Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of

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Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Dienes: An Experimental and DFT Study Yun-Xuan Tan, Fang Zhang, Pei-Pei Xie, Shuo-Qing Zhang, YiFan Wang, Qing-Hua Li, Ping Tian, Xin Hong, and Guo-Qiang Lin J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05583 • Publication Date (Web): 25 Jul 2019 Downloaded from pubs.acs.org on July 25, 2019

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Journal of the American Chemical Society

Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Dienes: An Experimental and DFT Study Yun-Xuan Tan,† Fang Zhang,‡ Pei-Pei Xie,§ Shuo-Qing Zhang,§ Yi-Fan Wang,† Qing-Hua Li,‡ Ping Tian,*,†,‡ Xin Hong,*,§ and Guo-Qiang Lin*,†,‡ †CAS

Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China §Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou, 310027, China Supporting Information ABSTRACT: Due to the inherent difficulty in differentiating two olefins, development of metal-catalyzed asymmetric

cyclization of 1,6-dienes remains challenging. Herein, we describe Bpin Rh(I)-Rh(III) the first rhodium(III)-catalyzed asymmetric borylative cyclization B O Catalytic Cycle R3 H O [Rh(Phebox)] R2* of cyclohexadienone-tethered mono-, 1,1-di- and (E)-1,2-di** B pin X R3 * substituted alkenes (1,6-dienes), affording optically pure cisR1 2 X R X = O or N R1 bicyclic skeletons bearing three or four contiguous stereocenters 25-93 yield, 90-99% ee with high yields (25-93%), excellent diastereoselectivities (> 20:1 An Experimental Study A DFT Study O O anti-Markovnikov vs. Markovnikov Borylation (R =R =H) 91% yield 39% yield dr), and enantioselectivities (90-99% ee). This mild catalytic 95% ee 98% ee O O Me approach is generally compatible with a wide range of functional Me Me E/Z mixture groups, which allows several facile conversions of the cyclization 1,6-diene O O 25% yield 73% yield 94% ee 98% ee products. Furthermore, based on our SAESI-MS experiment and O O Me Me 1,6-diene computational study, a Rh(I)/(III) catalytic cycle is proposed in O Me this tandem reaction and the Rh(I) active species catalyzes the overall transformation via sequential oxidative addition of B2pin2, olefin insertion, cyclizing conjugate addition and reductive elimination. The irreversible conjugate addition determines the overall regioselectivity of borylative cyclization, and the ring strain favors the formation of 5,6-bicyclic structure. This highlights the control of ring strain in diene cyclizations, which provides a useful basis for future reaction designs. O

2

2

O

N

Rh

N

O

O

N

Rh

Bpin

N

Bpin

SAESI-MS Analysis

DFT calculations

2

Rh

VS

3

Rh

6

1

Bpin

tert-alkyl-Rh intermediate



INTRODUCTION

The development of efficient asymmetric annulation protocols is particularly important in organic synthesis due to the wealth of carbo- and heterocycles in natural products, pharmaceutical compounds, and functional materials. In view of their importance, great efforts have been devoted to the development of transition-metal-catalyzed asymmetric cyclizations of 1,6-bifunctional molecules, typically involving 1,6-enynes and 1,6-dienes.1 In comparison to 1,6-enynes,2 the metal-catalyzed asymmetric cyclization of 1,6-dienes remains more challenging due to the requisite differentiation of the two olefins in 1,6-dienes. In recent years, a handful of Ni-, Pt, and Rh-catalyzed asymmetric cycloisomerizations of 1,6dienes have been successfully achieved.3 However, the described reactions only employ intramolecular C‒C bond formation with hydrogen atom transfer, and the lack of functional groups limits the potential for further elaboration of the products. In order for a direct derivatization of products, transition-metal-catalyzed asymmetric cyclization initiated by an external nucleophile consequentially becomes

6

G = 0.0 kcal/mol

Bpin


more attractive. To the best of our knowledge, only a Pdcatalyzed asymmetric silylative cyclization of 1,6-dienes has been reported to proceed with good enantioselectivities (7991% ee, Scheme 1a).4 Herein, we present the first rhodiumcatalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-dienes with high to excellent yields and excellent enantioselectivities. In 2003, Morken and coworkers described the first enantioselective diboration of simple alkenes catalyzed by a chiral rhodium(I) catalyst with bis(catecholato)diboron (B2cat2).5 However, this efficient catalytic system was supposed to be ineffective for activation of bis(pinacolato)diboron (B2pin2) since the reactivity of the tetraalkoxydiboranes is considerably lower than that of the catecholate analogs.6 Ten years later, Nishiyama and coworkers realized the asymmetric diboration of nonactivated terminal alkenes with B2pin2 using a chiral NCNpincer rhodium(III) complex, rhodium[bis(oxazolinyl)phenyl] complex (Scheme 1b).7 During the catalytic process, the bulky rhodium was placed at the less

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Scheme 1. Strategic Design a) Palladium-Catalyzed Asymmetric Silylative Cyclization of 1,6-Dienes[4] Pd

R R

SiEt3

R R

HSiEt3

H

b) Rhodium(III)-Catalyzed Asymmetric Diboration of Terminal Alkenes[7] [Rh(Phebox)] Catalyst B2pin2

Markovnikov Bororhodation

O R

O N

Bpin

N

Rh

Bpin Rh

R

Bpin

R

i-Pr AcO OH OAc i-Pr 2

c) Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of 1,6-Dienes activated alkene

"B" R2

X

non-activated alkene

O

(S,S)-[Rh(Phebox-i-Pr)]

B2pin2 (2)

R

O N

C N N Bpin Rh Bpin 2

O TS2

 X

R

1

secondary interaction

Rh

favorable

N

-Bororhodation anti-Markovnikov Bororhodation (IF R2 = H)

Enantioselectivity



Bpin Bpin BisborylRhodium(III) Complex

R

2

?

N  Bpin

C

Rh

TS3

X

N Bpin O

R1 2

-Bororhodation (anti-Markovnikov Bororhodation, R = H) Pathway -Bororhodation (Markovnikov Bororhodation, R2 = H) Pathway

C

boron is placed at either external carbon [β-bororhodation (anti-Markovnikov bororhodation, R2 = H)] or internal carbon [α-bororhodation (Markovnikov bororhodation, R2 = H)], affording the corresponding borylated alkylrhodium intermediates TS3 or TS9. The interaction between the rhodium and cyclohexadienone enables the subsequent intramolecular conjugate addition in a syn-facial manner to furnish highly enantioenriched cis-fused bicyclic frameworks 3 (5,6-bicycles) or 4 (6,6-bicycles) bearing three (R2 = H) or four (R2  H) contiguous stereogenic carbon centers.11 Considering the ring strain of the fused carbocycles, the 5membered ring-closure is favored with respect to a 6membered ring-closure, and thus the 5,6-bicycles 3 are the main products. Whatever, the selective borylation taking place at the non-activated alkenes, rather than the activated alkenes, i.e. cyclohexadienones, is an intrinsic paradox and still remains particularly challenging.



R1 3

O

?

R

stereogenic centers

TS1

1

three or four

O contiguous

X

1

Regioselectivity



Bpin H

R2 H

 X

N

N N C Bpin Bpin Rh Bpin N -Bororhodation X Rh Bpin R2 2 R O Markovnikov O unfavorable  Bororhodation Bpin  (IF R2 = H)  TS9 TS8 X X R1 R1

R2

X

H

O

R1 4

hindered terminal carbon atom, and such a Markovnikov bororhodation regioselectivity was confirmed by the latest report of Aggarwal and coworkers on rhodium(III)-catalyzed Markovnikov hydroboration of terminal alkenes.8 However, as a limitation of Nishiyama’s method, 1,2-disubstituted alkenes failed to undergo the reaction.7 To overcome this limitation, we hypothesized that incorporation of additional functional groups on the substrate may promote the reactivity of these non-activated disubstituted alkenes, causing by the secondary interaction between alkenes and the additional functional groups. To test this hypothesis, the cyclohexadienone-tethered non-activated alkenes 1 were prepared (Scheme 1c), hoping that the interaction between the alkene and cyclohexadienone could significantly enhance the reactivity of the non-activated alkenes. In Nishiyama’s diboration reaction, a bis(pinacolatoboryl)Rh(III) species was also speculated in the proposal of an alternative catalytic cycle.9 We envisage that this bisborylRh(III) species, rather than monoboryl-Rh(III) complex, involves the bororhodation of alkenes. In our case, as the direct conjugate borylation is largely impeded by the bulk neighboring steric repulsion,10 the bororhodation proceeds preferentially on the non-activated alkenes rather than cyclohexadienones. During the bororhodation process, the

Page 2 of 21

RESULTS AND DISCUSSION

Reaction Development and Optimization. We began our investigation using the cyclohexadienone-tethered terminal alkene 1a as a model substrate and the results are summarized in Table 1. In the presence of Nishiyama’s [(S,S)Rh(Phebox-Me)(OAc)2.H2O] catalyst C1 at room temperature, it’s exciting that the desired diastereoselectively pure (d.r. > 20:1) borylative cyclization product 3a was acquired, albeit with low yield (30%) and moderate enantioselectivity (76% ee) (Table 1, Entry 1). In contrast to Aggarwal’s observations,8 the regioselectivity of addition to the terminal alkene was reversed to favor the antiMarkovnikov carboboration product.12 Several other of Nishiyama’s catalysts C2−C6 were subsequently screened,13 however, only [(S,S)-Rh(Phebox-i-Pr)(OAc)2.H2O] (C2) and [(S,S)-Rh(Phebox-s-Bu)(OAc)2.H2O] (C3) provided both good yield and excellent enantioselectivity (Table 1, Entries 2−6). As for catalyst C2, prolonging the reaction time to 24 h could lead to an increase in yield to 92% (Table 1, Entry 7). Raising the reaction temperature to 40 oC allowed for the use of lesser equivalents of B2pin2 (2) with a shortened reaction time while maintaining excellent yield and enantioselectivity (Table 1, Entry 8). As for catalyst C3, both excellent yield and enantioselectivity could be achieved by simply prolonging the reaction time (Table 1, Entry 9); but either lowering the B2pin2 (2) loading or raising the reaction temperature led to different levels of erosion in both yields and enantioselectivities (Table 1, Entries 10−12). In line with our expectations, no 6,6-fused bicyclic product 4a was detected in all cases. Substrate Scope of Cyclohexadienone-Tethered Nonactivated Alkenes (1,6-Dienes). Having established the optimal reaction conditions for this rhodium-catalyzed asymmetric borylative cyclization of cyclohexadienonetethered alkenes (1,6-dienes), we focused our effort on the substrate scope of this cascade transformation. First, cyclohexadienone-tethered monosubstituted terminal alkenes were investigated with respect to various cyclohexadienone components and the results are summarized in Table 2. With the R1 substituents as alkyl, cycloalkyl, vinyl, allyl, benzyl, and phenyl groups, the reactions occurred smoothly with high to excellent yields (81–93%) and excellent enantioselectivities (94–96% ee,


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Table 1. Reaction Development and Optimizationa,b anti-Markovnikov carboboration

O

Bpin

B2pin2 (2) Catalyst (5 mol%)

O

1a

O

O

Me 3a

O (S)

O N

R AcO

N

Rh

(S)

OH OAc R 2

R = Me R = i-Pr R = s-Bu R = i-Bu R = t-Bu R = Bn

O

Me 4a

[Rh(Phebox-s-Bu)] (C3)

Chiral rhodium-[bis(oxazolinyl)phenyl] catalysts: [Rh(Phebox)] C1: C2: C3: C4: C5: C6:

H

Bpin

O +

t-BuONa (10 mol %) MeOH (2.5 equiv) THF

Me

H

Markovnikov carboboration

[Rh(Phebox-Me)] [Rh(Phebox-i-Pr)] [Rh(Phebox-s-Bu)] [Rh(Phebox-i-Bu)] [Rh(Phebox-t-Bu)] [Rh(Phebox-Bn)]

O

O

(S)

(S)

N

Rh

N

(S)

AcO OH OAc 2

(S)

entry

catalyst

1a:2

temp (oC)

time (h)

conv (%)c

yield of 3a (%)c

ee of 3a (%)d

1

C1

1:2

rt

16

100

30

76

2

C2

1:2

rt

16

89

88

93

3

C3

1:2

rt

16

68

66

94

4

C4

1:2

rt

16

39

30

91

5

C5

1:2

rt

16

15

-

-

6

C6

1:2

rt

16

100

36

81

7

C2

1:2

rt

24

100

92

93

8

C2

1:1.2

40

10

100

93

92

9

C3

1:2

rt

24

100

96(91)e

95

10

C3

1:1.8

rt

24

87

84

95

11

C3

1:1.2

40

10

100

92

94

12

C3

1:1.2

50

7

78

71

93

aReactions

were carried out with 1a (0.2 mmol, 1.0 equiv), B2pin2 (2), rhodium catalyst (5 mol %), t-BuONa (10 mol %), MeOH (2.5 equiv), and THF (1.0 mL) under Ar atmosphere. bAll d.r. > 20:1. cDetermined by 1H NMR analysis of unpurified mixtures with CH2Br2 as an internal standard. dDetermined by HPLC analysis. eYield of isolated product 3a.

Table 2, 3a–3i). Introduction of para-substituents, including F, Br, CN groups, on the phenyl ring had almost no impact on the reaction, uniformly resulting in excellent levels of enantiocontrol (96% ee) (Table 2, 3j–3m). With a heteroatom (O, Si, N, Cl or Br) as part of R1 substituent in substrates 1, both reaction yields and enantioselectivities remained high to excellent (76–92% yield, 94–96% ee, Table 2, 3n−3u). Notably, chloro- and bromoalkyl groups in substrates 1t and 1u were well tolerated in this transformation (Table 2, 3t and 3u). As for the N-linked 1,6-diene 1v, the corresponding cishydroindole product 3v was also uneventfully constructed with good diastereoselectivity (5:1 dr) and excellent enantioselectivities for both isomers. The readily available terminal alkenes 1w and 1x derived from dehydrocholic acid and estrone were subjected to this transformation, affording cis-hydrobenzofuran products with good yields and excellent catalyst-controlled diastereoselectivities (Table 2, 3w, 3w’, 3x, and 3x’). Much to our surprise and delight, the cyclohexadienonetethered 1,1-disubstituted terminal alkene 5a was also feasible for this transformation, albeit in low yield (Table 2, 6a). This finding suggests that the involvement of a bulky tertiary alkyl-rhodium intermediate is capable of undergoing

intramolecular conjugate addition.14 It is noteworthy that in all cases employing cyclohexadienone-tethered terminal alkenes, carboboration products were delivered with exclusive anti-Markovnikov regioselectivity, i.e. C–B bond formation occurring at the terminal carbon atoms.8,12 As described above, we were particularly interested in applying this approach to the cyclohexadienone-tethered 1,2disubstituted alkenes. As for 1,2-disubstituted cis-alkene (Z)5b, no desired cyclization product was observed; whereas for 1,2-disubstituted trans-alkene (E)-5b, we were encouraged to find the expected borylative bicyclic product bearing four contiguous stereogenic carbon centers, which was produced as a single isomer with 37% yield and 98% ee (Table 2, 6b). Subsequently, a mixture of E/Z-isomers of 1,2-disubstituted alkenes 5c derived from the trans/cis mixture (95:5) of crotyl alcohol was subjected to this reaction. In line with our expectations, only a single isomer is furnished with 39% yield and 98% ee, suggestive that cis-internal alkenes are not competent in the reaction (Table 2, 6c). Several other cyclohexadienone-tethered trans-1,2-disubstituted internal alkenes were examined next. With a heteroatom (O, Si, or N) as part of R2 substituents in substrates 5, the reactions proceeded equally well with excellent enantioselectivities



Page 4 of 21

Table 2. Substrate Scope of Cyclohexadienone-Tethered Alkenes (1,6-Dienes)

R2

X R4

R3 Bpin R2 H R4

B2pin2 (2) C2 or C3 (5 mol % )

O

R3

t-BuONa (10 mol%) MeOH (2.5 equiv) THF

R1

X = O or N

1 or 5

3/4 Contiguous Stereogenic Carbon Centers Generally >20:1 dr, Up to 99% ee anti-Markovnikov Carboboration (Terminal Alkenes) Broad Substrate Scope Good Functional Group Compatibility

O

X

R1 3 or 6

Monosubstituted Terminal Alkenes (R2 = R3 = R4 = H): a Bpin H O

Bpin H

O

O

Me c

3a, 91% yield >20:1 dr,d 95% eee Bpin H

Bpin H

O

O

Et

3b, 84% yield >20:1 dr, 95% ee Bpin H

O

O

Bpin H

O

O

CO2Me 3n, 87% yield >20:1 dr, 94% ee Bpin H

Bpin H

O

Bpin H

Br

Me O O

H H

H O

estrone derivativeb with (S,S)-C2, 3x, 88% yield, 95:5 dre with (R,R)-C2, 3x', 84% yield, 5:95 dre

tertiary alkyl-Rh intermediate

Bpin

O

H

Rh Condition B

Me

Cl 3t, 92% yield >20:1 dr, 95% ee

O

H MeO Me dehydrocholic acid derivativeb with (S,S)-C2, 3w, 84% yield, 96:4 dre with (R,R)-C2, 3w', 85% yield, 4:96 dre

1,1-Disubstituted Terminal Alkene: b

O

Me

O

O

NHBoc

Bpin H

H H

Bpin H

O

O

3v,b 65% yield, 5:1 dr major isomer: 90% ee minor isomer: 90% ee

3u, 87% yield >20:1 dr, 95% ee

Me

O

O

N Ts Me

CN 3m, 86% yield >20:1 dr, 96% ee

3s, 76% yield >20:1 dr, 94% ee

O

O

O

O

OTBS

H

O H

Bpin H

O

Bpin H

3r, 89% yield >20:1 dr, 95% ee

O

3f, 84% yield >20:1 dr, 96% ee

Br 3k, 87% yield >20:1 dr, 96% ee

O

O

O

Cy

O

O

OAc

O

Bpin H

O

Bpin H

O

Bpin H

3e, 93% yield >20:1 dr, 95% ee

F 3j, 74% yield >20:1 dr, 96% ee

3q, 85% yield >20:1 dr, 96% ee

O

O

t-Bu

O

O

3p, 85% yield >20:1 dr, 96% ee

O

O

Bpin H

CO2Me

O

Bpin H

3i, 82% yield >20:1 dr, 95% ee

O

Bpin H

3d, 93% yield >20:1 dr, 95% ee

O

Bpin H

O

O

i-Pr

Bpin H

3h, 87% yield >20:1 dr, 95% ee

O

O

3c, 88% yield >20:1 dr, 94% ee

O

3g, 81% yield >20:1 dr, 95% ee

Bpin H

5a

O

Me

O Me 6a, 25% yield >20:1 dr, 94% ee

ORTEP of 3a

ORTEP of 6a

ORTEP of 6b

1,2-Disubstituted Internal Alkenes: b O (Z)

O

Rh Condition B

Me

O no desired product

(E)

O

(Z)-5b

R

O Me 5d-5g

Condition B

Me

Bpin

MeO Rh Condition B

H

H O

Me

6d, 38% yield >20:1 dr, 97% ee

Bpin

BnO O

H

Bpin

Bpin * H *

O

* *

O

H

Me

H O

Me

6e, 62% yield >20:1 dr, 97% ee

H

H O

Me

6f, 66% yield >20:1 dr, 98% ee

aCondition

O

Me

H

H

O

O

Me 6c, 39% yield >20:1 dr, 98% ee

Bpin

NPhth O

Me

Condition B

5c E/Z = 95/5

Bpin

TBSO O

Rh

O

Me 6b, 37% yield >20:1 dr, 98% ee

(E)-5b

O 2

Rh

H

H O

O

O NPhth =

Me

N O

6g, 45% yield >20:1 dr, 99% ee

A: Reactions were performed using 1 (0.2 mmol, 1.0 equiv), B2pin2 (2.0 equiv), C3 (5 mol %), t-BuONa (10 mol %), MeOH (2.5 equiv), THF (1.0 mL) under Ar atmosphere, rt, 24 h. bCondition B: Reactions were performed using 5 (0.2 mmol, 1.0 equiv), B2pin2 (1.2 equiv), C2 (5 mol %), t-BuONa (10 mol %), MeOH (2.5 equiv), THF (1.0 mL) under Ar atmosphere, 40oC, 10 h. cYield of isolated product. dDetermined by 1H NMR analysis of unpurified mixtures. eDetermined by HPLC analysis.


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(97–99% ee, Table 2, 6d–6g). The absolute configuration of the cyclization products 3a, 6a and 6b was unambiguously established by X-ray crystallography.15 The data summarized in Table 2 support that the order of reactivity of substrates is mono- > (E)-1,2-di-  1,1-di- ≫ (Z)-1,2-di-substituted alkenes.

Scheme 2. The Competitive Borylative Cyclization (a) The Competitive Borylative Cyclization Between Two Formal 1,6-Dienes "B" 1,6-diene

The Competitive Borylative Cyclization of the Multifunctionalized 1,6-Dienes. To further support that additional interaction from the appended dienone promotes reactivity of non-activated alkenes, substrate 5h (two formal 1,6-dienes) containing one non-activated monosubstituted terminal alkene, one non-activated trans-1,2-disubstituted internal alkene and two activated cis-1,2-disubstituted alkenes, was prepared. When subjected to the standard reaction conditions, regioselective borylation takes place at the internal alkene rather than the more reactive terminal alkene and activated alkenes, and the corresponding cyclization product 6h is afforded in high yield (73%) and excellent enantioselectivity (98% ee, Scheme 2a). Equal regioselectivity was also observed in reaction of substrate 5i (composed of a 1,6-enyne as well as 1,6-diene) containing an internal alkyne, internal alkene and cyclohexadienone components (Scheme 2b). These findings proved once again that the aforementioned interaction between alkene and cyclohexadienone indeed promoted the reactivity of nonactivated alkenes.

O

1,6-diene

H

H

t-BuONa (10 mol %) MeOH (2.5 equiv) THF, 40 oC, 10 h

Me

Bpin

O

O B pin (2) (1.2 equiv) 2 2

Catalyst: C2 (5 mol%)

O

O Me 6h, 73% yield >20:1 dr, 98% ee

5h

(b) The Competitive Borylative Cyclization Between Formal 1,6-Enyne & 1,6-Diene "B" 1,6-diene

O B2pin2 (2) (1.2 equiv)

O


Me

1,6-enyne

Bpin

O


O

H

H

Me 6i, 58% yield >20:1 dr, 98% ee

addition with B2pin2 to afford the bisboryl-Rh(III) species III, which was observed by SAESI-MS analysis. Then the terminal alkene of 1a is coordinated and inserted into bisboryl-Rh(III) complex III (anti-Markovnikov), and the resulting complex V undergo successive intramolecular conjugate addition, reductive elimination and protonation to offer the final borylative cyclization product 3a and regenerate the Rh(I)complex II. It should be noted that the interaction between alkene and enone may play an important role during the alkene insertion step. Path B: the Rh(I)-complex II coordinates with 1a to form the complex VIII, which was also detected by SAESI-MS analysis. The Rh(I)-complex VIII undergoes oxidative cyclometallation to generate the Rh(III)complex IX. Subsequently, the Rh(III)-complex IX could also produce the final borylative cyclization product 3a and regenerate the Rh(I)-complex II through σ-metathesis, reductive elimination and protonation.

Scheme 3. Proposed Reaction Mechanisms C3 B2pin2 t-BuONa

metathesis

O

O O

O conjugate addition

N s-Bu Bpin

O

O N s-Bu Bpin O V

O

N Bpin s-Bu

Rh

Bpin s-Bu H

O

Bpin

Bpin

H

O

Me

O MeOH

insertion

N s-Bu

s-Bu

secondary interaction

O Me

O IV

O

s-Bu

Me VII protonation

Path B

N s-Bu

1a

Bpin

Rh

MeOH

coordination

O

O

O

O

N Bpin s-Bu

III bisboryl-Rh(III) detected by SAESI-MS


N

Rh

s-Bu

oxidative cyclometalation

N

s-Bu O O Me VIII Rh(I)-complex detected by SAESI-MS

s-Bu

Rh

N

MeOBpin

3a

O coordination

B2pin2

metathesis

O O

N

1a Path A

N Bpin s-Bu H

s-Bu

Bpin H

B2pin2 oxidative addition

O Rh

Rh II

protonation 3a

N Bpin

N Rh N s-Bu Bpin O H Bpin reductive O Me VI elimination

O

O Me VII

O

O

Bpin

O

MeOBpin

O

dissociation and R.E. X Bpin H 2O

reductive elimination

VI

Me

Rh

N

s-Bu OH2 X X = OAc or Ot-Bu I

N

Rh

O

O

5i

Proposed Reaction Mechanisms. Based on our experiments and literature report,6a,7,9 the proposed reaction mechanisms are illustrated in Scheme 3. In the beginning, the monoboryl-Rh(III) complex I is obtained from Rhprecatalyst C3 through σ-metathesis with B2pin2 (2). Subsequently, its dissociation of water and reductive elimination of boronate (X-Bpin) affords a key Rh(I)-complex II, which is the catalytic active species and initiates the catalytic cycles. From II, there are two tentative catalytic cycles. Path A: the Rh(I)-complex II undergoes oxidative

N s-Bu Bpin

O

H O

Me IX

N s-Bu O


Several Transformations of the Cyclization Product 3a. As a demonstration of the practicality and robustness of this method, the transformation of cyclohexadienonetethered terminal alkene 1a was carried out on a 4-mmol scale at 40 oC (Scheme 4). We were able to lower the catalyst loading to 1 mol% with no decrease in enantioselectivity (95% ee) despite a slight loss in yield (83%). To further demonstrate the utility of this methodology, several transformations were conducted and elaborated in Scheme 4. Upon treatment of 3a with NaBO3, the resulting primary alcohol in situ underwent an intramolecular oxa-Michael addition to give the six-membered O-bridged cyclic product 7a in almost quantitative yield, and the absolute configuration of the newly formed ether was established by X-ray crystallographic analysis (Scheme 4a).15 Alternatively, the primary alcohol 8a could also be isolated using H2O2 as oxidant (Scheme 4b). Next, the selective Luche reduction of the enone led to the formation of chiral allylic alcohol 9a, and the absolute configuration of the secondary alcohol was also confirmed by X-ray crystallographic analysis (Scheme 4c).15 Additionally, the alkyl-boronate 3a was easily converted, through Suzuki-Miyaura cross-coupling to an aryl-product 10a (Scheme 4d). Lastly, according to Aggarwal’s coupling protocol,16 successive treatment of boronic ester 3a with 2-thienyllithium and NBS readily affords thienyl-coupling product 11a accompanying by the thienyl addition to the ketone (Scheme 4e). All the above transformations proceeded smoothly with almost no loss of the enantiomeric purity. Computational Studies of Reaction Mechanisms and Origins of Regioselectivity. We next studied the reaction mechanism and regioselectivity of the rhodium catalysis through density functional theory (DFT) calculations17 using the experimental catalyst C2 and 1,6-diene substrate 1a. DFTcomputed free energy changes of the most favorable pathway are shown in Figure 1. From the Rh(I) active catalyst 12,18 the oxidative addition with B2pin2 is quite facile through TS1, generating the bisboryl-Rh(III) intermediate 14. Subsequent endergonic 1,6-diene complexation leads to intermediate 15, which undergoes the alkene enone-facilitated insertion via TS2 to afford the alkylrhodium(III) species 16. This enonefacilitation originates from the non-covalent interaction between the enone moiety and the inserting alkene, which was confirmed by Independent Gradient Model (IGM) analysis19 (Figure S5). The insertion of cyclohexadienone double bond is significantly less favorable (Figure S6), which highlights the ability of Rh(I) catalyst to differentiate the two double bonds of 1,6-diene substrate. From 16, the coordination of cyclohexadienone allows the subsequent cyclization via TS3, leading to the bicyclic intermediate 18. 18 then undergoes a facile rhodium migration through TS4 to the corresponding oxygen-coordinated intermediate 19.20 This migration allows the B−O reductive elimination via TS5 to generate the Rh(I) species 20. Subsequent solventfacilitated methanolysis occurs in a cyclic fashion via TS6,21 which regenerates the active Rh(I) catalyst 12 and eventually produce the observed product 3a. Based on the computed free energy profile, the proposed pathway A is operative. The alkylrhodium(III) species 16 is the on-cycle resting state, and

Page 6 of 21

Scheme 4. Gram-Scale Experiment and Several Transformations of the Cyclization Product 3a O + O


B2pin2


Me 6.0 mmol, 2

4.0 mmol, 1a

MeO2C

H

O

Bpin H

O

O

Me 3a, 0.97 g 83% yield, 95% ee

H

S

S OH

O Me 10a 67% yield, 98% ee Bpin H

OH

(d)

(c)

O Me 11a, 86% yield 96% ee, >20:1 dr

(e)

Bpin H

O

(a)

Me O

O

Me 9a, 87% yield 94% ee, >20:1 dr

O

O

Me 3a 95% ee

O

7a, 98% yield 95% ee, >20:1 dr

(b) OH H O

ORTEP of 9a

O

Me

8a 55% yield, 95% ee

ORTEP of 7a

NaBO3.4H2O,

Conditions: (a) THF/H2O, rt, 2 h. (b) H2O2 (30% aq.), THF, rt, 16 h. (c) NaBH4, CeCl3.7H2O, MeOH, 0 oC, 10 min. (d) KHF2, MeOH/H2O, rt, 5 h; then methyl 4bromobenzoate, Pd(OAc)2, PPh3, K2CO3, toluene/H2O, 95 oC, 10 h. (e) 2-thienyllithium, THF, -78 oC; then NBS, -78 oC.

the rate-determining cyclization step via TS3 requires a 22.9 kcal/mol overall barrier. Our mechanistic model also applies to the 1,2-disubstituted internal alkene. The rate-determining cyclization step is insensitive to the 1,2-disubstitution (Figure S9), which is consistent with the experimental reactivities (Table 2). The proposed pathway B involving oxidative cyclometalation is significantly less favorable than pathway A, and the DFT-computed free energy changes are in Figure 2. From the Rh(I) catalyst 12, the exergonic coordination of terminal double bond of 1,6-diene leads to the complex 23. Subsequent oxidative cyclometalation via TS7 requires an unsurmountable barrier of 35.0 kcal/mol to generate the fivemembered rhodacycle intermediate 25. Comparing the determining transition states of the two proposed pathways (TS7 of Pathway B vs. TS3 of Pathway A), pathway B is less favorable by 15.9 kcal/mol. Therefore, pathway B is not operative for this transformation due to the difficult oxidative cyclometalation.


Page 7 of 21 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


Figure 1. DFT-Computed Free Energy Changes of the Most Favorable Pathway G(kcal/mol), M06/6-311+G(d,p)-SDD-SMD(tetrahydrofuran)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ O O

O Rh N

N i-Pr Bpin

N

Rh N H Bpin i-Pr

Bpin i-Pr

i-Pr Bpin

Me

O

6.8 15

B2pin2

0.0 12

0.3 TS1

-1.1 13

i-Pr Bpin B

-6.7 17 O

Rh N

O

O

O

O

Rh N (I)

N i-Pr

S

i-Pr

15

12

O Me

O

O Me

N Rh N i-Pr Bpin Bpin i-Pr

O

O

i-Pr Bpin

N i-Pr Bpin

O

O

i-Pr Bpin

H O

Bpin

OH

i-Pr HOMe

O

Bpin OMe

Me

Bpin

H

Rh N

N

21

H

OH

N

22

i-Pr

O

Rh O

H

O

H O Bpin

Me

-37.3 21

2 HOMe

N Bpin i-Pr

HOMe + 12 + MeO Bpi n

-52.1 20

Bpin

i-Pr

-57.3 22

O

O Rh

N

O Bpin

H

-71.2 3a

i-Pr

3a O

oxidation addition

[Rh] H O

-32.9 TS6

Me

Me

H O

N

O

Me

Bpin

O

O

Me

O

i-Pr

Me

-26.4 TS5

Rh N Bpin i-Pr H O

Bpin O

Bpin

-32.9 19

R S S

O

O

[Rh] = 12

O

O

N

Rh

TS5

-25.8 18 -26.8 TS4

Rh N Bpin i-Pr

N O

O

O

i-Pr S Bpin

-11.3 16

i-Pr H

Rh N Bpin i-Pr O O Me

N

i-Pr

O

O N

Bpin i-Pr

Me

TS4

O

O

i-Pr Bpin

Rh N

N

N Bpin i-Pr O

11.6 TS3

Bpin

N

O

O

O

6.7 TS2

-2.6 14 O

Rh

H

TS3

TS2

1a

i-Pr Bpin

H O Me

O

TS1

N

Rh N Bpin i-Pr O

H

O

O

O

O

O

N i-Pr Bpin

cyclization

olefin insertion

isomerization

reductive elimination

Me methanolysis

product liberation

Figure 2. Comparisons of the Proposed Pathway B G(kcal/mol), M06/6-311+G(d,p)-SDD-SMD(tetrahydrofuran)//B3LYPD3(BJ)/6-31G(d)-LANL2DZ

O

27.5 TS7

O N

Rh N

i-Pr

O

H

i-Pr

O Me

O

O N

12 0.0 O i-Pr

1a O

N

Rh N (I)

-1.0 24

i-Pr

i-Pr O

O Me

-7.5 i-Pr

Rh N

23

O

-4.9

O N

25

Rh N

i-Pr

O

i-Pr O Me

O N

i-Pr

Our mechanistic model provides a useful rationale for the regioselectivity of olefin insertion. Figure 3a includes the free energy changes of the competing regioisomeric borylations. From the bisboryl-Rh(III) intermediate 15, the insertion of terminal double bond of 1,6-diene is reversible via TS2 and TS8.22 This leads to the equilibrium between the two alkylrhodium(III) intermediates 16 and 26. Subsequent irreversible cyclization overrules the regioselectivity of olefin insertion, favoring the anti-Markovnikov borylation by 2.5 kcal/mol (TS3 and TS9). These cyclization transition states are differentiated by the ring strain of the forming bicyclic structure (Figure 3b). The 6,6-bicyclic moiety of TS9 is more strained than the 5,6-bicyclic moiety of TS3, which is confirmed by the calculations of the corresponding carbocycles. Therefore, the DFT calculations highlight the importance of ring strain that can serve as a control of overall regioselectivity of 1,6-diene cyclizing functionalization.

Rh N H

O O

O

i-Pr

Me



Page 8 of 21

Figure 3. Competition between anti-Markovnikov and Markovnikov Borylation a)

G(kcal/mol), M06/6-311+G(d,p)-SDD-SMD(tetrahydrofuran)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ

Markovnikov borylation

O

O

O N

i-Pr Bpin H O Me

O

O

O

O Me

14.1 TS9

-6.0 27 O

O N

O N i-Pr Bpin S

O

O

6.7 TS2 O

O Me

Rh N R

N Rh N i-Pr Bpin i-Pr i-Pr Bpin Bpin O R

i-Pr S Bpin

-11.3 16 O

R S

S

Me O

O

Bpin

i-Pr Bpin R O

S S

Me

Me

O

O N

Rh

Rh

i-Pr Bpin H O Me

TS3

Bpin


In conclusion, the rhodium(III)-catalyzed asymmetric borylative cyclization between cyclohexadienone-tethered alkenes (1,6-dienes) and B2pin2 has been accomplished to afford optically pure cis-hydrobenzofuran frameworks bearing three or four contiguous stereocenters. This versatile method was applicable to cyclohexadienonetethered mono-, 1,1-di- and (E)-1,2-di-substituted alkenes, and tolerated a wide range of functional groups on both cyclohexadienone and alkene components. Especially for cyclohexadienone-tethered terminal alkenes, their carboboration products were offered with exclusive antiMarkovnikov regioselectivity. Moreover, the alkyl-boronate

O

Rh N Bpin i-Pr H O

4.8 kcal/mol 4.8 kcal/mol

N H Rh Bpin i-Pr O H O Me

CONCLUSIONS

O N

O

O N

i-Pr Bpin

H

R O

Me

0.0 kcal/mol R= Bin 0.0 kcal/mol R= H

Rh

-25.8 18

O

Rh N Bpin i-Pr O Me

H

Rh N Bpin i-Pr O O Me

O N

i-Pr Bpin

R

O N

O

Rh N Bpin i-Pr H O

O



-6.7 17 O

O

O Me

b)

N H Rh Bpin i-Pr O H O Me

11.6 TS3

O

O Me

O

i-Pr Bpin

Me

N Rh N i-Pr Bpin HBpini-Pr

-7.0 26

O N

11.0 TS8

O

-22.6 28

O

O O

6.8 15

i-Pr Bpin

O Rh N H Bpin i-Pr

N i-Pr Bpin

N Rh N i-Pr Bpin Bpin i-Pr H

N Bpin i-Pr O

Rh

anti-Markovnikov borylation

N Bpin i-Pr O

TS9


and enone functional groups in the cyclization products could be subjected to various transformations for elaborating the synthetic utility. DFT calculations revealed a Rh(I)-Rh(III) catalytic cycle involving bisboryl-Rh(III) intermediate. The tandem reaction proceeds via olefin insertion, conjugate addition and subsequent reductive elimination. The cyclizing conjugate addition is the regioselectivity-determining step, and ring strain favors the formation of 5,6-bicyclic carbocycle. Further investigation and applications of cyclohexadienone-tethered alkenes (1,6dienes) in organic synthesis are underway in our laboratory and will be reported in due course.


Page 9 of 21 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




ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxxxxxxxxx. Experimental procedures, characterizations, and analytical data of new compounds, X-ray diffraction data for 3a, 6a, 6b, 7a and 9a, and spectra of NMR and HPLC for new compounds (PDF) X-ray data for compound 3a (CIF) X-ray data for compound 6a (CIF) X-ray data for compound 6b (CIF) X-ray data for compound 7a (CIF) X-ray data for compound 9a (CIF)



AUTHOR INFORMATION

Corresponding Author *[email protected] or [email protected] (P.T.) *[email protected] (X.H.) *[email protected] (G.-Q.L.)

ORCID Ping Tian: 0000-0002-5612-0664 Xin Hong: 0000-0003-4717-2814

Notes The authors declare no competing financial interest.



ACKNOWLEDGMENT

Financial support was generously provided by the National Natural Science Foundation of China (Nos. 21871184, 21572251, and 21572253; 21702182 and 21873081, X.H.); the Shanghai Municipal Education Commission (2019-01-07-0010-E00072); the Science and Technology Commission of Shanghai Municipality (18401933500); the Ministry of Science and Technology of the People's Republic of China (973 project 2015CB856600); the Chinese Academy of Sciences (Nos. XDB 20020100 and QYZDY-SSW-SLH026); “Fundamental Research Funds for the Central Universities” (X.H.); Zhejiang University (X.H.) and China Postdoctoral Science Foundation (2018M640546, S.–Q. Z.). Calculations were performed on the high-performance computing system at the Department of Chemistry, Zhejiang University. We thank Jie Sun (SIOC) for X-ray crystallographic analysis and Dr. Hanqing Dong (Arvinas Inc.) for manuscript preparation.



REFERENCES

(1) For selected recent reviews, see: (a) Yamamoto, Y. Transition-metal-catalyzed cycloisomerizations of α,ω-dienes. Chem. Rev. 2012, 112, 4736−4769. (b) Aïssa, C. Stereoselectivity of metal-catalyzed cyclizations of 1,6-dienes. Synlett 2014, 25, 2379−2384. (2) For selected recent examples, see: (a) He, Z.-T.; Tian, B.; Fukui, Y.; Tong, X.; Tian, P.; Lin, G.-Q. Rhodium-catalyzed asymmetric arylative cyclization of meso-1,6-dienynes leading to enantioenriched cis-hydrobenzofurans. Angew. Chem., Int. Ed. 2013, 52, 5314−5318. (b) Masutomi, K.; Noguchi, K.; Tanaka, K. Enantioselective cycloisomerization of 1,6-enynes to bicyclo[3.1.0]hexanes catalyzed by rhodium and benzoic acid. J. Am. Chem. Soc. 2014, 136, 7627−7630. (c) Yu, S.;Wu, C.; Ge, S. Cobaltcatalyzed asymmetric hydroboration/cyclization of 1,6-enynes with

pinacolborane. J. Am. Chem. Soc. 2017, 139, 6526−6529. (d) Chen, J.; Han, X.; Lu, X. Enantioselective synthesis of tetrahydropyrano[3,4b]indoles: palladium(II)-catalyzed aminopalladation/1,4-addition sequence. Angew. Chem., Int. Ed. 2017, 56, 14698−14701. (e) Gollapelli, K. K.; Donikela, S.; Manjula, N.; Chegondi, R., Rhodiumcatalyzed highly regio- and enantioselective reductive cyclization of alkyne-tethered cyclohexadienones. ACS Catal. 2018, 8, 1440−1447. For selected examples on metal-catalyzed borylative cyclization of tethered pi-systems, see: (f) Onozawa, S.-y.; Hatanaka, Y.; Tanaka, M. Palladium-catalysed borylsilylation of alkynes and borylsilylative carbocyclization of diynes and an enyne compound. Chem. Commun. 1997, 1229−1230. (g) Suginome, M.; Matsuda, T.; Ito, Y. Nickel-catalyzed silaborative dimerization of alkynes. Organometallics 1998, 17, 5233−5235. (h) Marco-Martínez, J.; López-Carrillo, V.; Buñuel, E.; Simancas, R.; Cárdenas, D. J. Pdcatalyzed borylative cyclization of 1,6-enynes. J. Am. Chem. Soc. 2007, 129, 1874−1875. (i) Persson, A. K.; Jiang, T.; Johnson, M. T.; Bäckvall, J. E. Palladium-catalyzed oxidative borylative carbocyclization of enallenes. Angew. Chem., Int. Ed. 2011, 50, 6155−6159. (j) Jiang, T.; Bartholomeyzik, T.; Mazuela, J.; Willersinn, J.; Bäckvall, J. E. Palladium(II)/Bronsted acid-catalyzed enantioselective oxidative carbocyclization-borylation of enallenes. Angew. Chem., Int. Ed. 2015, 54, 6024−6027. (k) Posevins, D.; Qiu, Y.; Bäckvall, J. E. Highly diastereoselective palladium-catalyzed oxidative carbocyclization of enallenes assisted by a weakly coordinating hydroxyl group. J. Am. Chem. Soc. 2018, 140, 3210−3214. For a recent review, see: (l) Buñuel, E.; Cárdenas, D. J. Borylative cyclization reactions. Eur. J. Org. Chem. 2016, 5446−5464. (3) (a) Bogdanović, B. Selectivity control in nickel-catalyzed olefin oligomerization. Adv. Organomet. Chem. 1979, 17, 104-140. (b) Böing, C.; Franciò, G.; Leitner, W. Nickel catalysed asymmetric cycloisomerisation of diethyl diallylmalonate. Chem. Commun. 2005, 1456-1458. (c) Böing, C.; Franciò, G.; Leitner, W. Cationic nickel complexes with weakly coordinating counterions and their application in the asymmetric cycloisomerisation of 1,6-dienes. Adv. Synth. Catal. 2005, 347, 1537−1541. (d) Feducia, J. A.; Campbell, A. N.; Doherty, M. Q.; Gagné, M. R. Modular catalysts for diene cycloisomerization: rapid and enantioselective variants for bicyclopropane synthesis. J. Am. Chem. Soc. 2006, 128, 13290−13297. (e) Böeing, C.; Hahne, J.; Franciò, G.; Leitner, W. Stereoselective nickel-catalyzed cycloisomerization of 1,6-dienes. Adv. Synth. Catal. 2008, 350, 1073−1080. (f) Schmitz, C.; Leitner, W.; Franciò, G. Nicatalyzed asymmetric cycloisomerization of dienes by using TADDOL phosphoramidites. Chem. Eur. J. 2015, 21, 10696−10702. (g) Park, J.-W.; Chen, Z.; Dong, V. M. Rhodium-catalyzed enantioselective cycloisomerization to cyclohexenes bearing quaternary carbon centers. J. Am. Chem. Soc. 2016, 138, 3310−3313. (h) Li, K.; Li, M.-L.; Zhang, Q.; Zhu, S.-F.; Zhou, Q.-L. Highly enantioselective nickel-catalyzed intramolecular hydroalkenylation of N- and O-tethered 1,6-dienes to form six-membered heterocycles. J. Am. Chem. Soc. 2018, 140, 7458−7461. (4) (a) Perch, N. S.; Widenhoefer, R. A. Asymmetric cyclization / hydrosilylation of functionalized 1,6-dienes catalyzed by enantiomerically pure palladium pyridine-oxazoline complexes. J. Am. Chem. Soc. 1999, 121, 6960−6961. (b) Pei, T.; Widenhoefer, R. A. Use of pentamethyldisiloxane in the palladium-catalyzed cyclization/hydrosilylation of functionalized dienes. Org. Lett. 2000, 2, 1469−1471. (c) Perch, N. S.; Pei, T.; Widenhoefer, R. A. Enantioselective diene cyclization/hydrosilylation catalyzed by optically active palladium bisoxazoline and pyridine−oxazoline complexes. J. Org. Chem. 2000, 65, 3836−3845. (d) Pei, T.; Widenhoefer, R. A. Palladium-catalyzed asymmetric diene cyclization/hydrosilylation employing functionalized silanes and disiloxanes. J. Org. Chem. 2001, 66, 7639−7645. (e) Widenhoefer, R. A. Synthetic and mechanistic studies of the cycloisomerization and cyclization/hydrosilylation of functionalized dienes catalyzed by cationic palladium(II) complexes. Acc. Chem. Res. 2002, 35, 905-913. (5) Morgan, J. B.; Miller, S. P.; Morken, J. P. Rhodium-catalyzed enantioselective diboration of simple alkenes. J. Am. Chem. Soc. 2003, 125, 8702−8703.



(6) (a) Nguyen, P.; Lesley, G.; Taylor, N. J.; Marder, T. B.; Pickett, N. L.; Clegg, W.; Elsegood, M. R. J.; Norman, N. C. Oxidative addition of B-B bonds by rhodium(I) phosphine complexes: molecular structures of B2cat2 (cat = 1,2-O2C6H4) and its 4-But and 3,5-But2 analogs. Inorg. Chem. 1994, 33, 4623−4624. (b) Ramı́rez, J.; Segarra, A. M.; Fernández, E. Metal promoted asymmetry in the 1,2-diboroethylarene synthesis: diboration versus dihydroboration. Tetrahedron: Asymmetry 2005, 16, 1289−1294. (7) Toribatake, K.; Nishiyama, H. Asymmetric diboration of terminal alkenes with a rhodium catalyst and subsequent oxidation: enantioselective synthesis of optically active 1,2-diols. Angew. Chem., Int. Ed. 2013, 52, 11011−11015. (8) Smith, J. R.; Collins, B. S. L.; Hesse, M. J.; Graham, M. A.; Myers, E. L.; Aggarwal, V. K. Enantioselective Rhodium(III)catalyzed Markovnikov hydroboration of unactivated terminal alkenes. J. Am. Chem. Soc. 2017, 139, 9148−9151. (9) For an X-ray single-crystal structure of bis(catecholatoboryl)-Rh(III) complexes, see: (a) Baker, R. T.; Calabrese, J. C.; Westcott, S. A.; Nguyen, P.; Marder, T. B. Insertion of alkenes into rhodium-boron bonds. J. Am. Chem. Soc. 1993, 115, 4367−4368. For a theoretical calculations of bis(ethylenglycolatoboryl)-Rh(III) complexes, see: (b) PubillUlldemolins, C.; Poyatos, M.; Bo, C.; Fernandez, E. Rhodium-NHC complexes mediate diboration versus dehydrogenative borylation of cyclic olefins: a theoretical explanation. Dalton Trans. 2013, 42, 746−752. (c) In fact, such a bisboryl-Rh(III) species was observed by SAESI-MS analysis of our reaction mixture (for details, see Supporting Information). (10) (a) Shiomi, T.; Adachi, T.; Toribatake, K.; Zhou, L.; Nishiyama, H. Asymmetric β-boration of α,β-unsaturated carbonyl compounds promoted by chiral rhodium-bisoxazolinylphenyl catalysts. Chem. Commun. 2009, 5987−5989. (b) Liu, P.; Fukui, Y.; Tian, P.; He, Z. T.; Sun, C. Y.; Wu, N. Y.; Lin, G. Q. Cu-catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes. J. Am. Chem. Soc. 2013, 135, 11700−11703. (11) For selected recent metal-catalyzed asymmetric desymmetrization of cyclohexadienones, see: (a) He, Z. T.; Tang, X. Q.; Xie, L. B.; Cheng, M.; Tian, P.; Lin, G. Q. Efficient access to bicyclo[4.3.0]nonanes: copper-catalyzed asymmetric silylative cyclization of cyclohexadienone-tethered allenes. Angew. Chem., Int. Ed. 2015, 54, 14815−14818. (b) Clarke, C.; Incerti-Pradillos, C. A.; Lam, H. W. Enantioselective nickel-catalyzed anticarbometallative cyclizations of alkynyl electrophiles enabled by reversible alkenylnickel E/Z isomerization. J. Am. Chem. Soc. 2016, 138, 8068−8071. (c) Kumar, R.; Hoshimoto, Y.; Tamai, E.; Ohashi, M.; Ogoshi, S. Two-step synthesis of chiral fused tricyclic scaffolds from phenols via desymmetrization on nickel. Nat. Commun. 2017, 8, 32. (d) Shu, T.; Zhao, L.; Li, S.; Chen, X. Y.; von Essen, C.; Rissanen, K.; Enders, D. Asymmetric synthesis of spirocyclic βlactams through copper-catalyzed Kinugasa/Michael domino reactions. Angew. Chem., Int. Ed. 2018, 57, 10985−10988. (12) For selected metal-catalyzed anti-Markovnikov carboboration of terminal alkenes, see: (a) Su, W.; Gong, T. J.; Lu, X.; Xu, M. Y.; Yu, C. G.; Xu, Z. Y.; Yu, H. Z.; Xiao, B.; Fu, Y. Ligandcontrolled regiodivergent copper-catalyzed alkylboration of alkenes. Angew. Chem., Int. Ed. 2015, 54, 12957−12961. (b) Xu, Z. Y.; Jiang, Y. Y.; Su, W.; Yu, H. Z.; Fu, Y. Mechanism of ligandcontrolled regioselectivity-switchable copper-catalyzed alkylboration of alkenes. Chem. Eur. J. 2016, 22, 14611−14617. (13) (a) Kanazawa, Y.; Tsuchiya, Y.; Kobayashi, K.; Shiomi, T.; Itoh, J.; Kikuchi, M.; Yamamoto, Y.; Nishiyama, H. Asymmetric conjugate reduction of α,β-unsaturated ketones and esters with chiral rhodium(2,6-bisoxazolinylphenyl) catalysts. Chem. Eur. J. 2005, 12, 63−71. (b) Morisaki, K.; Sawa, M.; Yonesaki, R.; Morimoto, H.; Mashima, K.; Ohshima, T. Mechanistic studies and expansion of the substrate scope of direct enantioselective alkynylation of αketiminoesters catalyzed by adaptable (Phebox)Rhodium(III) complexes. J. Am. Chem. Soc. 2016, 138, 6194−6203. (c) Naganawa, Y.; Kawagishi, M.; Ito, J.; Nishiyama, H. Asymmetric induction at remote quaternary centers of cyclohexadienones by rhodiumcatalyzed conjugate hydrosilylation. Angew. Chem., Int. Ed. 2016, 55,

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6873−6876. (d) Ito, J.-i.; Nishiyama, H. Chiral pincer complexes for asymmetric reactions. In Pincer Compounds, 2018; pp 1-18. (14) For selected recent work on tertiary alkyl-rhodium intermediates, see: (a) Lazzaroni, R.; Uccello-Barretta, G.; Scamuzzi, S.; Settambolo, R.; Caiazzo, A. 2H NMR Investigation of the rhodium-catalyzed deuterioformylation of 1,1-diphenylethene: evidence for the formation of a tertiary alkyl−metal intermediate. Organometallics 1996, 15, 4657−4659. (b) Lazzaroni, R.; Settambolo, R.; Marchetti, M.; Paganelli, S.; Alagona, G.; Ghio, C. Rhodiumcatalyzed deuterioformylation of the ketal-masked β-isophorone: evidence for a tertiary alkyl rhodium intermediate as a precursor of the main reaction product acetaldehyde derivative. Inorg. Chim. Acta 2009, 362, 1641−1644. (c) Ros, A.; Aggarwal, V. K. Complete stereoretention in the rhodium-catalyzed 1,2-addition of chiral secondary and tertiary alkyl potassium trifluoroborate salts to aldehydes. Angew. Chem., Int. Ed. 2009, 48, 6289−6292. (d) Eshon, J.; Foarta, F.; Landis, C. R.; Schomaker, J. M. α-Tetrasubstituted aldehydes through electronic and strain-controlled branchselective stereoselective hydroformylation. J. Org. Chem. 2018, 83, 10207−10220. (15) CCDC 1888900 (3a), 1888901 (6a), 1888902 (6b) 1888903 (7a), and 1888904 (9a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (16) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Enantiospecific sp2-sp3 coupling of secondary and tertiary boronic esters. Nat. Chem. 2014, 6, 584−589. (17) Computations were performed with Gaussian 09 software package; computational details are included in the Supporting Information. (18) The generation of the Rh(I) active catalyst 12 is very facile from the catalyst precursor S-1, related computational results are included in Figure S4. (19) Lefebvre, C.; Rubez, G.; Khartabil, H.; Boisson, J. C.; Contreras-Garcia, J.; Henon, E. Accurately extracting the signature of intermolecular interactions present in the NCI plot of the reduced density gradient versus electron density. Phys. Chem. Chem. Phys. 2017, 19, 17928−17936. (20) The Gibbs free energy of TS4 is slightly lower than that of 18, due to the small changes of saddle point position from the level of theory for optimization to that for single point energy calculation. (21) We carefully studied the possible methanolysis pathways, the explored alternatives are included in Figure S7 and S8. (22) We found that the enone-facilitaton is not operative for the Markovnikov borylation. Having the enone fragment proximal to the insertion alkene leads to an unfavorable isomer of TS8. Details are included in the Supporting Information (Figure S10).


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For Table of Contents Only B

[Rh(Phebox)]

X

R3 R

2

Bpin

Rh(I)-Rh(III) Catalytic Cycle

O O

B2pin2

R1

O N

Rh

N

O N

Rh

Bpin

X = O or N

DFT calculations

O

O

Bpin

O Me

O

E/Z mixture

Me

tert-alkyl-Rh intermediate

73% yield 98% ee 1

O

O

R1

25-93 yield, 90-99% ee

1,6-diene

6

O

anti-Markovnikov vs. Markovnikov Borylation (R2=R3=H)

Me

1,6-diene

O

25% yield 94% ee

H

** * X

A DFT Study

O

39% yield 98% ee

Me

Me

N

SAESI-MS Analysis

An Experimental Study 91% yield 95% ee

R3 R2*

O

O

Rh

VS

Rh

6

Me

Bpin



Bpin


11


Table of Contents 82x44mm (300 x 300 DPI)


Page 12 of 21

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Strategic Design 84x128mm (300 x 300 DPI)



Reaction Development and Optimization 115x49mm (300 x 300 DPI)


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Substrate Scope of Cyclohexadienone-Tethered Alkenes (1,6-Dienes) 163x220mm (300 x 300 DPI)



The Competitive Borylative Cyclization 83x58mm (300 x 300 DPI)


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Proposed Reaction Mechanisms 165x96mm (300 x 300 DPI)



Gram-Scale Experiment and Several Transformations of the Cyclization Product 3a 80x93mm (300 x 300 DPI)


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DFT-Computed Free Energy Changes of the Most Favorable Pathway 170x135mm (300 x 300 DPI)



Comparisons of the Proposed Pathway B 81x84mm (300 x 300 DPI)


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Competition between anti-Markovnikov and Markovnikov Borylation 293x312mm (300 x 300 DPI)


Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of

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