to note that the recovered 1a was also enantioenriched, indicating a kinetic resolution of the racemic substrate. To further improve the yield of 2a by using ligand L7, screening of solvents, concentration and other reaction

Me

OH

O

Ph

30 mol % base 4Å MS, solvent, 50 oC, 24 h

OH Ar

kinetic resolution of SM at 52-54% conv.

R1

Ph (±)-1a

50-90 °C convergent isomerization

[Rh]/L7 base

2.5 mol % [Rh(COD)2]BF4 5 mol % ligand

OH

b) This work: Stereoconvergent isomerization of secondary homoallylic/bishomoallylic alcohols

catalytic [Rh]/L7 catalytic base

Page 2 of 7

Ph

+

Ph

Ph (S)-1a

2a

entry

ligand

solvent

base

2a yield (%)b

2a ee (%)c

1a ee (%)c

1

L1

toluene

Ag2CO3

60

38

44

2

L2

toluene

Ag2CO3

45

32

54

3

L3

toluene

Ag2CO3

49

10

22

4

L4

toluene

Ag2CO3

18

30

62

5

L5

toluene

Ag2CO3

14

30

56

6

L6

toluene

Ag2CO3

81

70

--

7

L7

toluene

Ag2CO3

30

86

50

8

L8

toluene

Ag2CO3

95

20

--

9

L7

TBME

Ag2CO3

93

70

--

10

L7

TBME

DABCO

72

84

98

11d

L7

TBME

DABCO

88

84

--

12d

L7

TBME

DBU

50

90

98

aReactions

were carried out with 0.1 mmol of 1a, 2.5 mol % [Rh(COD)2]BF4, 5 mol % chiral ligand, 30 mol % base and 50 mg 4 Å MS in 0.5 mL of solvent. bIsolated c yield. Determined by chiral HPLC analysis. d48 h reaction time.

PPh2 PPh2

L1: (R)-BINAP

F F

O

F F

O

O

O

PPh2 PPh2

O

PPh2 PPh2

PAr2 PAr2

O O

O

L2: (S)-DifluorPhos

Ar = 3,5-tBu2-4-MeOC6H2

L3: (R)-SDP

L4: (R)-DTBM-SegPhos Ph2P

Fe

t

PCy2 Cy2P Me

L5: (R)-JosiPhos

Me

L6

Fe

PCy2

Cy2P

Fe

L7

Bu Pt Bu Me

PPh2 PPh2 Fe

Me

L8

The excellent enantioselectivity obtained for the recovered 1a pointed to the possibility of a highly efficient oxidative kinetic resolution. When DBU was used as the base, the reaction could be easily controlled at ~50% conversion. Both 2a and recovered 1a were obtained in excellent ee of 90% and 98%, respectively (entry 12). Therefore, either kinetic resolution or ennatioconvergent isomerization of homoallylic alcohols could be achieved. Remarkably, the same catalytic system promotes both alcohol oxidation and alkene reduction steps with high level of enantiocontrol. We first examined the scope of enantioselective isomerization of homoallylic alcohols via the kinetic resolution approach (Scheme 2). For the model substrate 1a, the S factor was determined to be >50. A methyl substitution on either aryl ring in the substrate structure could be well-tolerated; the resolution/isomerization of 1b and 1c both worked out to be excellent. For other substituted substrates, the observed lower reactivity necessitated the use of DABCO and elevated temperature of 70 °C to achieve 50-55% conv. The selectivity


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Journal of the American Chemical Society remained excellent in most cases. The electronic property of the aryl substituent and in turn the oxidation of the benzylic alcohol, however, showed a strong influence on the selectivity. For more electron-rich substrate such as 1e, the enantioselectivity dropped to S = 10. It is noteworthy that functionalities such as halide or ester could be well-tolerated ( 1f and 1g). For the case of 1h, the valuable acrylate-derived alcohol could be recovered in a high 96% ee. Scheme 2. Rh-catalyzed kinetic resolution of homoallylic alcohols via isomerizationa 2.5 mol % [Rh(COD)2]BF4 5 mol % L7

OH R1

R2

Me R1

30 mol % base 4Å MS, solvent temp, time

()-1

O

OH +

R2

R1

2

R2 (S)-1

Condition A: DBU, TBME, 50 oC, 48 h OH

OH Ph

OH

Ph

Ph

Ph

Me

Me

1a: 43%, 98% ee

1b: 46%, 96% ee

1c: 47%, 98% ee

2a: 50%, 90% ee 54% Conv., S >50

2b: 50%, 95% ee 52% Conv., S >50

2c: 53%, 92% ee 53% Conv., S >50

We then examined the scope of the enantio-convergent isomerization to deliver ketone 2 (Scheme 3). The reaction worked well for a range of aryl-substituted substrates to deliver the ketones bearing a β-stereocenter in good to high level of enantioselectivity and good isolated yield. Electronic variation of the aryl group on the alcohol side was well-tolerated, ranging from the very electron-donating dimethyl amino group (2i) to electron-withdrawing ester (2g). Notably, the 1,4-dicarbonyl product 2h was also accessed in good enantioselectivity, which represents a challenge in the alternative enantioselective conjugate addition to acyclic enones.14 A limitation of this catalytic system is the requirement of a benzylic alcohol substrate to achieve good reactivity and selectivity for the isomerization reaction. When a furansubstituted homoallylic alcohol (R2 = furan) was tested, the ketone product was obtained with a good 86% ee, albeit with very low efficiency (50

2hb: 50%, 84% ee 53% Conv., S = 48

aSee

supporting information for details. The S factor was calculated using conversion (C) determined by crude NMR and ee of SM 1: S = log[(1-C)(1-ee)]/log[(1-C)(1+ee)]. bThe reaction was carried out in TBME and 50 oC for 72 h.

Scheme 3. Rh-catalyzed convergent isomerization of homoallylic alcoholsa 2.5 mol % [Rh(COD)2]BF4 5 mol % L7

OH R1

R2

Me

()-1

O

R1

30 mol % DABCO 4Å MS, solvent, temp, 48 h

R2 2

Condition C: TBME, 50 oC, 48 h Me

Me

O

Ph

O

Me Ph

Ph

O

Ph

Me 2a: 88%, 84% ee

Me 2b: 95%, 84% ee

2c: 80%, 86% ee

Condition D: toluene, 90 oC, 48 h Me

Me

O Me

Ph

Me

O

O

Ph

Ph

NMe2

OMe 2d: 85%, 78% ee

Me

2e: 90%, 70% ee

O

Me

Ph

aSee

O

Me MeO

Ph Br

2f: 81%, 84% ee

2i: 85%, 72% ee

CO2Me 2g: 82%, 76% ee

O Ph

O 2hb: 75%, 76% ee

supporting information for details. bThe reaction was carried out in 70 oC.

Figure 1. Sequential selective oxidation and reduction It is interesting to note that this catalytic enantioselective isomerization involves two sequential enantio-determining steps. To clearly illustrate that, the enantioselectivity of 1a and 2a at different conversions was examined. As shown in Figure 1, the ee of the recovered substrate 1a gradually increased with the conversion, which is characteristic of a kinetic resolution process. On the other hand, the ee of 2a remained largely constant throughout the reaction, even at high conversion. In this isomerization reaction, the oxidative alcohol kinetic resolution and enantioselective reduction of the alkene thus operate independently, remarkably under the control of the same chiral Rh-catalyst. To understand the pathway involved in the isomerization reaction, deuterium-labelling studies were carried out with alcohols 1a-D-a and 1a-D-b (Scheme 4a). For the reaction of 1a-D-a, the deuterium was cleanly transferred to the terminal position of the double bond, consistent with a redoxisomerization mechanism. In the case of 1a-D-b, one of the deuteriums on the α-carbon was transferred to the β-carbon in the product structure. This observation provided a strong support for a “chain-walking” of the alkyl rhodium intermediate. Notably, both methylene protons in 2a-D-b were deuterium-labeled, suggesting that either proton may be transferred to the adjacent carbon in the chain-walking process.



Scheme 4. Mechanistic studies of homoallylic alcohol isomerization a) Deuterium-labelling studies to elucidate H-transfer pathways of homoallylic alcohols 2.5 mol % [Rh(COD)2]BF4 5 mol % L7

(95%) D

30 mol % DABCO 4Å MS, TBME, 50 oC, 48 h

Ph

HO D (95%) Ph

Ph 1a-D-a

OH D D

Ph

2a-D-a 85%, 85% ee (83%) D Me O

same as above

Ph

Ph

O

Ph Ph H/D D/H (42%) (42%) 2a-D-b 80%, 84% ee

(83%)

1a-D-b

b) Cross-over experiment (95%) D

HO D (95%) Ph

Ph 1a-D-a +

Ph

2a-D-a 82%, 70% ee

2.5 mol % [Rh(COD)2]BF4 5 mol % L7

+

30 mol % DABCO 4Å MS, toluene, 90 oC, 48 h

OH

Ph

OMe

2e 91%, 70% ee

OMe

20:1 E:Z

b) Me Ph

Ph

Me

5 mol% [Rh(COD)2]BF4, 10 mol% (R)-BINAP

Ph

Ph

OH

O

40 mol% Ag2CO3 4Å MS, toluene, 100 oC, 24 h

(±)-5a

4a >95% conv. 80% ee

An intriguing observation was made when the previous optimal ligand L7 was used (Scheme 6a). No desired 4a was observed at all; instead, 3a was cleanly converted to the corresponding racemic internal homoallylic alcohol 5a as a single geometric isomer. This represents a complete switch in mechanism: this Rh/L7 catalyst promotes a simple alkene isomerization of 3a instead of the desired redox isomerization. It is interesting to note that 5a is also a homoallylic alcohol analogous to 1. Compared to the 1,1-disubstituted alkene in 1, the trisubstituted alkene in 5a is likely much more sterically congested so no effective isomerization of 5a can occur with the Rh/L7 catalytic system. Scheme 7. Scope for alkene isomerization of bishomoallylic alcohol 3

R1

Me

Me

OH

Ph O

4j: 90%, 84% ee 96% ee after recrystalization

OH 5k: 85%

Me Ph

OH 5l: 95%

Me

Me Ph

Ph O 4l: 69%, 82% ee

O 4m: 80%, 76% ee

OH

Me

Ph

4j

Me

Ph O

Me

Ph

Ph

Me Ph

4k: 89%, 84% ee 5f (R = Me): 91% 5g (R = OMe): 95% 5h (R = Cl): 95% 5i (R = F): 85% 5j (R = Ph): 90%

5b (R = Me): 90% 5c (R = OMe): 87% 5d (R = Cl): 92% 5e (R = F): 85%

Me

4b (R = Me): 83%, 85% ee 4c (R = OMe): 75%, 80% ee 4d (R = Cl): 88%, 82% ee 4e (R = F): 80%, 82% ee

O 4f (R = Me): 86%, 82% ee 4g (R = OMe): 76%, 76% ee 4h (R = Cl): 85%, 74% ee 4i (R = F): 91%, 78% ee

Me

Ph

OH

Me

Ph

O

R

4a: 90%, 80% ee

R

Me Ph

Me R

Me Ph

R

5a: 90%

O 4

Me Ph

(±)-5

Ph

40 mol% Ag2CO3 4Å MS, toluene, 100 oC, 24 h

Me

>20:1 E:Z

Ph

OH (±)-5

R2

R1

OH

(±)-3

Me

Me

5 mol% [Rh(COD)2]BF4 10 mol% (R)-BINAP

R2

R1

R2

R1 20 mol % Ag2CO3 4Å MS, toluene, 50 oC, 24 h

OH

Me

O

2.5 mol % [Rh(COD)2]BF4 5 mol % L7

R2

62% ee for direct isomerization of 3a to 4a). In this step, partial kinetic resolution of 5a was also observed, but the selectivity was less than satisfactory. We then focused our effort on the two-step isomerization of bishomoallylic alcohols to deliver valuable chiral ketones bearing a γ–stereocenter. The alkene isomerization step catalyzed by Rh/L7 is summarized in Scheme 7. Various substituents either on the aryl group on 1,1-disubstituted alkene or on the benzylic alcohol side were well-tolerated. The internal alkene products were obtained in uniformly high yield of 85-95% as a single olefin isomer. It is important to note that ligand L7 proved essential in this non-stereoselective step, possibly due to its steric bulkiness and substitution pattern. The subsequent isomerization of trisubstituted alkenes 5 to deliver the valuable chiral ketones 4 is shown in Scheme 8. The optimal set of conditions worked uniformly well for all the substrates (5a-5m) to yield aryl ketones 4a-4m bearing a γstereocenter with high yield and high enantioselectivity. Recrystallization of 4j improved its enantioselectivity to 96% ee, X-ray analysis of which confirmed the absolute configuration of this class of products. Aliphatic alcohol substrates instead of benzylic ones were also examined. The alkene isomerization step worked smoothly; however, the redox isomerization step proved to be much less efficient. Minimal conversion to the desired ketone products was observed. Scheme 8. Scope for isomerization of internal homoallylic alcohols

OH 5m: 80%

Considering this significant ligand effect in bishomoallylic alcohol isomerization, we decided to examine the isomerization of 5a to 4a using the effective ligands in Table 2 (Scheme 6b). The use of Rh/BINAP resulted in an efficient isomerization of 5a to 4a, and with a much-improved ee of 80% (compared to

We were intrigued by the nature of this two-stage isomerization reactions and carried out deuterium-labeling studies for the two orthogonal steps. As shown in Scheme 9a, in the alkene isomerization step catalyzed by Rh/L7, the deuterium stayed at the benzylic position in 5a-D, suggesting that the hydroxyl group is not directly involved in this alkene isomerization step. In contrast, enantioselective isomerization of homoallylic alcohol 5a-D by Rh/BINAP produced 4a-D bearing the same pattern as 1a-D-a, suggesting a similar isomerization pathway as that in Scheme 5. From entry 1, Table 2, Rh/BINAP can promote a direct isomerization of 3a to 4a. We were curious whether that proceeds through a direct isomerization or a two-stage alkene



isomerization followed by redox isomerization. In order to probe that, the isomerization of 3a-D was carried out using Rh/BINAP. As the result, 4a-D bearing deuterium labelling at both positions was obtained (Scheme 9b). This strongly suggests that both mechanisms are operative using the Rh/BINAP system: either a direct isomerization of bishomoallylic alcohol resulting in deuterium labelling at the terminal position (80%), or a sequential alkene isomerization followed by redox isomerization leading to 15% deuterium labelling in the tertiary position. While the two-stage isomerization provides 4a-D in 80% ee, the direct isomerization represents the major and likely less enantioselective reaction pathway. The combination of two pathways then resulted in a lower enantioselectivity for the formation of 4a. Scheme 9. Mechanism studies for bishomoallylic alcohol isomerization

Page 6 of 7

alcohols, a two-step sequential isomerization was developed to yield enantioenriched ketones with distant chiral center in good yield and high enantioselectivity. Mechanistic studies including deuterium-labelling experiments provided strong support for the alkene isomerization, redox isomerization as well as a chain-walking mechanism for this versatile catalytic system. Current efforts in our laboratory are focused on the development of other enantioselective redox isomerization processes to deliver valuable compounds in an economical fashion. Scheme 10. Probe of alkene isomerization a) Alkene isomerization for other substrates 2.5 mol % [Rh(COD)2]BF4 5 mol % L7

Ph

Ph

Me

20 mol % Ag2CO3 4Å MS, toluene, 50 oC, 24 h

O 6

Ph

Ph 7 80% E/Z >10

a) Deuterium-labelling studies of two isomerizations Ph

Ph

HO D

(95%)

Me

conditions in Scheme 7 (Rh/L7)

Ph

Ph

HO D (95%) 5a-D 85%

3a-D Me Ph

Ph

conditions in Scheme 8

Me

(95%) D

Ph

HO D (95%) 5a-D

Ph HO D

Me

3a-D

same as above

Ph

Ph

11 95%

D (15%)

Ph (95%)

9 90% E/Z >10

10

conditions in Scheme 8

Me

Ph

8

b) Deuterium-labelling study of direct isomerization of 3 to 4

Ph

Me

same as above

Me

Ph

Ph

O 4a-D 87%, 80% ee

(80%) D

O

Ph

b) Proposed alkene isomerization via allylhydride intermediate

O

4a-D 90%, 62% ee

H R

Ph H

R

Ph

[Rh]

H H

Exploration of the alkene isomerization To further probe the substrate requirement for the alkene isomerization step, the corresponding alkenyl ketone 6 as well as a simple 1,1-disubstituted alkene 8 were subjected to the isomerization conditions (Scheme 10). Interestingly, high efficiency could be obtained for both isomerization reactions. These results suggest that this transformation requires no hydride source or any polar functionality to proceed. An exocyclic alkene 10 was also examined under the standard conditions. Interestingly, a facile reaction took place to deliver exclusively the endocyclic alkene 11, in which the alkene is not in conjugation with the aryl substituent. This strongly suggests that the isomerization is under kinetic control. Based on the ample literature precedents on transition metal-catalyzed alkene isomerization,16-17 we propose that this reaction likely proceeds through an π-allylhydride mechanism as illustrated in Scheme 10b instead of metal-hydride insertion.

CONCLUSIONS

H

[Rh]

[Rh]

R

Ph

R

Ph

H

H H H [Rh] R

Ph H

ASSOCIATED CONTENT Supporting Information This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author

In conclusion, we have developed an unprecedented and versatile rhodium-catalyzed enantioselective isomerization of homoallylic and bishomoallylic secondary alcohols. This catalytic redox-neutral process does not require any stoichiometric reagent and generates no waste at all en route to valuable chiral ketone products. For the homoallylic alcohols, an oxidative kinetic resolution of the racemic substrates is followed by enantioselective reduction to deliver ketones bearing a β- stereocenter in a stereoconvergent fashion with high level of enantiopurity. In the case of bishomoallylic

*[email protected]; *[email protected] ORCID Yu Zhao: 0000-0002-2944-1315 Tang-Lin Liu: 0000-0002-7318-4520

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT


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Journal of the American Chemical Society We are grateful for the financial support provided by the National University of Singapore, the Ministry of Education (MOE) of Singapore (R-143-000-613-112), A*STAR SERC (R-143-000648-305) and Chinese Fundamental Research Funds for the Central Universities (XDJK2018C044).

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