Synthesis 2014; 46(17): 2272-2282
DOI: 10.1055/s-0034-1378514
feature article
© Georg Thieme Verlag Stuttgart · New York

Preparation of the Zinc Enolate Equivalent of Amides by Zinciomethylation of Isocyanates: Catalytic Asymmetric Reformatsky-Type Reaction

Ryosuke Haraguchi
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan   Fax: +81(75)3832438   Email: matsubara.seijiro.2e@kyoto-u.ac.jp
,
Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan   Fax: +81(75)3832438   Email: matsubara.seijiro.2e@kyoto-u.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 02 June 2014

Accepted after revision: 25 June 2014

Publication Date:
31 July 2014 (online)

 


Abstract

Bis(iodozincio)methane [CH2(ZnI)2] transforms isocyanates (R–N=C=O) into the enolate equivalent of amides via zinciomethylation. The reactivity of the enolate equivalent as a nucleophile toward aldehydes depends on the R group of the isocyanate. For the enolate equivalent formed from phenyl isocyanate, the addition of a catalytic amount of an optically active amino alcohol, which acts as an activator, leads to a catalytic asymmetric Reformatsky-type reaction.


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Biographical Sketches

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Ryosuke Haraguchi was born in 1988 and raised in Chiba, Japan. He obtained his B.Eng. degree from Kyoto University in 2009. He then started his master’s thesis on organozinc chemistry using microflow systems in the group of Prof. Seijiro Matsubara, and obtained his M.Eng. degree in 2013. He is continuing his work on organozinc chemistry during his Ph.D. studies, focusing on bis(iodo­zincio)methane reactions.

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Seijiro Matsubara was born in 1959 and raised in Kobe, Japan. He obtained his B.Eng. degree in 1981 and M.Eng. degree in 1983 in the group of Prof. Hitosi Nozaki at Kyoto University. He obtained a Ph.D. degree from Kyoto University in 1986 under the direction of Prof. Hitosi Nozaki and Prof. Kiitiro Utimoto. In 1984–1985, he also studied fluorine chemistry in the group of Prof. Manfred Schlosser, Université de Lausanne, Switzerland. He joined Kyoto University as an assistant professor in Prof. Utimoto’s group in 1986. After postdoctoral research with Prof. Barry M. Trost in 1988–1989 at Stanford University, USA, he became an associate professor at Kyoto University in 1995. In 2006, he became a full professor at Kyoto University. His research focuses on the preparation of cyclic compounds using organozinc reagents, transition-metal-catalyzed reactions, and organocatalytic reactions. He received the Inoue Research Award for Young Scientists in 1986 and the Incentive Award in Synthetic Organic Chemistry, Japan in 1998.

Organozinc reagents have been widely used as versatile nucleophiles, which possess reasonable reactivity and high compatibility with various functional groups.[1] Some classical methods, such as metal–zinc exchange, deprotonation, and halogen–zinc exchange, have been utilized to prepare these reagents. These methods are problematic, as the conditions used are often too harsh for some functional groups in the target organozinc species. However, the use of complex reagent systems has changed the situation dramatically. For example, it has been shown that the insertion of zinc into organic halides is facilitated in the presence of a stoichiometric amount of lithium chloride.[2] Amide zincates[3] and the zinc–magnesium–lithium complex base, (tmp)2Zn·2 MgCl2·2 LiCl,[4] have been shown to be useful reagents to provide heteroarylzinc compounds by deprotonation. These reagents have led to a renewed interest in organozinc species as an indispensable tool for organic synthesis.[5]

To increase the value of organozinc reagents as synthetic tools, a completely different strategy for the preparation of these reagents may be significant. We have studied the reactivity of bis(iodozincio)methane (1),[6] which is easily obtained from diiodomethane and zinc powder.[7] A number of specific molecular transformations, based on its reactivity as a gem-dimetal species, have been shown.[8] Among these transformations, a zinciomethylation reaction can be focused on as a new method for the preparation of organozinc species.[9] For example, a palladium-catalyzed cross-coupling reaction of iodobenzene with 1 gave a benzylzinc reagent. Moreover, treatment of acylating reagents with 1 gives α-iodozinciocarbonyl compounds, which can tautomerize into the corresponding enolates. In fact, treatment of a thioester with dizinc 1 and trimethylsilyl chloride in the presence of a palladium catalyst gave the corresponding silyl enolate via Fukuyama coupling [Scheme [1, ](1)].[10] In this study, we focus on the use of isocyanates as electrophiles [Scheme [1, ](2)]. We discuss the synthesis and reactivity of the zinc enolate equivalent of amides, which can be prepared by the addition of dizinc 1 to isocyanates 2.[11]

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Scheme 1 Homologative zinc enolate preparation: (1) cross-coupling reaction of a thioester with 1; (2) addition of 1 to isocyanates 2

Various isocyanates were treated with dizinc 1 (Table [1]). A tetrahydrofuran solution of 1 (0.13 M, 1.5 mL) was added to a solution of the isocyanate 2 (0.2 mmol) in solvent (4 mL). The resulting reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. At 25 °C, benzoyl isocyanate (2a, R = Bz) gave the corresponding amide 3a and the diamide 4a; the diamide 4a is the adduct of the initial zinciomethylated product with another equivalent of isocyanate 2a (Table [1], entry 1). Lowering the reaction temperature (–60 °C), to prevent the formation of 4a gave 3a selectively (Table [1], entry 3). Aryl and alkyl isocyanates 2be were less electrophilic than 2a in the reaction with dizinc 1. To complete the addition of 1 to phenyl isocyanate (2b), a higher reaction temperature (80 °C) was required (Table [1], entries 4 and 5). The use of toluene as a less polar solvent did not affect the yield of 3b (Table [1], entry 6). The addition of substituents to the aryl isocyanates to tune the electron density on the benzene ring resulted in a slight decrease in the yield (Table [1], entries 7 and 8). An alkyl (cyclohexyl) isocyanate also gave the corresponding amide 3e at 80 °C (Table [1], entry 9).

The addition of benzaldehyde in place of the aqueous workup was examined to perform a Reformatsky-type reaction. The corresponding enolate equivalent formed from benzoyl isocyanate (2a) showed high nucleophilicity toward benzaldehyde (5a), even at –40 °C, and gave the adduct 6aa in 90% yield (Table [2], entry 1). In the case of the enolate equivalent formed from phenyl isocyanate (2b), a higher reaction temperature (140 °C) was required to give the corresponding adduct 6ba in reasonable yield (Table [2], entry 5). The other isocyanates, 2ce, also gave the corresponding adducts 6caea in poor yields at 25 °C (Table [2], entries 6–8).

Table 1 Reaction of Dizinc 1 with Isocyanates 2 a

Entry

R

Solvent

Temp (°C)

Yieldb (%) of 3

Yieldb (%) of 4

1

Bz (2a)

THF

 25

 6

88

2

Bz (2a)

THF

  0

32

62

3

Bz (2a)

THF

–60

73

16

4

Ph (2b)

THF

 25

48

<1

5

Ph (2b)

THF

 80

99

<1

6

Ph (2b)

toluene

 80

99

<1

7

4-MeOC6H4 (2c)

THF

 80

88

<1

8

4-F3CC6H4 (2d)

THF

 80

96

<1

9

Cy (2e)

THF

 80

95

<1

a Reaction conditions: dizinc 1 (0.13 M in THF, 1.5 mL, 0.2 mmol), isocyanate 2 (0.2 mmol), solvent (4 mL).

b Isolated yields.

The enolate equivalent adduct of dizinc 1 and an isocyanate 2 has three possible forms, 7ac (Scheme [2]). Although these structures are in equilibrium, the contribution of each structure depends on the R group. 1H NMR analysis of the mixture resulting from the reaction of dizinc 1 and benzoyl isocyanate (2a) or phenyl isocyanate (2b) in tetrahydrofuran-d 8 gave some insight on the preferred structure of the formed enolate equivalents. The singlet peak at –1.3 ppm from the reaction of 1 and 2a (R = Bz) suggests the formation of imine-like 7a, while the singlet peak at 1.8 ppm from the reaction of 1 and 2b (R = Ph) implies the formation of C-enolate 7b.[12] The upfield chemical shift of the enolate equivalent from 2a implies this compound has a stronger anionic character than that of the enolate equivalent from 2b. The higher nucleophilicity observed for the 2a enolate equivalent in the reaction with aldehydes can be understood in this way. As shown in Scheme [3], it is also plausible that enolate equivalent 7a, formed from 2a, may form chelated structures 8a and 8b. There is some enhancement of negative charge on the α-carbon atom in 8b.

Table 2 Reformatsky-Type Reaction Starting from Dizinc 1 and Isocyanates 2 a

Entry

R

Solvent

T1 (°C)

T2 (°C)

Yieldb (%) of 6

1

Bz (2a)

THF

–60

–40

90 (6aa)

2

Ph (2b)

THF

 80

–40

<5 (6ba)

3

Ph (2b)

THF

 80

 25

13 (6ba)

4

Ph (2b)

toluene

 80

 25

20 (6ba)

5

Ph (2b)

toluene

 80

140

85 (6ba)

6

4-MeOC6H4 (2c)

toluene

 80

 25

22 (6ca)

7

4-F3CC6H4 (2d)

toluene

 80

 25

39 (6da)

8

Cy (2e)

toluene

 80

 25

 6 (6ea)

a Reaction conditions: dizinc 1 (0.13 M in THF, 0.2 mmol), isocyanate 2 (0.2 mmol), solvent (4 mL), aldehyde 5a (0.2 mmol).

b Isolated yields.

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Scheme 2 Possible structures of the adduct formed from dizinc 1 and an isocyanate 2
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Scheme 3 Possible chelation of the enolate equivalent 7a formed from 1 and 2a

Treatment of 1,1-diiodoethane with zinc powder in the presence of a lead catalyst also gives the corresponding gem-dizinc reagent, 1,1-bis(iodozincio)ethane (9).[13] The reaction of 9 and isocyanates 2 affords the zinc enolate equivalent of propionamide. As shown in Table [3], the formation of the enolate equivalent was evaluated by the yield of the protonated amide products.

Table 3 Reaction of Dizinc 9 with Isocyanates 2 a

Entry

R

Solvent

Temp (°C)

Yieldb (%) of 10

Yieldb (%) of 11

1

Bz (2a)

THF

–20

53

<5

2

Bz (2a)

THF

–40

48

<5

3

Ph (2b)

THF

–60

53

<5

4

Ph (2b)

THF

 25

<5

<5

5

Ph (2b)

THF

 80

13

<5

6

Ph (2b)

toluene

 80

22

<5

a Reaction conditions: dizinc 9 (0.13 M in THF, 0.2 mmol), isocyanate 2 (0.2 mmol), solvent (4 mL).

b Isolated yields.

The Reformatsky-type reaction was also examined for the enolate equivalents formed from dizinc 9 and isocyanates 2. As shown in Table [4] (entry 1), the enolate equivalent formed from 9 and 2a reacted with benzaldehyde (5a) to give the adduct 12aa in 47% yield with a syn/anti diastereoselectivity of 6:1.[14] The reactivity of the enolate equivalent formed from 9 and 2b was too low to undergo the Reformatsky-type reaction with 5a (Table [4], entries 2–4).

Table 4 Reformatsky-Type Reaction Starting from Dizinc 9 and Isocyanates 2 a

Entry

R

T1 (°C)

T2 (°C)

Yieldb (%) of 12

syn/anti

1

Bz (2a)

–60

–40

47 (12aa)

6:1

2

Ph (2b)

 80

–40

<5 (12ba)

3

Ph (2b)

 80

 25

<5 (12ba)

4

Ph (2b)

 80

140

<5 (12ba)

a Reaction conditions: dizinc 9 (0.13 M in THF, 0.2 mmol), isocyanate 2 (0.2 mmol), solvent (4 mL), aldehyde 5a (0.2 mmol).

b Isolated yields.

The low reactivity to aldehyde at 25 °C of the enolate equivalents of amides prepared from dizinc 1 and phenyl isocyanate (2b) or cyclohexyl isocyanate (2e) (Table [2], entries 4 and 8), implied the possibility of asymmetric induction of the Reformatsky-type reaction in the presence of a catalytic amount of an optically active activator. Although­ a variety of catalytic asymmetric alkylations of aldehydes using organozinc reagents have been developed­,[15] examples of the catalytic asymmetric Reformatsky­-type reaction using a zinc enolate are limited.[16] Several examples of the Reformatsky reaction using stoichiometric amounts of a chiral source[17] and a few examples of catalytic asymmetric zinc enolate aldol reactions[18] have already been reported.

Optically active amino alcohols 13, which were derived from l-proline, were added in a catalytic amount (30 mol%) to activate the enolate equivalent 7 formed from dizinc 1 and phenyl isocyanate (2b) for the addition to p-tolylaldehyde (5b) (Scheme [4]). In all cases, asymmetric induction was observed. Among the structures of 13, (S)-bis(4-fluorophenyl)(1-methylpyrrolidin-2-yl)methanol (13g)[19] induced the highest enantioselectivity (87% ee).

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Scheme 4 Asymmetric induction in the reaction of the enolate equivalent formed from 1 and 2b with p-tolylaldehyde (5b) in the presence of l-proline-derived amino alcohols 13

The reactions in Scheme [4] were performed under dilution conditions to ensure a slow reaction rate, as the milder conditions may benefit the asymmetric induction: in each case, the concentration of 5b was 2.5 mM. More concentrated conditions were examined, which resulted in slightly lower enantioselectivities (Table [5], entries 1 and 2). As indicated in Table [2], successful asymmetric induction was also expected in the case of the less reactive enolate equivalent 7 formed from dizinc 1 and cyclohexyl isocyanate (2e); unfortunately, the yields and enantioselectivity obtained for the asymmetric Reformatsky-type reaction were inferior to those obtained for the enolate equivalent formed from 1 and phenyl isocyanate (2b) (Table [5], entries 5 and 6).

Table 5 Optimization of the Catalytic Asymmetric Reformatsky-Type Reaction Using the Enolate Equivalent Formed from 1 and 2b or 2e in the Presence of 13g a

Entry

R

Temp (°C)

Concn of 5b (mM)

Yield (%) of 6

ee (%)

1

Ph (2b)

–40

10.0

88 (6bb)

73

2

Ph (2b)

–40

 5.0

59 (6bb)

79

3

Ph (2b)

–40

 2.5

36 (6bb)

87

4

Ph (2b)

  0

 2.5

36 (6bb)

61

5

Cy (2e)

–40

 2.5

 5 (6eb)

45

6

Cy (2e)

  0

 2.5

 3 (6eb)

60

a Reaction conditions: 1 (0.13 M in THF, 1.5 mL, 0.2 mmol) and 2 (0.2 mmol) in toluene (2.0 mL) were premixed for 0.5 h at 80 °C; toluene (2.5 mL for entry 1, 12.5 mL for entry 2, 32.5 mL for entries 3–6), 13g (0.03 mmol) in toluene (2.0 mL), and 5b (0.1 mmol) in toluene (2.0 mL), were subsequently added at –40 °C.

Optimization of the reaction parameters for the addition of the enolate equivalent 7 formed from dizinc 1 and phenyl isocyanate (2b) to p-tolylaldehyde (5b) in the presence of 13g was examined (Table [6]). When the reaction was performed by adding 2.5 equivalents of the enolate to 5b in the presence of 30 mol% 13g for 72 hours, the adduct 6bb was obtained in 99% yield with 84% ee (Table [6], entry 4). When less catalyst was used, the yield of the product was decreased (Table [6], entries 5 and 6).

Table 6 Optimization of the Reaction of the Enolate Equivalent Formed from 1 and 2b with p-Tolylaldehyde (5b) in the Presence of a Catalytic Amount of 13g a

Entry

Equiv of 2b and 1

mol% of 13g

Time (h)

Yield (%) of 6bb

ee (%)

1

2.0

30

24

36

87

2

2.0

30

48

35

83

3

2.0

30

72

52

84

4

2.5

30

72

99

84

5

2.5

20

72

68

81

6

2.5

10

72

56

75

a Reaction conditions: 1 (0.13 M in THF) and 2b in toluene were premixed for 0.5 h at 80 °C; 13g (0.03 mmol) in toluene, and 5b (0.1 mmol) in toluene, were subsequently added at –40 °C. The concentration of 5b was 2.5 mM.

As shown in Table [7], the reactions of this enolate equivalent with various aldehydes were examined using the conditions of entry 4 in Table [6]. In all cases, the products 6bbbn were obtained with over 76% ee. Compared to previously reported catalytic asymmetric Reformatsky-type reactions, the present results show competitive optical yields.

Table 7 Examples of the Reaction of 7 Formed from 1 and 2b with Aldehydes 5 in the Presence of a Catalytic Amount of 13g a

Entry

R

Yield (%) of 6

eeb (%)

1

4-Tol

99 (6bb)

84

2

2-Tol

91 (6bc)

84

3

4-FC6H4

77 (6bd)

89

4

4-ClC6H4

76 (6be)

79

5

4-BrC6H4

47 (6bf)

77

6

4-MeOC6H4

65 (6bg)

94

7

4-t-BuC6H4

57 (6bh)

84

8

Mes

63 (6bi)

84

9

2-Naph

89 (6bj)

88

10

2-thienyl

73 (6bk)

94

11

2-furyl

92 (6bl)

76

12

Me

45 (6bm)

76

13

t-Bu

49 (6bn)

83

a Reaction conditions: 1 (0.13 M in THF, 2.0 mL, 0.25 mmol) and 2b (0.25 mmol) in toluene (4.0 mL) were premixed for 0.5 h at 80 °C; toluene (32 mL), 13g (0.03 mmol) in toluene (2.0 mL) and aldehyde 5 (0.1 mmol) in toluene (2.0 mL) were subsequently added at –40 °C.

b The absolute configuration of the product in entry 12 was determined by comparison with an authentic sample.[20] The absolute configurations of the other products were deduced based on this result.

The moderate reactivity of the enolate equivalent 7 can realize an asymmetric Reformatsky-type reaction with aldehydes even in the presence of a keto group. As shown in Scheme [5], treatment of keto aldehyde 14 with the enolate equivalent 7 formed from dizinc 1 and phenyl isocyanate (2b) in the presence of amino alcohol 13g (30 mol%) afforded the corresponding product 15 in 81% yield with 93% ee; the keto group in the substrate remained intact.

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Scheme 5 Asymmetric induction in the chemoselective Reformatsky-type reaction

In conclusion, the enolate equivalents prepared from isocyanates and dizinc compounds have only moderate nucleophilicity, which can be enhanced by the addition of a catalytic amount of a 2-amino alcohol. When the added 2-amino alcohol is optically active, moderate to good asymmetric induction is observed. In addition, the asymmetric Reformatsky-type reaction with aldehydes can be performed chemoselectively, even in the presence of a keto group. This reaction of a dizinc compound with an isocyanate is a novel strategy for obtaining an amide enolate equivalent, which has unique reactivity. The reasonable catalytic asymmetric induction in these reactions was accomplished with an optically active Lewis base, not with an optically active Lewis acid.

Nuclear magnetic resonance spectra were recorded on a Varian Unity Inova 500 (1H, 500 MHz; 13C, 125.7 MHz) spectrometer using TMS as an internal standard for 1H NMR (δ = 0 ppm) and CDCl3 as an internal standard for 13C NMR (δ = 77.0 ppm) measurements. 1H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. High-resolution mass spectra were obtained with a Thermo Fisher Scientific Exactive (ESI, APCI) mass spectrometer. Infrared (IR) spectra were determined on a Shimadzu FTIR-8200PC spectrometer. Melting points were determined using a Yanako MP-500D apparatus. TLC analyses were performed by means of Merck Kieselgel 60 F254 (0.25 mm) plates. Visualization was accomplished with UV light (254 nm) and an aqueous vanillin solution followed by heating. Flash column chromatography was carried out using Kanto Chemical Co. silica gel (spherical, 40–100 μm). Unless otherwise noted, commercially available reagents were used without purification. Tetrahydrofuran (dehydrated, stabilizer free, ‘Super’) was purchased from Kanto Chemical Co., stored under argon, and used as is. Zinc powder was used after washing with 10% HCl according to the reported procedure.[21] The preparation methods and characterization of the chiral ligands 13, and spectra (NMR, HPLC) of all compounds, are given in the Supporting Information.


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Bis(iodozincio)methane (1)[6a]

A mixture of pure zinc dust (150 mmol), diiodomethane (1.0 mmol), and PbCl2 (0.005 mmol) in THF (5.0 mL) was sonicated for 1 h in an ultrasonic cleaner bath under argon. When pyrometallurgy zinc dust was used instead of pure zinc, it was not necessary to add PbCl2. Both pure zinc and pyrometallurgy zinc are commercially available. Diiodomethane (50 mmol) in THF (45 mL) was added dropwise to the mixture over 30 min at 0 °C with vigorous stirring. The mixture was then stirred for 4 h at 25 °C. After the stirring was stopped, the reaction vessel was allowed to stand undisturbed for several hours. Excess zinc was separated by sedimentation. The 1H NMR spectrum of the obtained supernatant showed a broad singlet at –1.2 ppm at 0 °C, which corresponds to the methylene protons of 1. The supernatant was used in further reactions as a solution of 1 in THF (0.1–0.5 M). The concentration of 1 was estimated by 1H NMR analysis using 2,2,3,3-tetramethylbutane as an internal standard. Bis(iodozincio)methane in THF can be kept for at least a month in a sealed reaction vessel.


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1,1-Bis(iodozincio)ethane (9)[13]

A mixture of pure zinc dust (150 mmol), 1,1-diiodoethane (1.0 mmol), and PbCl2 (0.005 mmol) in THF (5.0 mL) was sonicated for 1 h in an ultrasonic cleaner bath under argon. When pyrometallurgy zinc dust was used instead of pure zinc, it is not necessary to add PbCl2. Both pure zinc and pyrometallurgy zinc are commercially available. To the mixture, 1,1-diiodoethane (50 mmol) in THF (45 mL) was added dropwise over 30 min at 0 °C with vigorous stirring. Then, the mixture was stirred for 4 h at 25 °C. After the stirring was stopped, the reaction vessel was allowed to stand undisturbed for several hours. Excess zinc was separated by sedimentation. The 1H NMR spectrum of the obtained supernatant showed a quartet at –0.08 ppm at 20 °C, which corresponds to the methyne proton of 9; 1 H NMR (300 MHz, 20 °C): δ = 1.45 (d, J = 7.8 Hz, 3 H), –0.08 (q, J = 7.8 Hz, 1 H). The supernatant was used in further reactions as a solution of 9 in THF (0.1–0.5 M). The concentration of 9 was estimated by 1H NMR analysis using 2,2,3,3-tetramethylbutane as an internal standard. 1,1-Bis(iodozincio)ethane in THF can be kept unchanged for at least 2 days in a sealed reaction vessel.


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N,N′-Dibenzoylmalonamide (4a)

To a solution of benzoyl isocyanate (2a; 29.4 mg, 0.2 mmol) in THF (4.0 mL), dizinc 1 (0.13 M in THF, 0.2 mmol) was added dropwise at 25 °C under argon. The reaction mixture was stirred for 30 min at the same temperature. The resulting mixture was poured into aq NH4Cl (1 M, 10 mL). The mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4. Purification by silica gel column chromatography (hexane–EtOAc, 1:2) gave 4a [yield: 27.2 mg (88%)]; N-acetylbenzamide (3a) was also isolated in 6% yield (2.6 mg).

Yield: 27.2 mg (88%); white solid; mp 181.0–182.0 °C.

TLC: Rf  = 0.36 (hexane–EtOAc, 1:1).

IR (KBr): 3326.4, 3278.2, 2958.9, 2930.0, 1722.5, 1710.9, 1685.9, 1673.3, 1599.1, 1469.8, 1357.9, 1317.4, 1257.6, 1202.7, 1159.3, 706.9 cm–1.

1H NMR (CDCl3): δ = 8.79 (s, 2 H), 7.87 (d, J = 7.8 Hz, 4 H), 7.63 (t, J = 7.8 Hz, 2 H), 7.52 (t, J = 7.8 Hz, 4 H), 4.62 (s, 2 H).

13C NMR (CDCl3): δ = 168.6, 165.4, 133.5, 132.2, 129.1, 127.7, 48.1.

HRMS (ESI): m/z [M + H]+ calcd for C17H15N2O4: 311.1026; found: 311.1012.


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N-(3-Hydroxy-3-phenylpropanoyl)benzamide (6aa)

To a solution of benzoyl isocyanate (2a; 29.4 mg, 0.2 mmol) in THF (4.0 mL), dizinc 1 (0.13 M in THF, 0.2 mmol) was added dropwise at –60 °C under argon. The reaction mixture was stirred for 30 min at –60 °C. After the reaction mixture was warmed to –40 °C, benzaldehyde (5a; 20 μL, 0.2 mmol) was added to the resulting mixture. The mixture was stirred at –40 °C for 3 h, then poured into sat. aq NH4Cl (10 mL). The mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4. Purification by silica gel column chromatography (hexane–EtOAc, 1:1) gave compound 6aa.

Yield: 48.4 mg (90%); white solid; mp 125.5–126.0 °C.

TLC: Rf  = 0.30 (hexane–EtOAc, 1:1).

IR (KBr): 3475.9, 3286.8, 1700.3, 1668.5, 1510.3, 1469.8, 1375.3, 1304.9, 1248.0, 1183.4, 1032.0, 910.4, 770.6, 705.0 cm–1.

1H NMR (CDCl3): δ = 9.03 (s, 1 H), 7.85 (d, J = 7.8 Hz, 2 H), 7.62 (t, J = 7.5 Hz, 1 H), 7.50 (t, J = 7.8 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.31 (d, J = 6.9 Hz, 1 H), 5.27 (m, 1 H), 3.40 (m, 2 H).

13C NMR (CDCl3): δ = 174.6, 165.5, 142.4, 133.5, 132.4, 129.0, 128.6, 127.8, 127.7, 125.8, 70.1, 46.5.

HRMS (ESI): m/z [M + Na]+ calcd for C16H15NO3Na: 292.0944; found: 292.0937.


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Reformatsky-Type Reaction for the Formation of 6ba–6ea; General Procedure

To a solution of isocyanate 2 (0.2 mmol) in THF or toluene (4.0 mL), dizinc 1 (0.13 M in THF, 0.2 mmol) was added dropwise at 80 °C under argon. The reaction mixture was stirred for 30 min at 80 °C. Then, benzaldehyde (5a; 20 μL, 0.2 mmol) was added to the resulting mixture at 25 °C. The mixture was stirred at 25 °C for 3 h, then poured into sat. aq NH4Cl (10 mL). The mixture was extracted with EtOAc (2 × 30 mL) and the combined organic layers were washed with brine (30 mL) and dried over Na2SO4. Purification by silica gel column chromatography (hexane–EtOAc) gave compound 6ba6ea.


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3-Hydroxy-N,3-diphenylpropanamide (6ba)

CAS Reg. No. [4198-15-6].

Yield: 9.6 mg (20%); white solid.

1H NMR (CDCl3): δ = 9.18 (s, 1 H), 7.40 (dd, J = 8.5, 1.0 Hz, 2 H), 7.25 (d, J = 8.5 Hz, 2 H), 7.17 (t, J = 7.0 Hz, 2 H), 7.11 (m, 3 H), 6.90 (t, J = 7.5 Hz, 1 H), 5.08 (d, J = 3.5 Hz, 1 H), 4.99 (m, 1 H), 2.62 (dd, J = 15.0, 9.5 Hz, 1 H), 2.53 (dd, J = 15.0, 3.0 Hz, 1 H).

13C NMR (CDCl3): δ = 169.9, 143.6, 138.0, 128.3, 128.0, 127.0, 125.3, 123.4, 119.6, 70.2, 45.7.


#

3-Hydroxy-N-(4-methoxyphenyl)-3-phenylpropanamide (6ca)

Yield: 11.9 mg (22%); white solid; mp 140.5–141.0 °C.

TLC: Rf  = 0.32 (hexane–EtOAc, 1:1).

IR (KBr): 3287.8, 3253.1, 1656.0, 1604.8, 1552.8, 1511.3, 1414.9, 1303.0, 1248.0, 1181.5, 1065.7, 1035.8, 967.3, 832.3, 776.4, 757.1, 698.3 cm–1.

1H NMR (CDCl3): δ = 8.92 (s, 1 H), 7.34 (t, J = 9.3 Hz, 4 H), 7.25 (t, J = 9.3 Hz, 2 H), 7.17 (t, J = 7.5 Hz, 1 H), 6.74 (td, J = 8.7, 3.3 Hz, 2 H), 5.04 (m, 2 H), 3.69 (s, 3 H), 2.64 (m, 2 H).

13C NMR (CDCl3): δ = 169.9, 155.9, 143.6, 131.1, 128.2, 127.2, 125.4, 121.6, 113.7, 70.5, 55.2, 45.5.

HRMS (ESI): m/z [M + Na]+ calcd for C16H17NO3Na: 294.1101; found: 294.1091.


#

3-Hydroxy-3-phenyl-N-[4-(trifluoromethyl)phenyl]propanamide (6da)

Yield: 24.1 mg (39%); white solid; mp 191.2–192.0 °C.

TLC: Rf  = 0.50 (hexane–EtOAc, 1:1).

IR (KBr): 3335.1, 1661.8, 1603.9, 1532.5, 1456.3, 1411.0, 1331.9, 1252.8, 1151.6, 1113.0, 1071.5, 1019.4, 973.1, 912.4, 888.3, 866.1, 836.2, 758.1, 702.1 cm–1.

1H NMR (CDCl3): δ = 9.56 (s, 1 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.20 (d, J = 8.1 Hz, 2 H), 7.10 (d, J = 7.2 Hz, 2 H), 7.02 (t, J = 7.5 Hz, 2 H), 6.93 (t, J = 8.1 Hz, 1 H), 5.00 (d, J = 3.9 Hz, 1 H), 4.85 (m, 1 H), 2.50 (dd, J = 15.0, 9.3 Hz, 1 H), 2.37 (dd, J = 14.7, 3.6 Hz, 1 H).

13C NMR (CDCl3): δ = 170.2, 143.5, 141.4, 127.9, 127.0, 125.4 (q, J = 14.4 Hz), 125.2, 124.4, 123.4 (q, J = 211.2 Hz), 119.0, 70.0, 46.0.

19F NMR (CDCl3): δ = –62.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H15F3NO2: 310.1049; found: 310.1036.


#

N-Cyclohexyl-3-hydroxy-3-phenylpropanamide (6ea)

Yield: 3.0 mg (6%); white solid; mp 129.2–129.5 °C.

TLC: Rf  = 0.43 (hexane–EtOAc, 1:2).

IR (KBr): 3302.3, 3087.2, 3023.6, 2933.9, 2854.8, 1638.6, 1553.7, 1450.5, 1360.8, 1207.5, 1054.1, 1020.4, 984.7, 893.1, 698.3 cm–1.

1H NMR (CDCl3): δ = 7.31 (m, 5 H), 5.55 (d, J = 7.2 Hz, 1 H), 5.09 (m, 1 H), 4.31 (d, J = 3.0 Hz, 1 H), 3.77 (m, 1 H), 2.53 (m, 2 H), 1.88 (m, 2 H), 1.65 (m, 3 H), 1.33 (m, 2 H), 1.10 (m, 3 H).

13C NMR (CDCl3): δ = 170.8, 143.0, 128.5, 127.6, 125.6, 70.9, 48.2, 44.7, 33.0, 25.4, 24.8.

HRMS (ESI): m/z [M + Na]+ calcd for C15H21NO2Na: 270.1465; found: 270.1456.


#

N-(3-Hydroxy-2-methyl-3-phenylpropanoyl)benzamide (12aa)

To a solution of benzoyl isocyanate (2a; 29.4 mg, 0.2 mmol) in THF (4.0 mL), dizinc 9 (0.13 M in THF, 0.2 mmol) was added dropwise at –60 °C under argon. The reaction mixture was stirred for 30 min at –60 °C. After the reaction mixture was warmed to –40 °C, benzaldehyde (5a; 20 μL, 0.2 mmol) was added to the resulting mixture. The mixture was stirred at –40 °C for 3 h, then poured into sat. aq NH4Cl (10 mL). The mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4. Purification by silica gel column chromatography (hexane–EtOAc, 3:2) gave compound 12aa as a diastereomeric mixture (syn/anti = 6:1).[14]

Yield: 26.6 mg (47%); colorless oil.

TLC: Rf  = 0.50 (hexane–EtOAc, 1:2).

IR (neat): 3410.3, 2981.1, 2937.7, 1730.2, 1680.1, 1601.0, 1507.4, 1484.3, 1369.5, 1264.4, 1159.3, 1121.7, 1027.1, 701.2, 665.5 cm–1.

1H NMR (CDCl3): δ = 9.07 (br s, 1 H), 7.85 (m, 2 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 2 H), 7.34 (m, 5 H), 5.24 (dd, J = 4.0, 3.0 Hz, 0.86 H), 4.85 (dd, J = 8.0, 6.0 Hz, 0.14 H), 3.75 (m, 1 H), 3.15 (d, J = 8.0 Hz, 0.14 H), 3.10 (d, J = 3.0 Hz, 0.86 H), 1.19 (d, J = 6.9 Hz, 3 H).

13C NMR (CDCl3): δ (major isomer) = 177.8, 165.2, 141.0, 133.3, 132.8, 129.0, 128.3, 127.7, 127.6, 126.0, 73.3, 47.2, 10.2.

HRMS (ESI): m/z [M + H]+ calcd for C17H18NO3: 284.1281; found: 284.1268.


#

Asymmetric Synthesis of β-Hydroxy Amides 6bb–6bn and 15; General Procedure

To a solution of phenyl isocyanate (2b; 30.0 mg, 0.25 mmol) in toluene (4.0 mL), dizinc 1 (0.13 M in THF, 2.0 mL, 0.25 mmol) was added dropwise at 80 °C under argon. After being stirred for 30 min at 80 °C, the mixture was diluted with toluene (32 mL) at –40 °C. To the resulting mixture, (S)-bis(4-fluorophenyl)(1-methylpyrrolidin-2-yl)methanol (13g; 9.1 mg, 0.03 mmol) in toluene (2.0 mL) and an aldehyde 5 (0.1 mmol) in toluene (2.0 mL) were added. The resulting mixture was stirred at –40 °C for 72 h, then poured into aq HCl (1 M, 10 mL). The mixture was extracted with EtOAc (2 × 30 mL) and the combined organic layers were washed with brine (30 mL) and dried over Na2SO4. Purification by silica gel column chromatography (hexane–EtOAc, 1:1) gave the adducts 6bb6bn efficiently.[20] The chemoselective Reformatsky-type reaction from 14 to 15 was also performed according to this procedure.


#

(S)-3-Hydroxy-N-phenyl-3-(p-tolyl)propanamide (6bb)

Yield: 25.2 mg (99%); 84% ee; white solid; mp 181.0–182.0 °C.

[α]D 20 –83.3 (c 0.06, CH2Cl2).

TLC: Rf  = 0.45 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 17.6 min, t R (major) = 20.0 min.

IR (KBr): 3330.2, 1657.9, 1601.0, 1540.2, 1498.8, 1442.8, 1363.7, 1064.8, 815.9, 752.3, 691.5, 502.5 cm–1.

1H NMR (CDCl3): δ = 8.86 (s, 1 H), 7.50 (d, J = 9.0 Hz, 2 H), 7.26 (m, 4 H), 7.12 (d, J = 7.5 Hz, 2 H), 7.04 (t, J = 7.5 Hz, 1 H), 5.09 (m, 1 H), 4.68 (d, J = 3.0 Hz, 1 H), 2.74 (dd, J = 15.0, 9.5 Hz, 1 H), 2.65 (dd, J = 15.5, 3.0 Hz, 1 H), 2.29 (s, 3 H).

13C NMR (CDCl3): δ = 170.1, 140.5, 138.1, 137.1, 129.0, 128.7, 125.5, 123.9, 119.9, 70.5, 45.9, 21.0.

HRMS (ESI): m/z [M + Cl] calcd for C16H17NO2Cl: 290.0942; found: 290.0956.


#

(S)-3-Hydroxy-N-phenyl-3-(o-tolyl)propanamide (6bc)

Yield: 23.2 mg (91%); 84% ee; white solid; mp 161.2–162.0 °C.

[α]D 20 –41.7 (c 0.12, CH2Cl2).

TLC: Rf  = 0.53 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralpak IA, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 14.0 min, t R (major) = 16.8 min.

IR (KBr): 3304.2, 1659.8, 1599.1, 1540.2, 1499.7, 1444.8, 1360.8, 1312.6, 1300.1, 1066.7, 1022.3, 756.1, 729.1, 693.4, 498.6 cm–1.

1H NMR (CDCl3): δ = 7.76 (s, 1 H), 7.54 (m, 3 H), 7.34 (t, J = 8.0 Hz, 2 H), 7.26 (m, 1 H), 7.21 (dt, J = 1.5, 8.5 Hz, 1 H), 7.14 (m, 2 H), 5.45 (td, J = 2.5, 10.0 Hz, 1 H), 3.31 (d, J = 2.5 Hz, 1 H), 2.76 (dd, J = 15.0, 10.0 Hz, 1 H), 2.65 (dd, J = 16.0, 2.5 Hz, 1 H), 2.38 (s, 3 H).

13C NMR (CDCl3): δ = 169.8, 140.8, 137.6, 134.2, 130.6, 129.1, 127.8, 126.6, 125.1, 124.5, 120.1, 67.7, 44.9, 19.0.

HRMS (ESI): m/z [M + Cl] calcd for C16H17NO2Cl: 290.0942; found: 290.0954.


#

(S)-3-(4-Fluorophenyl)-3-hydroxy-N-phenylpropanamide (6bd)

Yield: 20.0 mg (77%); 89% ee; white solid; mp 169.0–170.0 °C.

[α]D 20 –20.8 (c 0.24, CH2Cl2).

TLC: Rf  = 0.32 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (major) = 16.0 min, t R (minor) = 19.0 min.

IR (KBr): 3335.1, 1654.0, 1602.9, 1540.2, 1512.3, 1499.7, 1444.8, 1227.7, 831.4, 756.1, 691.5 cm–1.

1H NMR (CDCl3): δ = 8.43 (s, 1 H), 7.51 (d, J = 8.5 Hz, 2 H), 7.38 (dt, J = 7.0, 1.5 Hz, 2 H), 7.30 (dt, J = 7.5, 2.0 Hz, 2 H), 7.09 (t, J = 7.5 Hz, 1 H), 7.03 (dt, J = 8.5, 1.5 Hz, 2 H), 5.16 (d, J = 8.5 Hz, 1 H), 4.50 (s, 1 H), 2.72 (m, 2 H).

13C NMR (CDCl3): δ = 170.0, 139.1, 137.9, 128.9, 127.3 (d, J = 8.3 Hz), 124.2, 120.0, 119.9, 115.3 (d, J = 21.4 Hz), 70.1, 45.9.

HRMS (ESI): m/z [M + Cl] calcd for C15H14FNO2Cl: 294.0692; found: 294.0706.


#

(S)-3-(4-Chlorophenyl)-3-hydroxy-N-phenylpropanamide (6be)

Yield: 21.0 mg (76%); 79% ee; white solid; mp 188.5–189.2 °C.

[α]D 20 –8.3 (c 0.03, CH2Cl2).

TLC: Rf  = 0.46 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 17.2 min, t R (major) = 22.8 min.

IR (KBr): 3328.3, 1656.0, 1602.0, 1540.2, 1499.7, 1444.8, 1425.5, 1369.5, 1092.7, 1067.7, 1012.7, 824.6, 756.1, 744.6, 692.5, 500.6 cm–1.

1H NMR (CDCl3): δ = 7.50 (s, 1 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.34 (m, 6 H), 7.14 (t, J = 7.0 Hz, 1 H), 5.21 (m, 1 H), 2.76 (dd, J = 15.0, 9.0 Hz, 1 H), 2.70 (dd, J = 15.0, 3.0 Hz, 1 H).

13C NMR (CDCl3): δ = 169.9, 137.8, 128.9, 128.6, 127.0, 124.3, 120.0, 119.9, 109.7, 70.1, 45.7.

HRMS (ESI): m/z [M – H] calcd for C15H13ClNO2: 274.0640; found: 274.0647.


#

(S)-3-(4-Bromophenyl)-3-hydroxy-N-phenylpropanamide (6bf)

Yield: 15.0 mg (47%); 77% ee; white solid; mp 186.0–186.6 °C.

[α]D 20 +25.0 (c 0.10, CH2Cl2).

TLC: Rf  = 0.44 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 41.1 min, t R (major) = 48.4 min.

IR (KBr): 3327.4, 1654.0, 1601.0, 1540.2, 1499.7, 1490.1, 1444.8, 1067.7, 1009.8, 821.7, 692.5 cm–1.

1H NMR (CDCl3): δ = 9.06 (s, 1 H), 7.46 (dd, J = 8.0, 1.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.22 (m, 4 H), 7.00 (tt, J = 7.0, 1.0 Hz, 1 H), 5.13 (d, J = 3.5 Hz, 1 H), 5.04 (m, 1 H), 2.63 (m, 2 H).

13C NMR (CDCl3): δ = 169.8, 142.7, 138.0, 131.3, 128.6, 127.3, 123.9, 121.0, 119.9, 69.9, 45.6.

HRMS (ESI): m/z [M + Cl] calcd for C15H14BrNO2Cl: 353.9891; found: 353.9911.


#

(S)-3-Hydroxy-3-(4-methoxyphenyl)-N-phenylpropanamide (6bg)

Yield: 17.6 mg (65%); 94% ee; white solid; mp 185.0–186.0 °C.

[α]D 20 –35.7 (c 0.07, CH2Cl2).

TLC: Rf  = 0.30 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 37.3 min, t R (major) = 41.9 min.

IR (KBr): 3325.4, 1658.9, 1601.0, 1538.3, 1515.1, 1499.7, 1443.8, 1365.7, 1300.1, 1178.6, 1065.7, 1037.8, 829.5, 753.2, 692.5, 502.5 cm–1.

1H NMR (CDCl3): δ = 8.96 (s, 1 H), 7.49 (d, J = 7.5 Hz, 2 H), 7.28 (m, 4 H), 7.26 (d, J = 7.5 Hz, 1 H), 6.82 (d, J = 9.0 Hz, 2 H), 5.06 (td, J = 3.0, 9.5 Hz, 1 H), 4.79 (d, J = 2.5 Hz, 1 H), 3.74 (s, 3 H), 2.73 (dd, J = 15.5, 9.5 Hz, 1 H), 2.62 (dd, J = 15.0, 3.0 Hz, 1 H).

13C NMR (CDCl3): δ = 170.2, 158.9, 138.1, 135.7, 128.7, 126.8, 123.8, 119.9, 113.7, 70.2, 55.1, 45.9.

HRMS (ESI): m/z [M – H] calcd for C16H16NO3: 270.1136; found: 270.1142.


#

(S)-3-(4-tert-Butylphenyl)-3-hydroxy-N-phenylpropanamide (6bh)

Yield: 17.0 mg (57%); 84% ee; white solid; mp 110.0–111.0 °C.

[α]D 20 –25.0 (c 0.20, CH2Cl2).

TLC: Rf  = 0.61 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (major) = 19.3 min, t R (minor) = 23.3 min.

IR (KBr): 3298.4, 2961.8, 1669.5, 1603.9, 1554.7, 1499.7, 1442.8, 1312.6, 1060.9, 819.8, 754.2, 690.6, 581.6 cm–1.

1H NMR (CDCl3): δ = 7.80 (s, 1 H), 7.50 (d, J = 8.5 Hz, 2 H), 7.40 (d, J = 8.5 Hz, 2 H), 7.33 (m, 4 H), 7.13 (t, J = 7.5 Hz, 1 H), 5.20 (m, 1 H), 3.35 (d, J = 2.5 Hz, 1 H), 2.83 (dd, J = 15.5, 9.5 Hz, 1 H), 2.71 (dd, J = 15.0, 3.0 Hz, 1 H), 1.32 (s, 9 H).

13C NMR (CDCl3): δ = 169.8, 151.0, 139.7, 137.5, 129.0, 125.6, 125.3, 124.5, 120.0, 70.9, 46.0, 34.6, 31.3.

HRMS (ESI): m/z [M + Cl] calcd for C19H23NO2Cl: 332.1412; found: 332.1425.


#

(S)-3-Hydroxy-3-mesityl-N-phenylpropanamide (6bi)

Yield: 17.9 mg (63%); 84% ee; white solid; mp 110.0–111.0 °C.

[α]D 20 –16.9 (c 0.74, CH2Cl2).

TLC: Rf  = 0.29 (hexane–EtOAc, 3:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (major) = 8.5 min, t R (minor) = 15.0 min.

IR (KBr): 3431.5, 3269.5, 2921.3, 1628.0, 1600.0, 1545.1, 1498.8, 1444.8, 1312.6, 1253.8, 1172.8, 1071.5, 850.6, 752.3, 690.6, 351.1 cm–1.

1H NMR (CDCl3): δ = 8.05 (s, 1 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.33 (t, J = 8.5 Hz, 2 H), 7.12 (t, J = 7.0 Hz, 1 H), 6.83 (s, 2 H), 5.65 (d, J =10.5 Hz, 1 H), 3.14 (dd, J = 15.5, 5.5 Hz, 1 H), 3.10 (s, 1 H), 2.49 (dd, J = 15.5, 2.0 Hz, 1 H), 2.43 (s, 6 H), 2.26 (s, 3 H).

13C NMR (CDCl3): δ = 170.0, 137.7, 137.2, 136.0, 134.8, 130.3, 129.0, 124.4, 120.0, 68.2, 42.7, 20.7, 20.7.

HRMS (ESI): m/z [M – H] calcd for C18H20NO2: 282.1500; found: 282.1487.


#

(S)-3-Hydroxy-3-(2-naphthyl)-N-phenylpropanamide (6bj)

Yield: 25.9 mg (89%); 88% ee; white solid; mp 173.0–174.0 °C.

[α]D 20 –250.0 (c 0.02, CH2Cl2).

TLC: Rf  = 0.44 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (major) = 30.7 min, t R (minor) = 39.2 min.

IR (KBr): 3299.4, 1664.6, 1602.0, 1549.9, 1499.7, 1488.2, 1445.7, 1363.7, 1314.5, 1068.6, 761.0, 744.6 cm–1.

1H NMR (CDCl3): δ = 8.71 (s, 1 H), 7.87 (s, 1 H), 7.81 (m, 3 H), 7.52 (t, J = 8.5 Hz, 3 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.29 (t, J = 7.0 Hz, 2 H), 7.07 (t, J = 7.5 Hz, 1 H), 5.33 (d, J = 9.5 Hz, 1 H), 4.79 (s, 1 H), 2.85 (dd, J = 16.0, 8.0 Hz, 1 H), 2.78 (dd, J = 15.5, 3.0 Hz, 1 H).

13C NMR (CDCl3): δ = 170.1, 140.8, 133.2, 132.9, 128.8, 128.3, 127.9, 127.6, 126.1, 125.8, 124.3, 124.1, 123.8, 121.1, 120.0, 70.9, 45.9.

HRMS (ESI): m/z [M + Cl] calcd for C19H17NO2Cl: 326.0942; found: 326.0954.


#

(S)-3-Hydroxy-N-phenyl-3-(2-thienyl)propanamide (6bk)

Yield: 18.1 mg (73%); 94% ee; white solid; mp 159.5–160.2 °C.

[α]D 20 –41.7 (c 0.12, CH2Cl2).

TLC: Rf  = 0.50 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 18.9 min, t R (major) = 21.4 min.

IR (KBr): 3297.5, 1679.1, 1663.7, 1607.7, 1599.1, 1554.7, 1498.8, 1444.8, 1319.4, 1254.8, 1236.4, 1086.0, 1046.4, 758.1, 700.2, 689.6 cm–1.

1H NMR (CDCl3): δ = 7.64 (s, 1 H), 7.50 (d, J = 4.0 Hz, 2 H), 7.34 (t, J = 8.0 Hz, 2 H), 7.28 (d, J = 3.0 Hz, 1 H), 7.14 (t, J = 8.0 Hz, 1 H), 7.03 (d, J = 2.0 Hz, 1 H), 6.98 (t, J = 2.5 Hz, 1 H), 5.49 (m, 1 H), 3.79 (d, J = 3.5 Hz, 1 H), 2.90 (m, 2 H).

13C NMR (CDCl3): δ = 169.3, 146.3, 137.2, 129.1, 126.8, 125.0, 124.7, 123.8, 120.1, 67.2, 45.8.

HRMS (ESI): m/z [M + Cl] calcd for C13H13NO2SCl: 282.0350; found: 282.0367.


#

(S)-3-(2-Furyl)-3-hydroxy-N-phenylpropanamide (6bl)

Yield: 21.2 mg (92%); 76% ee; white solid; mp 133.0–134.0 °C.

[α]D 20 –31.3 (c 0.24, CH2Cl2).

TLC: Rf  = 0.43 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 20:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 19.6 min, t R (major) = 22.8 min.

IR (KBr): 3284.9, 1669.5, 1608.7, 1559.5, 1491.0, 1445.7, 1314.5, 1168.0, 1060.9, 1018.5, 759.0, 744.6, 693.4, 598.0 cm–1.

1H NMR (CDCl3): δ = 7.71 (s, 1 H), 7.50 (d, J = 8.5 Hz, 2 H), 7.40 (m, 1 H), 7.34 (t, J = 7.0 Hz, 2 H), 7.13 (t, J = 7.5 Hz, 1 H), 6.35 (m, 1 H), 6.33 (d, J = 3.0 Hz, 1 H), 5.24 (m, 1 H), 3.62 (d, J = 4.5 Hz, 1 H), 2.96 (dd, J = 16.0, 8.5 Hz, 1 H), 2.87 (dd, J = 15.5, 3.5 Hz, 1 H).

13C NMR (CDCl3): δ = 169.4, 154.6, 142.3, 137.3, 129.0, 124.7, 120.1, 110.4, 106.5, 64.7, 42.0.

HRMS (ESI): m/z [M – H] calcd for C13H12NO3: 230.0823; found: 230.0812.


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(R)-3-Hydroxy-N-phenylbutanamide (6bm)

Yield: 8.06 mg (45%); 76% ee; white solid; mp 102.8–103.5 °C.

[α]D 20 –21.2 (c 0.70, CHCl3).

TLC: Rf  = 0.28 (hexane–EtOAc, 1:2).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 33:1, flow rate = 1.0 mL/min, λ = 254 nm, 40 °C): t R (major) = 34.7 min, t R (minor) = 38.8 min.

IR (KBr): 3250.2, 1662.7, 1601.0, 1553.7, 1500.7, 1445.7, 1338.7, 1319.4, 1128.4, 1064.8, 753.2, 694.4 cm–1.

1H NMR (CDCl3): δ = 7.72 (s, 1 H), 7.50 (d, J = 9.0 Hz, 2 H), 7.33 (t, J = 8.0 Hz, 2 H), 7.12 (t, J = 7.5 Hz, 1 H), 4.32 (m, 1 H), 3.17 (d, J = 3.0 Hz, 1 H), 2.55 (dd, J = 3.0, 15.5 Hz, 1 H), 2.48 (dd, J = 9.0, 15.5 Hz, 1 H), 1.30 (d, J = 6.5 Hz, 3 H).

13C NMR (CDCl3): δ = 170.3, 137.5, 129.0, 124.5, 120.0, 65.0, 45.2, 23.0.

HRMS (ESI): m/z [M + Cl] calcd for C10H13NO2Cl: 214.0629; found: 214.0643.


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(S)-3-Hydroxy-4,4-dimethyl-N-phenylpentanamide (6bn)

Yield: 8.8 mg (49%); 83% ee; yellow solid; mp 110.0–111.0 °C.

[α]D 20 –27.8 (c 0.27, CH2Cl2).

TLC: Rf  = 0.61 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel AD-H, hexane–i-PrOH, 33:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 13.0 min, t R (major) = 18.3 min.

IR (KBr): 3293.6, 2958.9, 1659.3, 1603.9, 1552.8, 1501.7, 1445.7, 1337.7, 1149.6, 1070.5, 754.2, 702.1, 419.5 cm–1.

1H NMR (CDCl3): δ = 7.86 (s, 1 H), 7.50 (d, J = 7.5 Hz, 2 H), 7.32 (t, J = 7.0 Hz, 2 H), 7.11 (t, J = 7.5 Hz, 1 H), 3.79 (d, J = 5.0 Hz, 1 H), 3.01 (s, 1 H), 2.54 (dd, J = 2.0, 15.5 Hz, 1 H), 2.43 (dd, J = 10.5, 15.5 Hz, 1 H), 0.96 (s, 9 H).

13C NMR (CDCl3): δ = 177.1, 137.7, 129.0, 124.4, 120.0, 76.4, 39.2, 34.7, 25.5.

HRMS (ESI): m/z [M – H] calcd for C13H18NO2: 220.1343; found: 220.1347.


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(S)-3-Hydroxy-3-{4-[2-(4-methoxyphenyl)-2-oxoethoxy]phenyl}-N-phenylpropanamide (15)

Yield: 32.8 mg (81%); 93% ee; white solid; mp 142.5–143.0 °C.

[α]D 20 +10.0 (c 0.25, CH2Cl2).

TLC: Rf  = 0.38 (hexane–EtOAc, 1:2).

IR (KBr): 3514.5, 3265.6, 2920.3, 1681.0, 1602.0, 1541.2, 1445.7, 1320.3, 1256.7, 1219.1, 1171.8, 978.0, 832.3, 758.1 cm–1.

1H NMR (CDCl3): δ = 8.00 (d, J = 9.0 Hz, 2 H), 7.73 (s, 1 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.33 (m, 3 H), 7.12 (t, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.5 Hz, 1 H), 6.97 (d, J = 8.5 Hz, 2 H), 6.93 (d, J = 8.5 Hz, 2 H), 5.23 (s, 2 H), 5.16 (d, J = 9.5 Hz, 1 H), 3.89 (s, 3 H), 3.45 (d, J = 2.5 Hz, 1 H), 2.78 (dd, J = 15.5, 9.5 Hz, 1 H), 2.67 (dd, J = 15.5, 3.0 Hz, 1 H).

13C NMR (CDCl3): δ = 193.0, 169.7, 164.1, 157.9, 137.5, 135.9, 130.6, 129.0, 127.6, 127.0, 124.5, 120.1, 115.0, 114.1, 70.8, 70.6, 55.5, 46.1.

HRMS (ESI): m/z [M + Cl] calcd for C24H23NO5Cl: 440.1259; found: 440.1276.

The enantiomeric excess of 15 was determined by HPLC analysis, after 15 was transformed into the corresponding p-bromobenzoyl ester 16.


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(S)-3-Anilino-1-{4-[2-(4-methoxyphenyl)-2-oxoethoxy]phenyl}-3-oxopropyl 4-Bromobenzoate (16)

To a solution of 15 (26.4 mg, 0.065 mmol) in CH2Cl2 (1.0 mL) was added 4-bromobenzoyl chloride (35.1 mg, 0.16 mmol), Et3N (26.4 μL, 0.19 mmol), and DMAP (1.6 mg, 0.013 mmol) at 25 °C. After being stirred for 40 min at 25 °C, the resulting mixture was poured into sat. aq NaHCO3 (30 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic layers were dried over Na2SO4. Purification by silica gel column chromatography (hexane–EtOAc, 1:1) gave compound 16.

Yield: 19 mg (50%); white solid; mp 129.0–130.0 °C.

[α]D 20 –250.7 (c 0.04, CH2Cl2).

TLC: Rf  = 0.43 (hexane–EtOAc, 1:1).

HPLC (Daicel Chiralcel OD-H, hexane–i-PrOH, 5.7:1, flow rate = 2.0 mL/min, λ = 254 nm, 40 °C): t R (minor) = 68.2 min, t R (major) = 79.7 min.

IR (KBr): 3342.8, 2965.7, 2932.9, 2361.9, 1717.7, 1684.9, 1656.9, 1602.0, 1513.2, 1441.9, 1267.3, 1217.1, 1171.8, 1117.8, 1104.3, 1007.9, 977.0, 829.4, 757.1, 695.4, 597.0, 545.9 cm–1.

1H NMR (CDCl3): δ = 8.56 (m, 1 H), 7.93 (dd, J = 9.0, 1.5 Hz, 2 H), 7.84 (d, J = 8.5 Hz, 2 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.44 (d, J = 7.5 Hz, 2 H), 7.36 (d, J = 9.0 Hz, 2 H), 7.22 (t, J = 7.5 Hz, 2 H), 7.01 (t, J = 7.5 Hz, 1 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 6.39 (d, J = 7.0 Hz, 1 H), 5.17 (s, 2 H), 3.84 (s, 3 H), 3.10 (dd, J = 15.0, 9.0 Hz, 1 H), 2.86 (dd, J = 15.0, 5.5 Hz, 1 H).

13C NMR (CDCl3): δ = 192.7, 167.2, 164.6, 164.0, 158.0, 138.0, 132.5, 131.6, 131.1, 130.4, 129.0, 128.7, 128.0, 127.8, 127.4, 124.0, 119.9, 114.9, 114.0, 73.3, 70.5, 55.4, 44.3.

HRMS (ESI): m/z [M + Cl] calcd for C31H26BrNO6Cl: 622.0627; found: 622.0650.


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Acknowledgment

This work was supported financially by the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Supporting Information



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Scheme 1 Homologative zinc enolate preparation: (1) cross-coupling reaction of a thioester with 1; (2) addition of 1 to isocyanates 2
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Scheme 2 Possible structures of the adduct formed from dizinc 1 and an isocyanate 2
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Scheme 3 Possible chelation of the enolate equivalent 7a formed from 1 and 2a
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Scheme 4 Asymmetric induction in the reaction of the enolate equivalent formed from 1 and 2b with p-tolylaldehyde (5b) in the presence of l-proline-derived amino alcohols 13
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Scheme 5 Asymmetric induction in the chemoselective Reformatsky-type reaction