Copper-Catalyzed Diastereoselective and Enantioselective Addition of

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Copper-Catalyzed Diastereoselective and Enantioselective Addition of 1,1-Diborylalkanes to Cyclic Ketimines and #-Imino Esters Jeongho Kim, Minkyeong Shin, and Seung Hwan Cho ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02931 • Publication Date (Web): 15 Aug 2019 Downloaded from pubs.acs.org on August 15, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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ACS Catalysis

Copper-Catalyzed Diastereoselective and Enantioselective Addition of 1,1-Diborylalkanes to Cyclic Ketimines and -Imino Esters Jeongho Kim, Minkyeong Shin and Seung Hwan Cho* Department of Chemistry, POSTECH, 37673, Pohang, Korea ABSTRACT: We report a broadly applicable copper catalytic conditions for the diastereoselective and enantioselective 1,2-addition of 1,1-diborylalkanes to cyclic ketimines and -imino esters. The developed method provides various -aminoboronate esters bearing adjacent stereocenters with high diastereo- and enantioselectivity. Synthetic applications for converting the resulting -aminoboronate esters to a diverse array of synthetically useful chiral molecules are demonstrated. KEYWORDS: copper catalysis, diastereoselectivity, enantioselectivity, -aminoboronate ester, boron The creation of contiguous stereocenters in a single catalytic reaction with controlling diastereo- and enantioselectivity is of considerable importance because such transformation enables the rapid synthesis of complex enantioenriched compounds.1 In particular, the stereoselective addition of prochiral nucleophiles to ketimines offers a potentially powerful approach for accessing sterically encumbered -tertiary amine and adjacent stereocenter, which exist in several pharmaceuticals, and biologically active compounds.2 Over the past decades, a strategy toward the stereoselective addition of carbonyl, nitro, and nitrile based nucleophiles to ketimines has been extensively explored.3 Nevertheless, the catalytic addition of prochiral organometallic reagents to ketimines with controlling diastereoand enantioselectivity has rarely been achieved. Trost and coworkers described a palladium-catalyzed cycloaddition of allylsilane derivatives to N-tosyl-protected ketimines with high diastereo- and enantioselectivity (Scheme 1a).4 Lam5a-c and Zhang5d reported the rhodium- or cobalt-catalyzed stereoselective addition of allylic potassium allyl trifluoroboronates to cyclic ketimines (Scheme 1b). Hoveyda et. al. disclosed a highly diastereoselective and enantioselective addition of allyl-Bpin reagents to various N-H ketimines catalyzed by chiral copper/NHC complex (Scheme 1c).6 Although these methods are very effective for the stereoselective addition of prochiral organometallic reagents to ketimines, all of reactions have been primarily focused on using allylsilanes or allylborons as coupling reagents.7,8 Thus, the development of stereoselective methods for the addition of prochiral alkylboron reagents to ketimines is still in demand and remains challenge. Recently, 1,1-diborylalkanes have been considered as useful prochiral nucleophiles in transition-metal-catalyzed coupling with prochiral electrophiles.9-11 These reagents enable the creation of two adjacent stereocenters derived from electrophiles and nucleophiles with high diastereo- and enantioselectvity. For example, Meek and coworkers reported a copper-catalyzed addition of 1,1-diborylalkanes to aldehydes10a and -ketoesters,10b affording enantioenriched -hydroxy-boronate esters. Our group also independently reported a copper catalyst ligated to a chiral phosphoramidite ligand was proved effective in the 1,2-addition of 1,1-diborylalkanes to aldimines, furnishing enantioenriched -aminoboronate esters with high

Scheme 1. Catalytic Stereoselective Addition of Prochiral Organometallics to Ketimines. a) Catalytic cycloaddition of functionalized allylsilane with ketimines (Trost4) N R1

Ts

Me3Si

+ Me

O O S N R

R1 Me CN

CN

and Zhang5d) O O S cat. [Rh],[Co]/L* NH 2 R * * 1 R R3 R4

b) Catalytic addition of allyl borons to ketimines (Lam

R

1

TsN

cat. [Pd]/L*

OAc

2

R3

+

BF3K R4

5a-c

c) Catalytic addition of allyl borons to N-H ketimines (Hoveyda6) N R1

H + R2

R2 NH2 Bpin

Bpin R

3

cat. [Cu]/L*

R1

Bpin

R3

d) This work: Copper-catalyzed addition of 1,1-diborylalkanes to ketimines N

PG

cat. [Cu]/L* LiOtBu

R2 +

pinB R1 Ar (R1 = aryl, vinyl, ester)

Bpin

via: L*/[Cu]

PGHN R1 Ar

rt - 50 oC

Bpin N

R2

R2

Ar

PG R1

Bpin

Creation of adjacent chiral -tertiary amine and secondary boronate ester Excellent diastereo- (up to >20:1) and enantioselectivity (up to 99% ee) Broad substrate scope

stereoselectivities.10d,e,12 The notable feature of these transformations was that the enantioselective transmetallation of 1,1-diborylalkanes with a chiral copper complex is expected to generate enantioenriched -boryl-alkyl-copper species that undergo addition reaction to prochiral electrophiles. With this consideration in mind, we envisaged that the reaction of the putative chiral -boryl-alkyl-copper species with ketimines would provide -aminoboronate esters containing contiguous tetrasubstituted and trisubstituted stereocenters. However, this strategy is challenging because ketimines proved to be intrinsically less reactive than aldimines. Herein, we report a

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Table 1. Optimization Study for the Copper-Catalyzed Addition of 2a to 1aa O

S

O

O

O N Ph

1 2

L

CuBr

L1

CuBr

L1

Table 2. Substrate Scope of Cyclic Ketimines and 1,1Diborylalkanesa–c

O NH Ph

O O S N

Me

Bpin

solvent 1,4-dioxane THF

yield (%)b

d.r.c

R1

ee (%)d

>20:1

76

O

S

CuBr

L1

toluene

78

>20:1

96

4

CuBr

L1

toluene/THF (1:1)

95

>20:1

98

6

CuCl

L1

CuI

L1

toluene/THF (1:1) toluene/THF (1:1)

97

>20:1

97

CuI

L2

toluene/THF (1:1)

88

>20:1

97

8

CuI

L3

toluene/THF (1:1)

97

>20:1

97

O

S

O

O O

Me

S

3d, 60% (81% ) (>20:1 d.r., 98% ee) O

S

O

Me

NH

O

NH Ph

O

CuI

L4

toluene/THF (1:1)

92

>20:1

91

10

CuI

L5

toluene/THF (1:1)

20:1

99

O

S

O

12e,f

CuI

L1

toluene/THF (1:1)

86

>20:1

S

O

Ar Ar O P R O

L1, R = NMe2 L2, R = NEt2 L3, R = N(CH2CH2)2O L4, R = N(Me)Bn

O

Me O

O Me P N Me O

O O Ph

Ar Ar L5, Ar = 4-(Me)C6H4

aThe

reaction was performed with 1a (0.20 mmol), 2a (1.5 equiv), [Cu] (5.0 mol %), ligand (10 mol %), and LiOtBu (2.0 equiv) in solvent (0.5 M) at room temperature for 24 h. b1H NMR yield using 1,1,2,2-tetrachloroethane as an internal standard. cDiastereomeric ratio was measured by 1H NMR of the crude reaction mixture. dEnantiomeric excess (% ee) was determined via. eCuI (3.0 mol %) and L1 (6.0 mol %) were used. fThe reaction was conducted at 50 oC for 12 h.

copper-catalyzed 1,2-addition of 1,1-diborylalkanes to cyclic ketimines and -imino esters that proceeds with high diastereoselectivity and enantioselectivity (Scheme 1d). Further transformations that convert the obtained -aminoboronate esters to synthetically beneficial chiral building blocks are also demonstrated. We initiated our study by choosing 4-phenyl-1,2,3benzoxathiazine-2,2-dioxide (1a) as a prochiral electrophile13 and 1,1-diborylethane (2a) as a coupling reagent (Table 1). When 1a and 2a were subjected in the presence of catalytic amounts of CuBr (5.0 mol %) and phosphoramidite ligand L1 (10 mol %), and LiOtBu in 1,4-dioxane at room temperature (Table 1, entry 1), the β-aminoboronate ester 3a was obtained in 79% yield. Notably, the product 3a was obtained with a diastereoselectivity (d.r.) greater than 20:1 and 93% enantioselectivity (% ee). The use of THF or toluene as a solvent yielded 3a with similar efficiency and higher % ee than

O

S

O NH CO2tBu Me Bpin

S

3i, 65%d (64%)e (>20:1 d.r., 95% ee)

O

O

NH Ph

O

S

O

OTBS

NH Ph

O

Bpin

Ph

3l, 79%f ,g (>20:1 d.r., 99% ee) O O S NH

F

Me

Me Bpin 3p, 77% (>20:1 d.r., 96% ee)

Bpin

3n, 70% (>20:1 d.r., 97% ee) O O S NH

Me

Me

Bpin

3m, 52%f ,g (>20:1 d.r., 98% ee) O O S NH

Bpin

3k, 71%f ,g (>20:1 d.r., 99% ee) O O S NH

NH Ph

O O

Bpin

3j, 65%f ,g (>20:1 d.r., 99% ee)

O

S

Bpin

Bpin

Me

O

Br

3h, 60% (88%)d (>20:1 d.r., 98% ee)

NH Ph

99

3f, 89% (>20:1 d.r., 99% ee)

Me

O

Me

Bpin

NH

Bpin

O

NH Ph

MeO

3e, 66% (>20:1 d.r., 98% ee)

O

3g, 80% (>20:1 d.r., 99% ee)

O

Me

O

S

Bpin

Me

9

3c, 79% (>20:1 d.r., 97% ee)

O

Cl

F

Me

Bpin OMe

Bpin

O

NH Ph

Me

3b, 89% (>20:1 d.r., 99% ee)

O NH Ph

O

S

Bpin

d

7

O

NH Ph

Me

99

Bpin

O

Me

3a, 97% (>20:1 d.r., 99% ee)

98

>20:1

S

O

Bpin

O

5

O

NH Ph

R3

3

O

98

3

R1

toluene/THF (1:1) rt, 24 h

2

93

>20:1

O O S NH 2 R

cat. CuI/L1 LiOtBu (2.0 equiv)

3

Bpin

pinB

1

O

79

R +

R2

3a

2a

[Cu]

S

solvent, rt, 24 h

Bpin

pinB

1a

entry

cat. [Cu]/ligand LiOtBu (2.0 equiv)

Me +

O

Page 2 of 7

3o, 71% (>20:1 d.r., 98% ee) O

Ph Bpin

3q, 46%f ,g (>20:1 d.r., 99% ee)

O Ph

S

O NH Me Me Bpin

3r, 20:1 d.r. and 98% ee. When CuBr was replaced by CuCl, the yield was improved slightly (entry 5), and the highest yield was obtained when CuI was employed as the catalyst (entry 6) with >20:1 d.r. and 99% ee. Reactions conducted in the presence of other phosphoramidite ligands (L2-L4) also afforded the product 3a in good yields, albeit with

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ACS Catalysis diminished efficiencies (entries 7–9). No reaction occurred when L5 was used as a ligand (entry 10). The catalyst loadings could be reduced to 3.0 mol % while maintaining the yields and stereoselectivities (entry 11).14,15 Increasing the reaction temperature to 50 oC shortened the reaction time to 12 h in a slightly low yield without compromising stereoselectivity (entry 12). Under optimized conditions, we investigated the scope of cyclic ketimines at room temperature (Table 2). Reactions of cyclic ketimines bearing an electron-donating substituent (3b, 3c, and 3f) with 2a provided the desired products in good yields (79%–89%) with stereoselectivities (>20:1 d.r. and >97% ee). Substrates bearing fluoride and chloride groups readily reacted with 2a, giving 3d and 3e in 60% and 66% yields, respectively, with >20:1 d.r. and 98% ee. Cyclic ketimines containing 4-tolyl, 4-bromopheyl, and ester group as the R2 substituent proved to be facile electrophiles, affording the corresponding products 3g-3i in good-to-moderate yields (64%–88%), with high diastereo- (>20:1) and enanantioselectivity (95–99% ee). Of note. the product 3i was isolated after oxidation of Bpin because of the instability on silica gel. Next, we examined the scope of 1,1-diborylalkanes. However, when 1a 1,1-diboryl-3-phenylpropane were subjected in the presence of 3.0 mol % of CuI and 6.0 mol % of L1, the product 3j was obtained in rather low yield (31%). To improve the yield, we conducted a re-optimization study and found that increasing the loading of the copper catalyst to 10 mol % in the presence of 2.0 equivalents of 1,1-diboryl-3phenylpropane afforded 3j in an acceptable yield (65%) with high diastereo- (>20:1) and enantioselectivity (99% ee) after 48 h.14 This re-optimized catalytic condition was immediately applied to reactions involving other 1,1-diborylalkanes. Reactions of a TBS-protected alcohol (3k), an acetal protected aldehyde (3l), and an olefin (3m) containing 1,1-diborylalkanes delivered the desired products in good yields (52%-79%) with high diastereo- (>20:1) and enantioselectivity (>98% ee). Intriguingly, five-membered cyclic ketimines also amenable to the 1,2-addition of 1,1-diborylalkanes. Reactions of fivemembered cyclic ketimines that bear phenyl, 4-tolyl, and 4fluorophenyl as a R2 substituent with 2a, providing the corresponding -aminoboronate esters 3n-3p (71-77%, >20:1 d.r., 96-98% ee).15 Phenyl-containing 1,1- diborylalkane smoothly reacted with a five-membered cyclic ketimine, resulting in the formation of 3q in moderate yields (46%) with good stereoselectivities (>20:1 d.r., 99% ee). Unfortunately, no reaction took place when methyl-containing cyclic ketimine (3r) was subjected to the reaction conditions. Since cyclic ketimine that bear enolizable -proton exhibited poor reactivity under the reaction conditions, we envisioned to develop two step sequences involving the 1,2-addition of 1,1diborylalkane to ,-unsaturated cyclic ketimine and subsequent hydrogenation (eq 1). However, this strategy should overcome the challenge associated with competitive 1,4addition of 1,1-diborylalkane to ,-unsaturated cyclic ketimine.16 Gratifyingly, when 1m was treated with 2a under the developed catalytic conditions at 50 oC, the desired 1,2addition product was solely obtained. Subsequent hydrogenation of the obtained product afforded the O O

S

O N

Me Ph

1m

+

pinB 2a

1) CuI (3.0 mol %) L1 (6.0 mol %) LiOtBu (2.0 equiv) toluene/THF (1:1) 50 oC, 24 h

Bpin 2) Pd/C (5.0 mol %) H2 (1 atm) MeOH, rt, 2 h

O O

S

O

Ph

NH Me Bpin

3s, 60% (2 steps) (>20:1 d.r., 99% ee)

(1)

Table 3. Evaluation of the N-Protecting Group (PG) of 4a likely via: Me

cat. CuBr/L1 PGNH CO2tBu PG Me N LiOtBu (2.0 equiv) Me + Ph 1,4-dioxane Bpin Ph CO2tBu pinB Bpin rt, 24 h 4aa-4ad

2a

PG N

5aa-5ad

entry

PG

yield (%)b

1

SO2Ph (4aa)

2

Ts (4ab)

3 4

Bpin [Cu]/L*

Ph

O OtBu

product

d.r.c

ee (%)d

94

5aa

15:1

96

93

5ab

15:1

93

SO2NMe2 (4ac)

94

5ac

>20:1

96

Boc (4ad)

20:1 d.r. and 99% ee). After achieving the 1,2-addition of 1,1-diborylalkanes to cyclic ketimines, we attempted to explore N-protected acyclic ketimines as electrophiles. To begin this study, we chose imino esters as electrophiles because the coordination of chiral copper species with nitrogen and oxygen atoms of the imino and ester group could facilitate the transfer of the -boryl-alkyl moiety to the adjacent electrophilic C=N bond.17 Furthermore, the reaction provided -boryl--amino acid derivatives, which can be used as versatile synthons in the preparation of unnatural peptide. To test the 1,2-addition reaction of 1,1-diborylalkanes to imino esters, we examined the reaction of various N-protected -imino ester (4) with 2a under the reaction conditions (Table 3). When phenylsulfonyl-protected -imino ester (4aa) and 2a were treated in the presence of 5.0 mol % of CuBr, 10 mol % of L1, and LiOtBu in 1,4-dioxane at room temperature, the corresponding -boryl--amino acid derivative 5aa was obtained in 94% yield with 15:1 d.r. and 96% ee (Table 3, entry 1). An analogous reaction of N-Ts-protected -imino ester (4ab) with 2a afforded 5ab in good yield and diastereoselectivity, albeit with slightly lower enantioselectivity (entry 2). The introduction of the N,N-dimethylsulfamoyl moiety (4ac) as the N-protecting group of -imino ester (entry 3) yielded the product 5ac in good yield (94%) with >20:1 d.r. and 96% ee.15 The use of Boc-protected -imino ester did not provide the coupled product (entry 4). Encouraged by these results, we examined the scope and limitations of the developed protocol (Table 4). We found that -imino esters bearing electron-donating (5b, 5c, and 5f) and electron-withdrawing (5d and 5e) substituents on the arene ring were well tolerated, giving the -boryl--amino acid derivatives products in good yields (80-95%) with high d.r. (>20:1) and enantioselectivity (92%-97% ee). A naphthylgroup-containing -imino ester also participated in the reaction, leading to the product 5g in 89% yield (>20:1 d.r. and 90% ee). In contrast, the reaction of 4ac with 1,1-diboryl-3phenylpropane afforded 5h in 61% yield with 18:1 d.r. and 60% ee,14 indicating the current limitation of the Cu/L1 catalyst system. The synthetic usefulness of the developed 1,2-addition process was demonstrated by conducting the developed

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Table 4. Substrate Scope of -Imino Esters and 1,1Diborylalkanesa–c O O S N NMe2 Ar

Bpin

pinB

CO2tBu 4

Bpin

5b, 95% (>20:1 d.r., 93% ee)

O O S NMe2

Bpin

MeO

5c, 93% (>20:1 d.r., 92% ee)

Bpin

HN CO2tBu Me

5d, 80% (>20:1 d.r., 97% ee)

5e, 80% (16:1 d.r., 93% ee)

5f, 75% (18:1 d.r., 97% ee)

O O S NMe2 HN CO2tBu Me Bpin 5g, 89% >20:1 d.r., 90% ee

O O S NMe2

Me

Me

HN CO2tBu Me

Me

Ph

Bpin

Bpin

3o, 62% (1.28 g) >20:1 d.r. 98% ee

5ac, 84% (1.97 g) >20:1 d.r. 96% ee

with CuI/L1 in toluene/THF

with CuI/L1 in toluene/THF

with CuBr/L1 in 1,4-dioxane

S

O

O

NH Ph

HN CO2tBu Me Bpin

O O S NH

3a, 72% (1.50 g) >20:1 d.r. 99% ee

O

Bpin

Cl

NH Ph

b) Further transformations of 3a, 3o, and 5ac

O O S NMe2 Me

Bpin

Bpin

HN CO2tBu Me

O O S NMe2

HN CO2tBu Me

O

O O S NMe2

HN CO2tBu Me Me

S

O

Me

OH

a

a,d

(f rom 3a)

(f rom 3o)

6, 99% >20:1 d.r., 99% ee

O

O S N

e

O

3a, 3o, or 5ac

O

Bpin

(4-tolyl) Me Ph 9, 40% >20:1 d.r., 98% ee

(f rom 5ac) f

7, 89% >20:1 d.r., 99% ee

5h, 61%d,e (18:1 d.r., 60% ee)

O O S NMe2 HN

a

The reaction was performed with 1 (0.20 mmol), 2 (1.5 equiv), CuBr (5.0 mol %), L1 (10 mol %), LiOtBu (2.0 equiv) in 1,4dioxane (0.5 M) at rt for 24 h. bDiastereomeric ratio was measured by 1H NMR of the crude reaction mixture. cThe enantiomeric excess (% ee) was determined via HPLC. dCuBr (10 mol %), L1 (20 mol %), and 2 (2.0 equiv) were used. eThe reaction was performed for 48 h.

b

OH Me

Ph

O

HN

Me

Ph

Me

8, 67% >20:1 d.r., 98% ee

H2N Ph

HN CO2tBu

O

(4-tolyl)

b,c

O O S NMe2

reaction on a gram scale. We were able to obtain the desired aminoboronate esters 3a, 3o, and 5ac in good yields while preserving the optical purity (Scheme 2a). Next, we focused on exploring further transformations of compounds 3a, 3o, and 5ac, as depicted in Scheme 2b. Oxidation of the Bpin group of 3a with H2O2 and NaHCO3 in THF/H2O produced the -amino alcohol 6 in an almost quantitative yield (>20:1 d.r., 99% ee). Subsequent deprotection of the sulfonyl group upon treatment with LiAlH4 and intramolecular Mitsunobu cyclization with triphenylphosphine and diethyl azodicarboxylate yielded the enantioenriched dibenzofuranamine derivative 7 in 89% yield in two steps (>20:1 d.r., 99% ee). After oxidation of Bpin moiety of 3o, the addition of trichloromethyl chloroformate with trimethylamine furnished the compound 8 in 67% yield in two steps. The compound 8 was readily converted into the oxazolidinone 9 by the removal of the sulfonyl group (40%, >20:1 d.r., 97% ee). The -boryl--amino acid derivative 5ac could also be transformed into other synthetically important enantioenriched molecules. Oxidation of the Bpin group of 5ac with H2O2 delivered -hydroxy-- amino acid derivative 10 in 94% yield (>20:1 d.r., 99% ee), which can be further manipulated by the reduction of ester group of 10 with LiAlH4 to yield the corresponding 2-amino- 1,3-diol 11 in 84% yield (18:1 d.r., 96% ee). Following acetal protection of 11 to give 12 (87%, 18:1 d.r., 96% ee), removal of N,N-dimethylsulfamoyl group with 1,3-diaminopropane gave the free amine 13 in 99% yield without racemization (18:1 d.r., 96% ee). Finally, the

Me

Ar

2a

(5.0 mmol)

O

PGHN R1

solvent, rt, 24 h

Bpin

pinB

R1

O

cat. [Cu]/L1 LiOtBu (2.0 equiv)

Me +

Ar

Bpin

O O S NMe2

HN CO2tBu Me

F3C

1,4-dioxane rt, 24 h

PG

N

5

O O S NMe2

5ac, 94% (>20:1 d.r., 96% ee)

a) Gram-scale reaction

HN CO2tBu R Ar

2

Bpin

Scheme 2. Synthetic Utility

O O S NMe2

cat. CuBr/L1 LiOtBu (2.0 equiv)

R +

Page 4 of 7

O O S NMe2

i

HN CO2tBu Me

OH

N tBuO2C Ph

Ph

OH

11, 84% 18:1 d.r., 96% ee

O O S NMe2

10, 94% >20:1 d.r., 96% ee

Me

14, 55% >20:1 d.r., 96% ee

g O O S NH

Me2N

Ph

Me

Me O O

12, 87%, 18:1 d.r. 96% ee

Me

NH2

h Ph

Me

Me O O

Me

13, 99% 18:1 d.r., 96% ee

aH

b 2O2, NaHCO3, THF/H2O, room temperature (rt). LiAlH4, THF, reflux, then H2O. cPPh3, diethyl azodicarboxylate (DEAD), CH2Cl2, 0 °C to rt. dTrichloromethyl chloroformate, Et3N, THF, 0 °C. eSodium naphthalide, DME, rt. fH2O2, NaHCO3, THF/H2O, 0 °C. g2,2-dimethoxypropane, p-TsOH·H2O, acetone, rt. h1,3diaminopropane, 140 °C. iPPh3, diisopropyl azodicarboxylate (DIAD), THF, 0 °C to rt.

reaction of 10 with diisopropyl azodicarboxylate and triphenylphosphine gave the 1,1,2-trisubstituted aziridine 14 in moderate yield (55%) with preservation of enantiopurity (>20:1 d.r., 96% ee). In summary, we have developed an efficient copper-catalytic condition for the diastereoselective and enantioselective addition of 1,1- diborylalkanes to various cyclic ketimines and -imino esters. The developed reaction provides aminoboronate esters bearing adjacent -tertiary amine and secondary boronate ester in good yields, with high diastereoand enantioselectiviy. The reaction can be conducted on gram scale and the synthetic utility of the obtained -aminoboronate esters was demonstrated by performing additional transformations, thus providing methods to afford various chiral libraries. Further studies are ongoing to understand the origin of

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ACS Catalysis this stereocontrol and develop new transformations of 1,1-diborylalkanes.

copper-catalyzed

ASSOCIATED CONTENT Supporting Information. Experimental procedures, characterization data, NMR, X-ray structures of 3a, 3n, and 5d, and HPLC spectra for new compounds. CCDC 1909710 (3a), 1909709 (3n), and 1909711 (5d) contain the supplementary crystallographic data for this paper. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Research Foundation of Korea (NRF-2019M1A2A2067940 and NRF2019R1A2C2004925).

REFERENCES (1) For selected reviews, see: (a) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. The Vinylogous Aldol and Related Addition Reactions: Ten Years of Progress. Chem. Rev. 2011, 111, 3076–3154; (b) Eppe, G.; Didier, D.; Marek, I. Stereocontrolled Formation of Several Carbon–Carbon Bonds in Acyclic Systems. Chem. Rev. 2015, 115, 9175–9206; (c) Kim, J. H.; Ko, Y. O.; Bouffard, J.; Lee, S. G. Advances in Tandem Reactions with Organozinc Reagents. Chem. Soc. Rev. 2015, 44, 2489–2507; (d) Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B. M. Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations. Chem. Rev. 2017, 117, 4528–4561; (e) Krautwald, S.; Carreira, E. M. Stereodivergence in Asymmetric Catalysis. J. Am. Chem. Soc. 2017, 139, 5627–5639; (f) Beletskaya, I. P.; Nájera, C.; Yus, M. Stereodivergent Catalysis. Chem. Rev. 2018, 118, 5080–5200; (g) Spielmann, K.; Niel, G.; de Figueiredo, R. M.; Campagne, J.-M. Catalytic Nucleophilic 'Umpoled' -allyl reagents. Chem. Soc. Rev. 2018, 47, 1159–1173; (h) Yamashita, Y.; Yasukawa, T.; Yoo, W.-J.; Kitanosono, T.; Kobayashi, S. Catalytic Enantioselective Aldol Reactions. Chem. Soc. Rev. 2018, 47, 4388–4480. (2) (a) Shibasaki, M.; Kanai, M. Asymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C − C Bond Formation to Ketones and Ketimines. Chem. Rev. 2008, 108, 2853– 2873; (b) Arrayas, R. G.; Carretero, J. C. Catalytic Asymmetric Direct Mannich Reaction: A Powerful Tool for the Synthesis of ,-Diamino Acids. Chem. Soc. Rev. 2009, 38, 1940–1948; (c) Kumagai, N.; Shibasaki, M. Asymmetric Catalysis with Bis(hydroxyphenyl)diamides/Rare-Earth Metal Complexes. Angew. Chem., Int. Ed. 2013, 52, 223–234; (d) Noble, A.; Anderson, J. C. Nitro-Mannich Reaction. Chem. Rev. 2013, 113, 2887–2939; (e) Kumagai, N.; Shibasaki, M. Recent Advances in Catalytic Asymmetric C–C Bond-Forming Reactions to Ketimines Promoted by Metal-Based Catalysts. Bull. Chem. Soc. Jpn. 2015, 88, 503–517. (3) (a) Du, Y.; Xu, L.-W.; Shimizu, Y.; Oisaki, K.; Kanai, M.; Shibasaki, M. Asymmetric Reductive Mannich Reaction to Ketimines Catalyzed by a Cu(I) Complex. J. Am. Chem. Soc. 2008, 130, 16146– 16147; (b) Rommel, M.; Fukuzumi, T.; Bode, J. W. Cyclic Ketimines as Superior Electrophiles for NHC-Catalyzed Homoenolate Additions with Broad Scope and Low Catalyst Loadings. J. Am. Chem. Soc. 2008, 130, 17266–17267; (c) Wieland, L. C.; Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. Ag-Catalyzed Diastereo- and Enantioselective Vinylogous Mannich Reactions of -Ketoimine Esters. Development of a Method and Investigation of its Mechanism. J. Am. Chem. Soc. 2009, 131, 570–576; (d) Guo, Q.-X.; Liu, Y.-W.; Li, X.-C.; Zhong, L.Z.; Peng, Y.-G. Enantioselective and Solvent-Controlled

Diastereoselective Mannich Reaction of Isatin Imines with Hydroxyacetone: Synthesis of 3-Substituted 3-Aminooxindoles. J. Org. Chem. 2012, 77, 3589–3594; (e) Kano, T.; Song, S.; Kubota, Y.; Maruoka, K. Highly Diastereo‐ and Enantioselective Mannich Reactions of Synthetically Flexible Ketimines with Secondary Amine Organocatalysts. Angew. Chem. Int. Ed. 2012, 51, 1191–1194; (f) Arai, T.; Matsumura, E.; Masu, H. Bis(imidazolidine)pyridine-NiCl2 Catalyst for Nitro-Mannich Reaction of Isatin-Derived N-Boc Ketimines: Asymmetric Synthesis of Chiral 3-Substituted 3-Amino-2oxindoles. Org. Lett. 2014, 16, 2768–2771; (g) Holmquist, M.; Blay, G.; Pedro, J. R. Highly Enantioselective Aza-Henry Reaction with Isatin N-Boc Ketimines. Chem. Commun. 2014, 50, 9309–9312; (h) Li, T.-Z.; Wang, X.-B.; Sha, F.; Wu, X.-Y. Organocatalyzed Enantioselective Mannich Reaction of Pyrazoleamides with IsatinDerived Ketimines. J. Org. Chem. 2014, 79, 4332–4339; (i) Bao, X.; Wang, B.; Cui, L.; Zhu, G.; He, Y.; Qu, J.; Song, Y. An Organocatalytic Asymmetric Friedel–Crafts Addition/Fluorination Sequence: Construction of Oxindole–Pyrazolone Conjugates Bearing Vicinal Tetrasubstituted Stereocenters. Org. Lett. 2015, 17, 5168–5171; (j) Engl, O. D.; Fritz, S. P.; Wennemers, H. Stereoselective Organocatalytic Synthesis of Oxindoles with Adjacent Tetrasubstituted Stereocenters. Angew. Chem. Int. Ed. 2015, 54, 8193–8197; (k) Lin, S.; Kawato, Y.; Kumagai, N.; Shibasaki, M. Catalytic Asymmetric Mannich‐Type Reaction of N‐Alkylidene‐‐Aminoacetonitrile with Ketimines. Angew. Chem. Int. Ed. 2015, 54, 5183–5186; (l) Zhao, J.; Fang, B.; Luo, W.; Hao, X.; Liu, X.; Lin, L.; Feng, X. Enantioselective Construction of Vicinal Tetrasubstituted Stereocenters by the Mannich Reaction of Silyl Ketene Imines with Isatin‐Derived Ketimines. Angew. Chem. Int. Ed. 2015, 54, 241–244; (m) Amr, F. I.; Vila, C.; Blay, G.; Muñoz, M. C.; Pedro, J. R. Organocatalytic Enantioselective Alkylation of Pyrazol‐3‐ones with Isatin‐Derived Ketimines: Stereocontrolled Construction of Vicinal Tetrasubstituted Stereocenters. Adv. Synth. Catal. 2016, 358, 1583–1588; (n) Lin, H.; Zhou, Z.; Cai, J.; Han, B.; Gong, L.; Meggers, E. Asymmetric Construction of 3,3-Disubstituted Oxindoles Bearing Vicinal Quaternary–Tertiary Carbon Stereocenters Catalyzed by a Chiral-atRhodium Complex. J. Org. Chem. 2017, 82, 6457–6467; (o) Shao, Q.; Wu, L.; Chen, J.; Gridnev, I. D.; Yang, G.; Xie, F.; Zhang, W. Copper (II)/RuPHOX‐Catalyzed Enantioselective Mannich‐Type Reaction of Glycine Schiff Bases with Cyclic Ketimines. Adv. Synth. Catal. 2018, 360, 4625–4633; (p) Zhu, J.-Y.; Yang, W.-L.; Liu, Y.-Z.; Shang, S.-J.; Deng, W.-P. A Copper(I)-Catalyzed Asymmetric Mannich Reaction of Glycine Schiff Bases with Isatin-Derived Ketimines: Enantioselective Synthesis of 3-Substituted 3-Aminooxindoles. Org. Chem. Front. 2018, 5, 70–74. (4) Trost, B. M.; Silverman, S. M. Enantioselective Construction of Highly Substituted Pyrrolidines by Palladium-Catalyzed Asymmetric [3+2] Cycloaddition of Trimethylenemethane with Ketimines. J. Am. Chem. Soc. 2010, 132, 8238–8240. (5) (a) Luo, Y.; Hepburn, H. B.; Chotsaeng, N.; Lam, H. W. Enantioselective Rhodium-Catalyzed Nucleophilic Allylation of Cyclic Imines with Allylboron Reagents. Angew. Chem. Int. Ed. 2012, 51, 8309–8313; (b) Hepburn, H. B.; Chotsaeng, N.; Luo, Y.; Lam, H. W. Enantioselective Rhodium-Catalyzed Allylation of Cyclic Imines with Potassium Allyltrifluoroborates. Synthesis 2013, 45, 2649–2661; (c) Hepburn, H. B.; Lam, H. W. The Isomerization of Allylrhodium Intermediates in the Rhodium‐Catalyzed Nucleophilic Allylation of Cyclic Imines. Angew. Chem. Int. Ed. 2014, 53, 11605–11610; (d) Wu, L.; Shao, Q.; Yang, G.; Zhang, W. Cobalt‐Catalyzed Asymmetric Allylation of Cyclic Ketimines. Chem. Eur. J. 2018, 24, 1241–1245. (6) Jang, H.; Romiti, F.; Torker, S.; Hoveyda, A. H. Catalytic Diastereo- and Enantioselective Additions of Versatile Allyl Groups to N–H Ketimines. Nat. Chem. 2017, 9, 1269–1275. (7) As alternative approaches, the steoselective addition of allylmetals to enantioenriched ketimines were was reported. (a) Reddy, L. R.; Hu, B.; Prashad, M.; Prasad, K. Asymmetric Synthesis of Homoallylic Amines Bearing Adjacent Stereogenic Centers by Addition of Substituted Allylic Zinc Reagents to N-tert-Butanesulfinylimines. Org. Lett. 2008, 10, 3109–3112; (b) Guo, T.; Song, R.; Yuan, B.-H.; Chen, X.-Y.; Sun, X.-W.; Lin, G.-Q. Highly Efficient Asymmetric Construction of Quaternary Carbon-Containing Homoallylic and Homopropargylic Amines. Chem. Commun. 2013, 49, 5402–5404.

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(8) The steoselective addition of enantioenriched allyl boron reagents to ketimines was reported. Chen, J. L. Y.; Aggarwal, V. K. Highly Diastereoselective and Enantiospecific Allylation of Ketones and Imines Using Borinic Esters: Contiguous Quaternary Stereogenic Centers. Angew. Chem., Int. Ed. 2014, 53, 10992–10996. (9) For recent reviews, see: (a) Miralles, N.; Maza, R. J.; Fernández, E. Synthesis and Reactivity of 1,1-Diborylalkanes towards C-C Bond Formation and Related Mechanisms. Adv. Synth. Cat. 2018, 360, 1306– 1327; (b) Nallagonda, R.; Padala, K.; Masarwa, A. gem-Diborylalkanes: Recent Advances in Their Preparation, Transformation and Application. Org. Biomol. Chem. 2018, 16, 1050–1064; (c) Wu, C.; Wang, J. Geminal Bis(boron) Compounds: Their Peparation and Synthetic Applications. Tetrahedron Lett. 2018, 59, 2128–2140. (10) (a) Joannou, M. V.; Moyer, B. S.; Meek, S. J. Enantio- and Diastereoselective Synthesis of 1,2-Hydroxyboronates through CuCatalyzed Additions of Alkylboronates to Aldehydes. J. Am. Chem. Soc. 2015, 137, 6176–6179; (b) Murray, S. A.; Green, J. C.; Tailor, S. B.; Meek, S. J. Enantio‐ and Diastereoselective 1,2‐Additions to ‐Ketoesters with Diborylmethane and Substituted 1,1‐Diborylalkanes. Angew. Chem., Int. Ed. 2016, 55, 9065–9069; (c) Park, J.; Lee, Y.; Kim, J.; Cho, S. H. Copper-Catalyzed Diastereoselective Addition of Diborylmethane to N-tert-Butanesulfinyl Aldimines: Synthesis of βAminoboronates. Org. Lett. 2016, 18, 1210–1213; (d) Kim, J.; Ko, K.; Cho, S. H. Diastereo- and Enantioselective Synthesis of βAminoboronate Esters by Copper(I)-Catalyzed 1,2-Addition of 1,1Bis[(pinacolato)boryl]alkanes to Imines. Angew. Chem., Int. Ed. 2017, 56, 11584–11588. (e) Kim, J.; Hwang, C.; Kim, Y.; Cho, S. H. Improved Synthesis of -Aminoboronate Esters via Copper-Catalyzed Diastereo- and Enantioselective Addition of 1,1-Diborylalkanes to Acyclic Arylaldimines. Org. Process Res. Dev. 2019, DOI: 10.1021/acs.oprd.9b00179. (11) (a) Potter, B.; Szymaniak, A. A.; Edelstein, E. K.; Morken, J. P. Nonracemic Allylic Boronates through Enantiotopic-Group-Selective Cross-Coupling of Geminal Bis(boronates) and Vinyl Halides. J. Am. Chem. Soc. 2014, 136, 17918–17921; (b) Sun, C.; Potter, B.; Morken, J. P. A Catalytic Enantiotopic-Group-Selective Suzuki Reaction for the Construction of Chiral Organoboronates. J. Am. Chem. Soc. 2014, 136, 6534–6537; (c) Sun, H.-Y.; Kubota, K.; Hall, D. G. Reaction Optimization, Scalability, and Mechanistic Insight on the Catalytic Enantioselective Desymmetrization of 1,1-Diborylalkanes via Suzuki– Miyaura Cross-Coupling. Chem. Eur. J. 2015, 21, 19186–19194; (d) Kim, J.; Cho, S. H. Access to Enantioenriched Benzylic 1,1Silylboronate Esters by Palladium-Catalyzed Enantiotopic-Group Selective Suzuki–Miyaura Coupling of (Diborylmethyl)silanes with Aryl Iodides. ACS Catal. 2019, 9, 230–235. (12) Hall and coworkers reported diastereoselective monoprotodeboronation of -sulfinimido 1,1-diboronate esters for the synthesis of -aminoboronate esters, see: Li, X.; Hall, D. G. Diastereocontrolled Monoprotodeboronation of -Sulfinimido gem-

Bis(boronates): A General and Stereoselective Route to , Disubstituted -Aminoalkylboronates. Angew. Chem., Int. Ed. 2018, 57, 10304–10308. (13) (a) Wang, H.; Jiang, T.; Xu, M.-H. Simple Branched Sulfur– Olefins as Chiral Ligands for Rh-Catalyzed Asymmetric Arylation of Cyclic Ketimines: Highly Enantioselective Construction of Tetrasubstituted Carbon Stereocenters. J. Am. Chem. Soc. 2013, 135, 971–974; (b) Hepburn, H. B.; Lam, H. W. The Isomerization of Allylrhodium Intermediates in the Rhodium‐Catalyzed Nucleophilic Allylation of Cyclic Imines. Angew. Chem., Int. Ed. 2014, 53, 11605– 11610; (c) Jiang, C.; Lu, Y.; Hayashi, T. High Performance of a Palladium Phosphinooxazoline Catalyst in the Asymmetric Arylation of Cyclic N‐Sulfonyl Ketimines. Angew. Chem. Int. Ed. 2014, 53, 9936–9939; (d) Jiang, T.; Wang, Z.; Xu, M.-H. Rhodium-Catalyzed Asymmetric Arylation of Cyclic N-Sulfonyl Aryl Alkyl Ketimines: Efficient Access to Highly Enantioenriched -Tertiary Amines. Org. Lett. 2015, 17, 528–531; (e) De Munck, L.; Vila, C.; Muñoz, M. C.; Pedro, J. R. Catalytic Enantioselective Aza‐Reformatsky Reaction with Cyclic Imines. Chem. Eur. J. 2016, 22, 17590–17594; (f) Martínez, J. I.; Smith, J. J.; Hepburn, H. B.; Lam, H. W. Chain Walking of Allylrhodium Species Towards Esters During Rhodium‐Catalyzed Nucleophilic Allylations of Imines. Angew. Chem., Int. Ed. 2016, 55, 1108–1112; (g) Quan, M.; Tang, L.; Shen, J.; Yang, G.; Zhang, W. Ni(ii)-Catalyzed Asymmetric Addition of Arylboronic Acids to Cyclic Imines. Chem. Commun. 2017, 53, 609–612. (14) See the Supporting Information for details. (15) The relative and absolute stereochemistry of 3a and 3n were assigned as (R, R), and 5d was assigned as (S, R) as determined by Xray analysis. The configurations of other products were assigned by analogy. See the Supporting Information for details. (16) (a) Lee, A.; Kim, H. Rhodium-Catalyzed Asymmetric 1,4Addition of ,-Unsaturated Imino Esters Using Chiral Bicyclic Bridgehead Phosphoramidite Ligands. J. Am. Chem. Soc. 2015, 137, 11250–11253; (b) Lee, A.; Kim, H. Chiral Bicyclic Bridgehead Phosphoramidite (Briphos) Ligands for Asymmetric RhodiumCatalyzed 1,2- and 1,4-Addition. J. Org. Chem. 2016, 81, 3520–3527; (c) Zhang, Y.-F.; Chen, D.; Chen, W.-W.; Xu, M.-H. Construction of Cyclic Sulfamidates Bearing Two gem-Diaryl Stereocenters through a Rhodium-Catalyzed Stepwise Asymmetric Arylation Protocol. Org. Lett. 2016, 18, 2726–2729; (d) Wu, C.-Y.; Zhang, Y.-F.; Xu, M.-H. Ligand-Controlled Rhodium-Catalyzed Site-Selective Asymmetric Addition of Arylboronic Acids to ,-Unsaturated Cyclic N-Sulfonyl Ketimines. Org. Lett. 2018, 20, 1789–1793. (17) (a) Taggi, A. E.; Hafez, A. M.; Lectka, T. -Imino Esters:   Versatile Substrates for the Catalytic, Asymmetric Synthesis of - and -Amino Acids and -Lactams. Acc. Chem. Res. 2003, 36, 10–19; (b) Eftekhari-Sis, B.; Zirak, M. -Imino Esters in Organic Synthesis: Recent Advances. Chem. Rev. 2017, 117, 8326–8419.

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ACS Catalysis

Table of Contents (TOC) N

PG

cat. [Cu]/L* LiOtBu

R2 +

pinB R1 Ar (R1 = aryl, vinyl, ester)

Bpin

via: L*/[Cu]

PGHN R1 Ar

rt - 50 oC

Bpin N

R2

R2

Ar

PG R1

Bpin

Creation of adjacent chiral -tertiary amine and secondary boronate ester Excellent diastereo- (up to >20:1) and enantioselectivity (up to 99% ee) Broad substrate scope

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