Highly enantioselective catalytic asymmetric Mukaiyama–Michael reactions of cyclic α-alkylidene β-oxo imides

Tetrahedron: Asymmetry 26 (2015) 262–270

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Highly enantioselective catalytic asymmetric Mukaiyama–Michael reactions of cyclic a-alkylidene b-oxo imides Harufumi Oyama, Kohei Orimoto, Takashi Niwa, Masahisa Nakada ⇑ Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan

a r t i c l e

i n f o

Article history: Received 8 November 2014 Accepted 15 January 2015 Available online 17 February 2015

a b s t r a c t Catalytic asymmetric Mukaiyama–Michael reactions of cyclic a-alkylidene b-oxo imides are described. The rationally designed cyclic a-alkylidene b-oxo imides show high enantioselectivity in the Mukaiyama–Michael reaction using a bisoxazoline/Cu(OTf)2 catalyst. The enantioselectivity can be well explained by the chelate model comprising an intramolecular hydrogen bond, wherein the cyclic a-alkylidene b-oxo imide coordinates with Cu(II) through the two imide carbonyls. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction The enantioselective construction of stereogenic carbon centers is very important for the total synthesis of bioactive natural products. Catalytic asymmetric reactions are favored over reactions using a chiral auxiliary to generate stereogenic carbon centers because a small amount of a chiral catalyst affords a large amount of chiral compound without requiring additional steps to remove the chiral auxiliary. Thus, catalytic asymmetric reactions are superior in terms of both atom and time economy. Moreover, both enantiomers of the desired product can usually be prepared using the appropriate enantiomer of the catalyst. a-Alkylidene b-oxo esters are highly reactive toward nucleophiles because their double bonds are highly electron deficient due to two electron-withdrawing groups; therefore, they are good dienophiles and undergo cycloadditions to afford cyclic compounds containing an all-carbon quaternary stereogenic center.1–3 The electrophilic nature of a-alkylidene b-oxo esters also makes them good Michael acceptors;4 moreover, the b-oxo esters formed by Michael reactions are potential intermediates in natural product synthesis because their chemistry is well established. Therefore, a-alkylidene b-oxo esters have been used in natural product synthesis such as the total synthesis of oubain,1a acutifolone A,1b 5,14-bis-epi-spirovibsanin A,1c lycopladine A,1d aplykurodinone-1,1e and drimane-type sesquiterpenoids.1f Lewis-acid-catalyzed asymmetric reactions of a-alkylidene boxo esters have been reported.2–5 However, the substrate scope is limited, and their use in the asymmetric total synthesis of natural products has not been reported, probably because the complex ⇑ Corresponding author. Tel./fax: +81 3 5286 3240. E-mail address: [email protected] (M. Nakada). http://dx.doi.org/10.1016/j.tetasy.2015.01.012 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

of an a-alkylidene b-oxo ester with a chiral Lewis acid suffers from low enantioselectivity. For example, the catalytic asymmetric Mukaiyama–Michael reaction of cyclic a-alkylidene b-keto ester 1 with silyl enol ether 2 in the presence of 20 mol % of bisoxazoline/Cu(II) catalyst has been reported (Scheme 1).4a However, although different Cu(II) reagents, bisoxazoline ligands, and solvents were examined, only moderate yields and enantioselectivities were obtained.

O

O N O

OtBu CO2 Me

1

+

Ph

N

(20 mol %)

O Ph

CO2 Me

OTMS

2

Cu(OTf)2 (20 mol %) toluene, –78 °C ~65%, 63% ee dr = 9/1

CO2 tBu H 3

Scheme 1. Catalytic asymmetric Mukaiyama–Michael reaction reported by Bernard, Colombo, and Scolastico.4a

An a-alkylidene b-oxo ester and a bisoxazoline/Cu(II) catalyst form a square-planar complex6 (complex A, Fig. 1). The relatively low enantioselectivity in the above reaction was attributed to the double bond in complex A, which is remote from the ligand’s chiral environment. On the other hand, N-acryloyloxazolidin-2-one7 and its derivatives have been used in diverse catalytic asymmetric reactions,8 because in complex B (Fig. 1), the bisoxazoline substituent is in close proximity to the s-cis alkene and effectively shields one side of the moiety.5

H. Oyama et al. / Tetrahedron: Asymmetry 26 (2015) 262–270

a-Alkylidene b-oxo imides are interesting compounds because the acidic imide hydrogen can form an intramolecular hydrogen bond (complex C) (Fig. 1), thus making a rigid conformation. Therefore, the two imide carbonyls act as a bidentate ligand and form a chelate, and the double bond can be placed at the same position as in complex B. Thus, complex C may differentiate the two enantiotopic faces of the double bond clearly, leading to high enantioselectivity.

O

O N R

O

Cu2+ O

O

O

N

N R

R

O

N Cu 2+ O

263

Therefore, in order to explore the scope and limitations of the use of cyclic a-alkylidene b-oxo imides in asymmetric catalysis, another type of catalytic asymmetric reaction was investigated. The catalytic asymmetric Michael reaction of cyclic a-alkylidene b-oxo imides is intriguing because the cyclic b-oxo imide products could be useful synthetic intermediates, since they can be easily transformed into diverse functional groups.11 To the best of our knowledge, although there are many Lewis-acid-catalyzed asymmetric Mukaiyama–Michael reactions,12 only one example of a cyclic aalkylidene b-oxo ester has been reported.4a Therefore, the catalytic asymmetric Mukaiyama–Michael reactions of cyclic a-alkylidene b-oxo imides were investigated, and the results are reported herein.

R

2. Results and discussion X

OR

N

complex A

O

complex B O

O N R

N

Cu2+ O

O

N X

R OR

H

O

hydrogen bond

complex C

Figure 1. Proposed structures of complexes formed by a bisoxazoline–Cu(II) catalyst with an a-alkylidene b-keto ester (complex A), N-acryloyl oxazolidin-2one (complex B), and cyclic a-alkylidene b-oxo imide (complex C).

Based on the above considerations, we recently studied [4+2] cycloadditions and Hosomi–Sakurai reactions of cyclic a-alkylidene b-oxo imides; both reactions proceeded in high yields and enantioselectivities.9 For example, the [4+2] cycloaddition of imide 4a with diene 5a in the presence of the L410/Cu(OTf)2 catalyst afforded product 6a in an excellent yield and with excellent enantioselectivity (Scheme 2); [4+2] cycloadditions of other imides 4b–d (Fig. 2) also gave excellent results.

O

H

N

O

CO2 Me O

L4–Cu(OTf)2 (10 mol %) MS 4 Å, –15 °C 17 h

+

O

CONHCO2 Me

O

OTIPS

4a

CH 2Cl2 / toluene = 1:5 98%, 97% ee

5a

OTIPS

H 6a

Scheme 2. Catalytic asymmetric [4+2] cycloaddition of 4a with 5a.

R2

R2

N R

O

O

O N

R1

1

O

H

N

CO2 Me

L1: R1 = i-Pr; R 2 = Me L2: R1 = t-Bu; R 2 = Me L3: R1 = i-Pr; R 2 = Bn

O

H

N

O

4b

MsHN

CO2 Me O

O N

O

N

L4 H

N

N

4c

Figure 2. Structures of L1–4 and 4b–d.

NHMs CO2 Me O

4d

First, the catalytic asymmetric Mukaiyama–Michael reaction of 4a with 7 (3.0 equiv) was investigated using L1/Cu(OTf)2 (10 mol %) in CH2Cl2 at 20 °C (Table 1, entry 1). The reaction afforded 8a in 56% yield with 36% ee. The relative configuration of 8a was elucidated as trans based on the observed NOE correlations shown in Figure 3. The use of an excess amount of 7 (5.0 equiv) increased the yield, but did not increase the ee (entry 2), while the reaction in the presence of MS 4 Å decreased the ee (entry 3). The reaction with a stoichiometric amount of L1/Cu(OTf)2 catalyst dramatically increased the ee to 89% (entry 4). The low ee values in entries 1–3 can be attributed to the background reaction. Indeed, the reaction in the absence of the catalyst afforded 8a in 77% yield after 8.5 h (entry 5). However, the background reaction did not occur in toluene (entry 6). This solvent effect can be attributed to the low solubility of the imide in toluene, thus retarding the background reaction. The reaction in toluene effectively improved the ee to 90% without decreasing the yield (entry 7). The use of bulky ligands, L2 (entry 8) and L3 (entry 9) was ineffective and decreased the yield and ee. The L4/Cu(OTf)2 catalyst was effective for the [4+2] cycloadditions and Hosomi–Sakurai reactions of cyclic a-alkylidene b-oxo imides,9 but was difficult to use in toluene due to its low solubility therein.12 It has been reported that the use of a proton source, such as an alcohol, accelerates the Mukaiyama–Michael reaction.13 However, the reaction in the presence of hexafluoroisopropanol (HFIP)13f,i,j as an additive gave poor results (entry 10). This is probably because weakly acidic and protic HFIP disturbs the intramolecular hydrogen bonding of imide 4a, resulting in low enantioselectivity. The use of molecular sieves accelerated the reaction (entries 11 and 12); finally, when the reaction was carried out at 40 °C, it afforded 8a in 87% yield and with 93% ee (entry 13). The reaction of 4a with 7 below 40 °C was sluggish, and a large amount of 4a was recovered. Next, the catalytic asymmetric Mukaiyama–Michael reaction of 4b with 7 was investigated (Table 2). The reaction of 4b with 7 (5.0 equiv) using L1/Cu(OTf)2 (10 mol %) in toluene at 20 °C afforded an inseparable mixture of 8b and 9b (8b/9b = 12:1, 65% yield) (entry 1). The relative configuration of 8b was elucidated as trans based on the observed NOE correlations shown in Figure 4. The mixture was treated with 6 M HCl in THF to convert 8b into 9b, which was obtained in 52% yield (two steps); the ee was determined to be 93% by HPLC analysis. When CH2Cl2 was used as the solvent, the ee decreased to 87% (entry 2). When 20 mol % of the catalyst was used, the yield increased to 81% without changing the ee (entry 3). The reaction at 30 °C required a longer reaction time (37 h) with a slight increase in the ee (entry 4); however, when MS 3 Å was used, both the yield and ee increased (65% yield over two steps, 96% ee, entry 5). As shown in Tables 1 and 2, the catalytic asymmetric Mukaiyama–Michael reactions of 4a and 4b with 7 afforded the products in high yields and with excellent enantioselectivities. These data

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H. Oyama et al. / Tetrahedron: Asymmetry 26 (2015) 262–270

Table 1 Catalytic asymmetric Mukaiyama–Michael reactions of 4a with 7

O

H

CO2 Me

O

N t

O

O

conditions

BuS

H

COStBu

+ OTMS

4a

a b c d

CONHCO 2Me

O H 8a

7

Entry

7 (equiv)

Solvent

Ligand–Cu(OTf)2 (mol %)

Additive

1 2 3 4 5 6 7 8 9 10 11 12 13

3.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene

L1 L1 L1 L1 — — L1 L2 L3 L1 L1 L1 L1

— — MS 4 Å — — — — — — HFIPd MS 4 Å MS 3 Å MS 3 Å

(10.0) (10.0) (10.0) (100.0)

(10.0) (10.0) (10.0) (10.0) (10.0) (10.0) (10.0)

Temp (°C) 20 20 20 20 20 20 20 20 20 20 20 20 40

Time (h)

8a Yielda (%)

8a eeb,c (%)

3 8.5 7 5 min 8.5 20 9.5 23 23 8 6 3.5 20

56 95 90 Quant 77 0 90 41 45 49 89 91 87

36 38 25 89 0 0 90 62 56 25 90 90 93

Isolated yields. Ee determined by HPLC: Daicel Chiral Cell IA-3, 0.46 cm a  25 cm, hexane/isopropanol = 4:1, flow rate = 1.0 mL/min, retention time: 24.7 min for ent-8a, 33.7 min for 8a. The absolute structure of 8a was determined as shown in Scheme 6. 2.0 equiv of HFIP was used.

The Mukaiyama–Michael reactions of other cyclic imides were also investigated. The reaction of sterically hindered cyclic imide 4c with 7 (Scheme 3) proceeded very slowly and required the use of an excess amount of the catalyst and a higher reaction temperature. After optimization, the reaction of 4c with 7 using 50 mol % of L1/Cu(OTf)2 in the presence of MS 3 Å in toluene at 10 °C for 40 h afforded an inseparable mixture of 8c0 and 9c (8c0 :9c = 3.3:1) in 94% yield (at 75% conv). Hence, in order to determine the ee, the mixture was treated with 6 M HCl to afford 9c in 84% yield; the ee of 9c was determined by HPLC (94% ee). The Mukaiyama–Michael reaction of imide 4d with 7 (Scheme 4) also resulted in high yield and enantioselectivity. Thus, the reaction using 20 mol % of L1/Cu(OTf)2 in the presence of MS 3 Å in toluene at 35 °C afforded 8d in 99% yield and with 92% ee after 41 h. The relative configuration of 8d was elucidated as trans based on the observed NOE correlations shown in Figure 5.

H H O

H

O H

H

R

CONHCO 2Me H

8a (R = COStBu)

Figure 3. NOE correlations in the NOESY spectrum of 8a in CDCl3.

indicate that the reaction of imide 4a is faster than that of imide 4b, even though an a,b-unsaturated ketone is generally more reactive and a better Michael acceptor than the corresponding a,bunsaturated lactone. It should be noted that no silylated products were observed in any of the Mukaiyama–Michael reactions of 4a and 4b; the silylated products may be unstable and decompose on TLC or upon work-up. Table 2 Catalytic asymmetric Mukaiyama–Michael reactions of 4b with 7

O O

H

CO 2Me

O

N t

O

BuS

conditions

+

a

Ligand–Cu(OTf)2 (mol %)

Additive

1 2 3 4 5

Toluene CH2Cl2 Toluene Toluene Toluene

L1 L1 L1 L1 L1

— — — — MS 3 Å

6 M HCl

O t

COS Bu

9b

THF, 60 °C

H

8b

Solvent

NH

+

H

7 (5.0 equiv)

Entry

(10.0) (10.0) (20.0) (20.0) (20.0)

O CONHCO2 Me COStBu

OTMS

4b

H

9b

Temp (°C)

Time (h)

20 20 20 30 30

21 20 22 37 22

8b + 9b Yielda (%) [8b:9b] 65 74 81 77 83

[12:1] [10:1] [14:1] [15:1] [16:1]

9b Yielda (%) (two steps) 52 58 64 61 65

9b eeb,c (%) 93 87 93 94 96

Isolated yields that were determined by 1H NMR. Ee determined by the HPLC of 9b: Daicel Chiral Cell AY-H, 0.46 cm a  25 cm; hexane/isopropanol = 4:1, flow rate = 1.0 mL/min, retention time: 15.1 min for 9b, 21.9 min for ent-9b. c The absolute configuration of 8b was determined as shown in Scheme 7. b

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H. Oyama et al. / Tetrahedron: Asymmetry 26 (2015) 262–270 H

O

H H O

4e

CONHCO2 Me

MS 3 Å toluene

H

R

H

OTMS

O

O

L1-Cu(OTf)2 (20 mol %)

StBu +

H CONHCO2 Me

H

CO 2Me

N

H

7 (5.0 equiv.)

8e 85%, 56% ee (20 °C, 4 h) 87%, 68% ee (40 °C, 24 h) 75%, 87% ee (60 °C, 70 h)

8b (R = COStBu)

Figure 4. NOE correlations in the NOESY spectrum of 8b in C6D6.

COStBu

O toluene

O

H

N

100 °C, 6 h 88%

CO2 Me StBu O

10e for HPLC analysis

+ OTMS

-10 °C, 40 h 8c' : 9c = 3.3 : 1 94% ( at 75% conv)

7 (5.0 equiv)

4c

COStBu

H

L1-Cu(OTf)2 (50 mol %) MS 3 Å, toluene

Scheme 5. Catalytic asymmetric Mukaiyama–Michael reaction of 4e with 7, transformation of 8e to 10e for HPLC analysis.

O HO

H

N

CO2 Me

O

O

COStBu

H

9c 94% ee

84%

H

H

t-BuSOC

6 M HCl, THF 50 °C, 5.5 h

O

+

COStBu

H

NH

H

H

R

O

8e (R = CONHCO 2Me) 9c

8c'

Figure 6. A NOE correlation in the NOESY spectrum of 8e in CDCl3. Scheme 3. Catalytic asymmetric Mukaiyama–Michael reaction of 4c with 7 and transformation of the products to 9c to determine the ee of 8c0 .

O

H

N

N

CO2 Me O

L1-Cu(OTf)2 (20 mol %)

OTMS +

MS 3 Å, toluene –35 °C, 41 h 99%, 92% ee

StBu

4d

7 (5.0 equiv)

O CONHCO2 Me

N

COStBu H 8d

Scheme 4. Catalytic asymmetric Mukaiyama–Michael reaction of 4d with 7.

H H

O

N H

R

H CONHCO 2Me H

H

8d (R = COStBu)

Figure 5. NOE correlations in the NOESY spectrum of 8d in acetone-d6.

The Mukaiyama–Michael reaction of cyclopentenone derived imide 4e with 7 (5.0 equiv) was also performed (Scheme 5). The reaction using 20 mol % of L1/Cu(OTf)2 in the presence of MS 3 Å in toluene at 20 °C afforded 8e in 85% yield after 4 h. The relative configuration of 8e was elucidated based on the observed NOE correlation shown in Figure 6. The ee of 8e was difficult to determine by HPLC because the enantiomers were inseparable, but the HPLC analysis of 10e, which was obtained by the de-isocyanation of 8e, successfully determined the ee. The ee of the product in the reaction at 20 °C was low (56% ee); the reaction at 40 °C proceeded slowly and was completed after 24 h, however, the ee was 68%. Finally, although the reaction at 60 °C required 70 h to afford 11 in 75% yield, the ee increased to 87%. The reaction mechanism may involve a hetero-Diels–Alder reaction because the oxabutadiene embedded in their structures was fixed as the s-cis isomer due to the imide hydrogen bond, thus facilitating the [4+2] cycloaddition. NMR studies of the reaction of 4e with 7 in the presence of the catalyst were unsuccessful because of the paramagnetism of Cu(OTf)2. Hence, the 1H and 13C NMR studies of the reaction of 4e with 7 were carried out in the absence

of the catalyst at a low-temperature (40 °C). The 1H and 13C NMR spectra indicated the formation of silyl enol ether derived from the extended transition state. No hetero-Diels–Alder products were observed, but the reaction mechanism in the absence of the catalyst could be different from that in the presence of the catalyst.13g,j Solution 1H NMR studies of the imides showed a noteworthy feature of the imide NH signal. Usually, the imide NH signal appears around d 7–8 ppm; however, the imide signals of 4a, 4b, 4c, 4d, and 4e were observed as relatively sharp signals at 10.71, 10.90, 10.90, 12.04, and 10.13 ppm, respectively. The sharp signal and downfield shift suggest the presence of the hydrogen bonding of the imide NH in solution. The enantioselectivity of five-membered imide 4e was relatively low when compared with those of the six-membered cyclic imides. This can be attributed to the fact that the hydrogen bond in 4e is weakened when compared with those in 4a, 4b, and 4c owing to the relatively long hydrogen bond due to the smaller ring size. The imide NH signal of 4e at d 10.13 ppm indicates that the hydrogen bond of 4e would be weakened because those of 4a, 4b, 4c, and 4d were observed in the downfield region (10.71, 10.90, 10.90, and 12.04 ppm, respectively). The absolute configuration of 8a was determined as shown in Scheme 6. Compound 8a underwent de-isocyanation in xylene at 130 °C to afford 10a; subsequent Fukuyama reduction afforded 11a. Product 11a was found to be the enantiomer of a known

O

H

O

O CONHCO 2Me

xylene

COStBu

130 °C 56%

H 8a

Et3SiH 10% Pd/C

O COStBu H

acetone 94%

10a

O O CHO H

11a:

[α]D25 = – 10 (c 0.070, CHCl3) 86% ee

ent-11a: lit.15 [α]D20 = +8.6 (c 2.30, CHCl3 ) 86% ee

Scheme 6. Transformation of 8a to 11a via 10a to elucidate the absolute configuration of 8a.

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H. Oyama et al. / Tetrahedron: Asymmetry 26 (2015) 262–270 O O

O

O NH

CONHCO2 Me

O

+

COStBu

10% Pd/C (5.0 equiv) Et3 SiH (15 equiv) m-xylene, 120 °C

COStBu

H

38 h, 11%

10e

H

8b

9b

O

ent-11e: lit.18

NBS, MeOH CO 2Me

CH2 Cl2 , rt, 69%

H 10b

H

CHO

11e 11e:

O

COStBu

acetone, rt, 15 min 46%

COStBu

H

O

[α]D20 [α]D22

= −49 (c 0.035, CHCl3 ) 87% ee = +148 (c 1.0, CH 2Cl2 ) 98% ee

Scheme 9. Transformation of 10e, which was prepared from 8e (Scheme 4), to 11e in order to determine the absolute configuration of 8e.

H 12b

12b: [α]D21 = − 20 (c 0.080, CHCl3 ) 96% ee lit.17 [α]D20 = − 9.4 (c 1, CHCl3 ) > 99% ee

Scheme 7. Transformation of 8b to 12b via 10b to elucidate the absolute configuration of 8b.

compound, ent-11a, which has a specific rotation of +8.6. Hence, the absolute configurations of 11a and 8a were determined as shown in Scheme 6.14 The absolute configuration of 8b was determined as shown in Scheme 7. A mixture of 8b and 9b, which was obtained under the reaction conditions in Table 2, was heated in m-xylene at 130 °C to afford 10b, which was converted into 12b under the reaction conditions reported by Minato.15 Product 12b was found to be a known compound, which has a specific rotation of 9.4.16 Hence, the absolute configurations of 12b and 8b were determined as shown in Scheme 7. The absolute configuration of 8c0 was determined as shown in Scheme 8. A mixture of 8c0 and 9c, which was obtained under the reaction conditions shown in Scheme 3, was heated in mxylene at 130 °C to afford 10c. The reaction of 10c with NaOMe afforded 12c, which was found to be a known compound, and showed a specific rotation of 8.5.16 Hence, the absolute configurations of 12c and 8c0 were determined as shown in Scheme 8. The absolute configuration of 8e was determined as shown in Scheme 9. Fukuyama reduction of 10e, which was obtained from 8e under the reaction conditions shown in Scheme 5, afforded 11e. Product 11e was found to be the enantiomer of a known compound, ent-11e, which has a specific rotation of +148.17 Hence, the absolute configurations of 11e and 8e were determined as shown in Scheme 5.

The absolute configuration of 8d was not determined because 8d could not be converted into a known compound and in addition, a crystalline derivative suitable for X-ray crystallographic analysis was not found. Nevertheless, the absolute configuration of other products, 8a–c and 8e, suggests that the reactions of 4a–e would proceed at the less hindered side of the double bond in complex C. Notably, the hydrogen bond in the imides would be retained in the Mukaiyama–Michael reactions. The above spectroscopic data and the absolute structure of products validate the design features of cyclic a-alkylidene b-oxo imides and the Mukaiyama– Michael reactions using the bisoxazoline/Cu(OTf)2 catalyst. Although the scope and limitations of a-alkylidene b-oxo imides require further investigation to verify their generality, the results indicate their potential utility in the Mukaiyama–Michael reaction. 3. Conclusion In conclusion, rationally designed cyclic a-alkylidene b-oxo imides showed high enantioselectivity in the Mukaiyama–Michael reaction using a bisoxazoline/Cu(OTf)2 catalyst. Previously, we reported that [4+2] cycloadditions and Hosomi–Sakurai reactions of cyclic a-alkylidene b-oxo imides afforded the products in high yields and with high enantioselectivities. Although further studies on the scope and limitations of catalytic asymmetric reactions using a-alkylidene b-oxo imides are required, the results obtained indicate the potential use of cyclic a-alkylidene b-oxo imides in asymmetric catalysis. The developed protocol as well as the products of the catalytic asymmetric Mukaiyama–Michael reactions of cyclic a-alkylidene b-oxo imides could be useful for the enantioselective total synthesis of natural products. Further studies on diverse asymmetric catalysis utilizing a-alkylidene b-oxo imides are currently underway. 4. Experimental

O HO

H

N

CO2 Me

O

4.1. General procedures NH m-xylene, 130 °C

O COStBu

O

+

6 h, 11%

COStBu H

H

9c

8c' 8c' : 9c = 3.3 : 1 O

O NaOMe (3.0 equiv) COStBu H

MeOH, rt, 43 h 79%

10c

CO2 Me H 12c

12c: [α]D20 lit.17 [α]D20

= −7.3 (c 0.055, CHCl3) 94% ee = −8.5 (c 1, CHCl3) > 99% ee

Scheme 8. Transformation of a mixture of 8c0 and 9c into 12c via 10c in order to determine the absolute configuration of 8c0 .

1

H and 13C NMR spectra were recorded on a JEOL AL-400 spectrometer. Chemical shifts are reported in ppm with the residual solvent resonance as internal standard. The following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; band, several overlapping signals; br, broad. IR spectra were recorded on a JASCO FT/IR-8300. Optical rotations were measured using a 2 mL cell with a 1 dm path length on a JASCO DIP-1000. Mass spectra and elemental analyses were provided at the Materials Characterization Central Laboratory, Waseda University. All reactions were carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous conditions, unless otherwise noted. Melting point (mp) is uncorrected and recorded on a Yamato capillary melting point apparatus. Chiral HPLC analysis was performed on a JASCO PU-980 and UV-970 detector. X-Ray crystallographic analysis was performed with a Rigaku R-AXIS RAPID-F. All reactions were monitored by thin-layer

H. Oyama et al. / Tetrahedron: Asymmetry 26 (2015) 262–270

chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and phosphomolybdic acid and heat as developing agents. Merck silica gel (60, particle size 0.040–0.063 mm) was used for flash chromatography. 4.2. Catalytic asymmetric Mukaiyama–Michael reaction 4.2.1. S-tert-Butyl 2-((3S,4R)-3-methoxycarbonylcarbamoyl-2oxotetrahydro-2H-pyran-4-yl)ethanethioate 8a To a stirred suspension of Cu(OTf)2 (14.6 mg, 0.0404 mmol) in toluene (1.0 mL) was added a solution of bisoxazoline ligand L1 (10.9 mg, 0.0409 mmol) in toluene (1.0 mL). The mixture was stirred at room temperature for 5 h to afford a clear blue solution of L1– Cu(OTf)2 complex (0.0202 M). To a suspension of imide 4a9a (15.3 mg, 0.0768 mmol) and MS 3 Å (77 mg) in toluene (0.37 mL) were added a solution of L1–Cu(OTf)2 complex in toluene (0.0202 M, 0.38 mL, 7.68  103 mmol) and a solution of TMS S,Oketene acetal 74c (78.5 mg, 0.384 mmol) in toluene (0.75 mL) via a cannula at 40 °C. The reaction mixture was stirred for 20 h at this temperature, quenched with saturated aqueous NaHCO3 solution (5 mL), and the aqueous layer was extracted with CH2Cl2 (5 mL  4). The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate = 4/1) and preparative TLC (benzene/ethyl acetate = 3/1) to afford product 8a (22.1 mg, 87%, 93% ee) as a clear oil: Rf = 0.50 (hexane/ethyl acetate = 1/1); 1H NMR (400 MHz, CDCl3) d 8.08 (1H, br), 4.49–4.38 (2H, m), 3.93 (1H, br), 3.79 (3H, s), 3.05–2.93 (1H, m), 2.66 (1H, dd, J = 15.6, 4.8 Hz), 2.50 (1H, dd, 15.6, 8.0 Hz), 2.13 (1H, dddd, 14.0, 4.4, 4.4, 4.4 Hz), 1.81– 1.69 (1H, m), 1.45 (9H, s); 13C NMR (100 MHz, CDCl3) d 198.1, 168.2, 167.3, 152.1, 68.3, 53.7, 53.3, 48.6, 47.7, 31.2, 29.6, 27.3; IR (ATR) mmax 3289, 2962, 1701, 1677, 1499, 1219, 1190, 1156, 980, 775, 734 cm1; HRMS (ESI) [M+Na]+ calcd for C14H21NO6SNa 354.0987, found 354.0975; [a]21 D = +45 (c 0.94, CHCl3); ee was determined by HPLC (235 nm); Daicel Chiral Cell IA-3 0.46 cm a  25 cm; hexane/isopropanol = 4:1; flow rate = 1.0 mL/min; retention time: 24.7 min for ent-8a, 33.7 min for 8a. 4.2.2. S-tert-Butyl (R)-2-(2,4-dioxo-3,4,5,6,7,8-hexahydro-2Hbenzo[e][1,3]oxazin-5-yl)ethanethioate 9b To a stirred suspension of Cu(OTf)2 (28.3 mg, 0.0782 mmol) in toluene (1.0 mL) was added a solution of bisoxazoline ligand L1 (21.1 mg, 0.0792 mmol) in toluene (1.0 mL) via a cannula at room temperature. The mixture was stirred at room temperature for 5 h to afford a clear blue solution of L1–Cu(OTf)2 complex (0.0391 M). To a stirred suspension of imide 4b9a (11.8 mg, 0.0598 mmol) and MS 3 Å (60 mg) in toluene (0.3 mL) were added a solution of L1– Cu(OTf)2 complex solution in toluene (0.0391 M, 0.30 mL, 0.0117 mmol) and a solution of TMS S,O-ketene acetal 7 (61.2 mg, 0.299 mmol) in toluene (0.6 mL) via a cannula at 30 °C. After stirring for 22 h at this temperature, the reaction mixture was cooled to 78 °C and quenched with 6 M HCl (0.1 mL). After stirring at 78 °C for 0.5 h, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution (5 mL) and the aqueous layer was extracted with Et2O (5 mL  4). The organic layer was combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (benzene/ethyl acetate = 30/1 to 10/1) to afford a mixture of products (16.2 mg, 83%, 8b/9b = 16/1) as a clear oil. To a stirred solution of the mixture obtained as above in THF (1 mL) was added 6 M HCl (0.1 mL) at room temperature. After stirring at 60 °C for 18 h, the reaction mixture was cooled to 0 °C, quenched with a saturated aqueous NaHCO3 solution (5 mL), and the aqueous layer was extracted with Et2O (5 mL  4). The organic layer was combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified

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by preparative TLC (benzene/ethyl acetate = 6/1) to afford product 9b (11.6 mg, 65% (2 steps), 96% ee) as a white solid: Rf = 0.60 (hexane/ethyl acetate = 1/1); 1H NMR (400 MHz, CDCl3) d 8.40 (1H, br), 3.30–3.20 (1H, m), 2.93 (1H, dd, J = 15.2, 3.2 Hz), 2.49 (1H, dd, J = 15.2, 6.8 Hz), 2.46–2.40 (2H, m), 1.89–1.73 (3H, m), 1.72–1.59 (1H, m), 1.46 (9H, s); 13C NMR (100 MHz, CDCl3) d 198.5, 165.2, 161.7, 147.4, 111.5, 48.5, 46.7, 29.9, 28.6, 27.0, 25.5, 17.6; IR (ATR) mmax 3153, 3042, 2948, 1797, 1665, 1427, 748 cm1; mp 157–158 °C; HRMS (ESI) [M+Na]+ calcd for C14H19NO4SNa 320.0933, found 320.0944; [a]23 D = +33 (c 0.37, CHCl3); ee was determined by HPLC (235 nm); Daicel Chiral Cell AY-H 0.46 cm a  25 cm; hexane/isopropanol = 4/1; flow rate = 1.0 mL/min; retention time: 15.1 min for 9b, 21.9 min for ent-9b. 4.2.3. S-tert-Butyl (S)-2-(6,6-dimethyl-2,4-dioxo-3,4,5,6,7,8hexahydro-2H-benzo[e][1,3]oxazin-5-yl)ethanethioate 9c To a stirred suspension of Cu(OTf)2 (208.4 mg, 0.576 mmol) in toluene (3.0 mL) was added a solution of L1 (21.9 mg, 0.0822 mmol) in toluene (2.0 mL) via a cannula at room temperature. The mixture was stirred at room temperature for 5 h to afford a clear blue solution of L1–Cu(OTf)2 complex (0.115 M). To a stirred suspension of imide 4c9a (259.6 mg, 1.15 mmol) and MS 3 Å (1.5 g) in toluene (3.0 mL) were added the L1–Cu(OTf)2 complex solution in toluene obtained as above (0.115 M, 5.0 mL, 0.576 mmol) and TMS S,O-ketene acetal 7 (1.178 mg, 5.76 mmol) in toluene (4.0 mL) via a cannula at 10 °C. After stirring at this temperature for 40 h, the reaction mixture was cooled to 78 °C and quenched with 6 M HCl (1 mL). After stirring at 78 °C for 0.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with Et2O (20 mL  4). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (benzene/ethyl acetate = 50/1, 20/1, 10/1, 8/1, 4/1) and preparative TLC (hexane/ethyl acetate = 1/1) to afford a mixture of 8c and 9c (8c/9c = 3.3/1, 283.7 mg, 94% (at 75% conv)) as a white amorphous solid. To a stirred solution of the mixture (14.0 mg, 0.0400 mmol) obtained as above in THF (1 mL) was added 6 M HCl (0.1 mL) at room temperature. After stirring at 50 °C for 5.5 h, the reaction mixture was cooled to 0 °C, quenched with saturated aqueous NaHCO3 solution (5 mL), and the aqueous layer was extracted with CH2Cl2 (5 mL  4). The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate = 3/2) to afford product 9c (10.9 mg, 84%, 94% ee) as a white amorphous solid: Rf = 0.65 (hexane/ethyl acetate = 1/1); 1H NMR (400 MHz, CDCl3) d 8.77 (1H, br), 3.03 (1H, dd, J = 8.0, 3.6 Hz), 2.64 (1H, dd, J = 15.6, 8.0 Hz), 2.52 (1H, dd, J = 15.6, 3.6 Hz), 2.50–2.35 (2H, m), 1.70 (1H, J = 16.8, 10.4, 7.6 Hz), 1.47–1.36 (10H, m), 1.03 (3H, s), 0.94 (3H, s); 13C NMR (100 MHz, CDCl3) d 198.5, 163.8, 162.2, 147.6, 111.6, 48.3, 45.8, 37.8, 32.5, 30.0, 29.8, 27.3, 26.5, 24.4; IR (ATR) mmax 2961, 1771, 1700, 1689, 1408, 1254, 1128, 989 cm1; HRMS (ESI) [M+Na]+ calcd for C16H23NO4SNa 348.1240, found 348.1240; [a]20 D = +3.2 (c 0.38, CHCl3); ee was determined by HPLC (235 nm); Daicel Chiral Cell IA-3 0.46 cm a  25 cm; hexane/isopropanol = 4/1; flow rate = 0.5 mL/min; retention time: 10.9 min for ent-9c, 12.4 min for 9c. 4.2.4. S-tert-Butyl 2-((3S,4R)-3-methoxycarbonylcarbamoyl-1methyl-2-oxopiperidin-4-yl)ethanethioate 8d To a stirred suspension of Cu(OTf)2 (118.0 mg, 0.326 mmol) in toluene (6.0 mL) was added L1 (87.8 mg, 0.330 mmol) in toluene (2.0 mL). The mixture was stirred at room temperature for 5 h to afford a clear blue solution of L1–Cu(OTf)2 complex (0.0408 M). To a stirred suspension of imide 4d (212.2 mg, 1.00 mmol) and MS 3 Å (1 g) in toluene (2.8 mL) was added an L1–Cu(OTf)2 complex

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solution in toluene (0.0408 M, 4.9 mL, 0.200 mmol) and TMS S,Oketene acetal 7 (1.02 g, 4.99 mmol) in toluene (3.3 mL) via a cannula at 35 °C. After stirring at this temperature for 41 h, the reaction mixture was cooled to 78 °C and quenched with 6 M HCl (2 mL). After stirring for 0.5 h at 78 °C, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution (10 mL) and extracted with EtOAc (20 mL  4). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (benzene/ethyl acetate = 3/1, 1/1, 1/2) to afford product 8d (340.7 mg, 99%, 92% ee) as a white amorphous solid: Rf = 0.30 (ethyl acetate); 1H NMR (400 MHz, CDCl3) d 9.46 (1H, br), 3.76 (3H, s), 3.46 (1H, br), 3.38–3.26 (2H, m), 3.07–2.97 (1H, m), 2.97 (3H, s), 2.62 (1H, dd, J = 15.1, 5.5 Hz), 2.45 (1H, d, J = 15.1, 8.2 Hz), 2.11–2.01 (1H, m), 1.74–1.63 (1H, m), 1.44 (9H, s); 13C NMR (100 MHz, CDCl3) d 198.3, 166.7, 166.0, 151.3, 53.1, 53.0, 48.7, 47.7, 47.1, 35.5, 30.8, 29.8, 25.4; IR (ATR) mmax 2961, 1788, 1681, 1627, 1506, 1206, 1163, 1047 cm1; HRMS (ESI) [M+Na]+ calcd for C15H24N2O5SNa 367.1298, found 367.1298; [a]21 D = +3.2 (c 0.56, CHCl3); ee was determined by HPLC (235 nm); Daicel Chiral Cell IF-3 0.46 cm a  25 cm; hexane/isopropanol = 2/1; flow rate = 1.0 mL/min; retention time: 45.7 min for 8d, 58.5 min for ent-8d. The absolute configuration of 8d was tentatively assigned based on the structural determination of other products. 4.2.5. Methyl (5-oxocyclopent-1-ene-1-carbonyl)carbamate 4e To a stirred solution of 2-tributylstannyl-2-cyclopentenone18 (1.647 g, 4.44 mmol) in THF (40 mL) were added Pd2(dba)3 (0.203 g, 0.222 mmol), Ph3As (0.408 g, 1.33 mmol), CuTC (2.54 g, 13.3 mmol), and methyl N-[methoxy(methylthio)methylene]carbamate9a (1.45 g, 8.89 mmol) at room temperature, and the resulting solution was stirred at 50 °C. After stirring at 50 °C for 1.5 h, the resulting mixture was cooled down to room temperature, and the mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate = 3/1) to afford an imino ether (518.3 mg) as a pale yellow oil. To a stirred solution of the imino ether (518.3 mg) obtained as above in THF (3 mL) was added 6 M HCl (0.1 mL) at 0 °C. After stirring at 0 °C for 10 min, CH2Cl2 (5 mL) was added to the solution and the aqueous layer was extracted with CH2Cl2 (5 mL  3). The combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate = 2/1 to 3/2 to 1/1) to afford 4e (350.2 mg, 43% (2 steps)) as a white solid: Rf = 0.30 (hexane/ethyl acetate = 1/2); 1H NMR (400 MHz, CDCl3) d 10.13 (1H, br), 8.75 (1H, t, J = 2.4 Hz), 3.80 (3H, s), 2.81 (2H, dt, J = 4.4, 2.4 Hz), 2.68 (2H, 4.4, 2.4 Hz); 13C NMR (100 MHz, CDCl3) d 207.2, 176.2, 158.1, 151.3, 137.0, 53.0, 36.1, 26.9; IR (ATR) mmax 3259, 1782, 1711, 1518, 1240, 1199, 774 cm1; mp 109–110 °C; HRMS (ESI) [M+Na]+ calcd for C8H9NO4Na 206.0424, found 206.0421. 4.2.6. S-tert-Butyl 2-((1R,2R)-2-methoxycarbonylcarbamoyl-3oxocyclopentyl)ethanethioate 8e To a stirred suspension of Cu(OTf)2 (35.8 mg, 0.0990 mmol) in toluene (1.0 mL) was added a solution of L1 (26.6 mg, 0.0999 mmol) in toluene (1.0 mL). The mixture was stirred for 5 h at room temperature to afford a clear blue solution of L1–Cu(OTf)2 complex (0.0495 M). To a stirred suspension of imide 4e (9.7 mg, 0.0530 mmol) and MS 3 Å (50 mg) in toluene (0.19 mL) was added a solution of L1– Cu(OTf)2 complex in toluene (0.0495 M, 0.21 mL, 0.0104 mmol) and TMS S,O-ketene acetal 7 (54.1 mg, 0.265 mmol) in toluene (0.6 mL) via a cannula at 60 °C. After stirring at this temperature for 70 h, the reaction mixture was cooled to 78 °C and quenched

with 6 N HCl (0.1 mL). After stirring at 78 °C for 0.5 h, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution (5 mL) and the aqueous layer was extracted with Et2O (5 mL  4). The organic layer was combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (benzene/ethyl acetate = 10/1) to afford product 8e (12.5 mg, 75%, 87% ee) as a white amorphous solid: Rf = 0.60 (hexane/ethyl acetate = 1:1); 1H NMR (400 MHz, CDCl3) d 8.34 (1H, br), 3.79 (3H, s), 3.67 (1H br), 3.11–2.97 (1H m), 2.86 (1H, dd, J = 14.4, 6.0 Hz), 2.64 (1H, dd, J = 14.4, 7.6 Hz), 2.54– 2.41 (1H, m), 2.40–2.23 (1H, m), 1.72–1.57 (1H, m), 1.44 (9H, s); 13 C NMR (100 MHz, CDCl3) d 211.9, 198.6, 166.9, 151.6, 60.0, 53.2, 48.5, 47.9, 38.5, 36.7, 29.8, 26.2; IR (ATR) mmax 3308, 2961, 2923, 1774, 1680, 1512, 1209, 1038 cm1; HRMS (ESI) [M+Na]+ calcd for C14H21NO5SNa 338.1033, found 338.1033; [a]21 D = 20 (c 0.37, CHCl3). Ee was determined by HPLC (235 nm) of 10e. 4.2.7. S-tert-Butyl (S)-2-(3-oxocyclopentyl)ethanethioate 10e A solution of 8e (11.5 mg, 0.0365 mmol) in toluene (1 mL) was stirred at 100 °C for 6 h, and then concentrated under reduced pressure. The residue was purified by preparative TLC (benzene/ethyl acetate = 8/1) to afford product 10e (6.9 mg, 88%, 87% ee) as a clear oil: Rf = 0.40 (hexane/ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3) d 2.69–2.51 (3H, m), 2.45 (1H, dd, J = 18.0, 6.8 Hz), 2.37–2.10 (3H, m), 1.89 (1H, dd, J = 18.0, 9.2 Hz), 1.66–1.54 (1H, m), 1.46 (9H, s); 13C NMR (100 MHz, CDCl3) d 218.3, 198.8, 49.7, 48.3, 44.5, 38.3, 34.3, 29.9, 29.2; IR (ATR) mmax 2962, 1742, 1680, 1364, 1158 cm1; HRMS (ESI) [M+Na]+ calcd for C11H18O2SNa 237.0920, found 237.0920; [a]25 D = 53 (c 0.13, CHCl3); ee was determined by HPLC (235 nm); Daicel Chiral Cell IC-3 0.46 cm a  25 cm; hexane/isopropanol = 4/ 1; flow rate = 0.5 mL/min; retention time: 22.4 min for ent-10e, 24.2 min for 10e. 4.3. Structure elucidation of 8a 4.3.1. S-tert-Butyl (S)-2-(2-oxotetrahydro-2H-pyran-4-yl)ethanethioate 10a A solution of 8a (23.1 mg, 0.0697 mmol) in m-xylene (2 mL) was stirred at 120 °C for 3 h, and then concentrated under reduced pressure. The residue was purified by preparative TLC (benzene/ethyl acetate = 4/1) to afford product 10a (9.0 mg, 56%, 86% ee) as a clear oil: Rf = 0.35 (hexane/ethyl acetate = 2/1); 1H NMR (400 MHz, CDCl3) d 4.41 (1H, ddd, J = 11.4, 4.6, 4.6 Hz), 4.27 (1H, ddd, J = 11.4, 11.4, 3.7 Hz), 2.74 (1H, dd, J = 17.4, 4.1 Hz), 2.56–2.44 (3H, m), 2.27–2.16 (1H, m), 1.99 (1H, dd, J = 13.6, 3.4 Hz), 1.68–1.54 (1H, m), 1.45 (9H, s); 13C NMR (100 MHz, CDCl3) d 198.0, 170.3, 68.4, 49.9, 48.8, 36.0, 29.8, 29.2, 28.5; IR (ATR) mmax 2960, 2922, 1734, 1677, 1251, 1085, 971 cm1; HRMS (ESI) [M+Na]+ calcd for C11H18O3SNa 253.0869, found 253.0869; [a]26 D = 13 (c 0.22, CHCl3). 4.3.2. (R)-2-(2-Oxotetrahydro-2H-pyran-4-yl)acetaldehyde 11a To a stirred solution of thiol ester 10a (4.1 mg, 0.0178 mmol) in acetone (2 mL) were added 10% Pd/C (94.7 mg, 0.0890 mmol) and Et3SiH (0.043 mL, 0.270 mmol). The reaction mixture was stirred at room temperature for 10 min, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate = 1/1) to afford aldehyde 11a (2.0 mg, 79%, 86% ee); 1H NMR (400 MHz, CDCl3) d 9.78 (1H, s), 4.43 (1H, ddd, J = 11.8, 5.4, 3.6 Hz), 4.31 (1H, ddd, J = 10.6, 10.6, 3.6 Hz), 2.78 (1H, ddd, J = 17.4, 5.5, 1.4 Hz), 2.66–2.52 (3H, m), 2.25–2.16 (1H, m), 2.09–2.00 (1H, m), 1.65– 1.52 (1H, m); 13C NMR (100 MHz, CDCl3) d 199.7, 170.3, 68.4, 49.7, 36.1, 28.7, 26.1; IR (ATR) mmax 1718, 1252, 1084 cm1; HRMS (ESI) [M+Na]+ calcd for C7H10O3Na 165.0522, found 165.0523; [a]25 D = 10 (c 0.070, CHCl3).

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4.4. Structure elucidation of 8b 4.4.1. S-tert-Butyl 2-((S)-3-oxocyclohexyl)ethanethioate 10b A solution of a mixture of 8b and 9b (56.9 mg, 0.174 mmol), which was obtained under the reaction conditions in entry 5 of Table 2, in m-xylene (3 mL) was stirred at 120 °C for 38 h. m-Xylene, 9b, and 10b were then separated by silica gel chromatography (hexane/ethyl acetate = 15/1, 10/1, 4/1, 2/1), and further purification by preparative TLC (9b: benzene/ethyl acetate = 4/1, 10b: benzene/ethyl acetate = 15/1) afforded 9b (15.1 mg, 29%) and 10b (4.5 mg, 11%, clear oil, 96% ee): Rf = 0.35 (hexane/ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3) d 2.52–2.19 (6H, m), 2.11–2.00 (2H, m), 1.98–1.88 (1H, m), 1.75–1.60 (1H, m), 1.48–1.36 (1H, m), 1.45 (9H, m); 13C NMR (100 MHz, CDCl3) d 210.6, 198.7, 50.8, 48.5, 47.5, 41.3, 36.4, 30.9, 29.9, 24.9; IR (ATR) mmax 2925, 1714, 1680, 1457, 1364, 1225, 1162, 1106, 989, 669 cm1; HRMS (ESI) [M+Na]+ calcd for C12H20O2SNa 251.1076, found 251.1078; [a]21 D = 42 (c 0.045, CHCl3). 4.4.2. Methyl 2-((S)-3-oxocyclohexyl)acetate 12b17 To a stirred solution of 10b (3.1 mg, 0.0136 mmol) in CH2Cl2 were added MeOH (0.027 mL, 0.0668 mmol) and NBS (3.6 mg, 0.0202 mmol) at room temperature. After being stirred for 2 h at this temperature, NBS (1.2 mg, 6.74  103 mmol) was added and stirred for 5 min. The reaction mixture was purified by silica gel chromatography (hexane/ethyl acetate = 8/1) to afford 12b (1.6 mg, 69%, 96% ee) as a clear oil. [a]21 D = 20 (c 0.080, CHCl3). 4.5. Structure elucidation of 8c0 4.5.1. S-tert-Butyl 2-((S)-2,2-dimethyl-5-oxocyclohexyl)ethanethioate 10c A solution of a mixture of 8c0 and 9c (8c0 /9c = 3.3/1, 214.3 mg), which was prepared under the reaction conditions in Scheme 3, in m-xylene (7 mL) was stirred at 130 °C for 6 h. m-Xylene, 9c, and 10c were then separated by silica gel chromatography (hexane/ ethyl acetate = 20/1, 10/1, 8/1, 3/1), and further purification by preparative TLC (9c: hexane/ethyl acetate = 2/1, 10c: hexane/ethyl acetate = 4/1) afforded 9c (76.0 mg, 38%, 94% ee) and 10c (16.6 mg, 11%, clear oil): Rf = 0.50 (hexane/ethyl acetate = 4/1); 1H NMR (400 MHz, CDCl3) d 2.63 (1H, dd, J = 19.3, 8.2 Hz), 2.46–2.24 (3H, m), 2.23–2.07 (3H, m), 1.75–1.58 (2H, m), 1.44 (9H, s), 1.04 (3H, s), 0.99 (3H, s); 13C NMR (100 MHz, CDCl3) d 210.7, 199.3, 48.5, 46.3, 43.6, 43.1, 39.8, 38.2, 32.7, 29.9, 28.8, 19.7; IR (ATR) mmax 2959, 2923, 2857, 1716, 1684, 1457, 1364, 1162, 1074, 989, 669 cm1; HRMS (ESI) [M+Na]+ calcd for C14H24O2SNa 279.1359, found 279.1390; [a]21 D = 7.5 (c 0.040, CHCl3). 4.5.2. Methyl 2-((S)-2,2-dimethyl-5-oxocyclohexyl)acetate 12c17 To a stirred solution of 10c (3.1 mg, 0.0121 mmol) in MeOH (0.35 mL) was added NaOMe (2.0 mg, 0.0369 mmol) at room temperature. After being stirred at room temperature for 43 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (1 mL). The aqueous layer was extracted with Et2O (3 mL  4), and the combined organic layer was washed with brine (3 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate = 15/1, 10/1, 6/1) to afford 12c (1.9 mg, 79%, 94% ee) as a clear oil: [a]20 D = 7.3 (c 0.055, CHCl3). 4.6. Structure elucidation of 8e 4.6.1. 2-((R)-3-Oxocyclopentyl)acetaldehyde 11e18 To a stirred solution of 10e (10.7 mg, 0.0534 mmol) in acetone (2 mL) were added 10% Pd/C (284.2 mg, 0.267 mmol) and Et3SiH (0.125 mL, 0.785 mmol). The reaction mixture was stirred at room

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temperature for 15 min, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate = 10/1, 4/ 1, 5/2) to afford aldehyde 11e (3.0 mg, 46%, 87% ee): [a]20 D = 49 (c 0.035, CHCl3). Acknowledgments This work was financially supported in part by The Grant-in-Aid for Scientific Research (B) (25293003) by MEXT, Japan and a Waseda University Grant for Special Research Projects. References 1. For recent examples, see: (a) Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew. Chem., Int. Ed. 2008, 47, 1272; (b) Hsieh, M.-T.; Liu, H.-J.; Ly, T. W.; Shia, K.-S. Org. Biomol. Chem. 2009, 7, 3285; (c) Li, W.; Liu, X.; Zhou, X.; Lee, C.-S. Org. Lett. 2010, 12, 548; (d) De Lorbe, J. E.; Lotz, M. D.; Martin, S. F. Org. Lett. 2010, 12, 1576; (e) Zhang, Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 9567; (f) Shi, H.; Fang, L.-C.; Tan, C.-H.; Shi, L.-L.; Zhang, W.-B.; Li, C.-C.; Luo, T.-P.; Yang, Z. J. Am. Chem. Soc. 2011, 133, 14944. 2. For the catalytic asymmetric cycloadditions of a-alkylidene b-keto esters, see: (a) Honda, Y.; Date, T.; Hiramatsu, H.; Yamauchi, M. Chem. Commun. 1997, 1411; (b) Yamauchi, M.; Aoki, T.; Li, M.-Z.; Honda, Y. Tetrahedron: Asymmetry 2001, 12, 3113; (c) Schotes, C.; Mezzetti, A. J. Am. Chem. Soc. 2010, 132, 3652; (d) Schotes, C.; Mezzetti, A. J. Org. Chem. 2011, 76, 5862–5866; (e) Schotes, C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011, 50, 3072; (f) Schotes, C.; Bigler, R.; Mezzetti, A. Synthesis 2012, 44, 513; (g) Schotes, C.; Althaus, M.; Aardoom, R.; Mezzetti, A. J. Am. Chem. Soc. 2012, 134, 1331. 3. For the catalytic asymmetric Diels–Alder reaction of quinones with an ester group, see: Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10162. 4. For the catalytic asymmetric Mukaiyama–Michael reactions of a cyclic aalkylidene b-keto ester, see: (a) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996, 37, 8921. In this paper, the authors described only one example affording the product in 65% yield with 63% ee.; For the catalytic asymmetric Mukaiyama–Michael reactions of alkylidene malonates, see: (b) Evans, D. A.; Rovis, T.; Kozlowski, M. C. J. Am. Chem. Soc. 1999, 121, 1994; (c) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134; For the catalytic asymmetric vinylogous Mukaiyama–Michael reactions of alkylidene malonates, see: (d) Zhang, Q.; Xiao, X.; Lin, L.; Liu, X.; Feng, X. Org. Biomol. Chem. 2011, 9, 5748; (e) Jusseau, X.; Retailleau, P.; Chabaud, L.; Guillou, C. J. Org. Chem. 2013, 78, 2289; (f) Fraile, J. M.; García, N.; Herrerías, C. I. ACS Catal. 2013, 3, 2710. 5. For the recent use of a-alkylidene b-keto esters in asymmetric catalysis, see: Schotes, C.; Mezzetti, A. ACS Catal. 2012, 2, 528. 6. Strictly speaking, the bisoxazoline–Cu(II) complex may have a distorted square-planar geometry. See: (a) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 6460; (b) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559. Also see Ref. 4b. 7. (a) Narasaka, K.; Inoue, M.; Yamada, T. Chem. Lett. 1986, 1109; (b) Narasaka, K.; Inoue, M.; Yamada, T. Chem. Lett. 1986, 1967; (c) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493; (d) Corey, E. J.; Imai, Nobuyuki; Hong, Yue J. Am. Chem. Soc. 1991, 113, 728; (e) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999, 121, 2617; (f) Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 1539; (g) Sudo, Y.; Shirasaki, D.; Harada, S.; Nishida, A. J. Am. Chem. Soc. 2008, 130, 12588; (h) Shimizu, Y.; Shi, S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2010, 49, 1103. 8. Selected references for the utility of N-acryloyl oxazolidin-2-one and its congeners. For 1,3-dipolar additions, see: (a) Kobayashi, S.; Kawamura, M. J. Am. Chem. Soc. 1998, 120, 5840; (b) Suga, H.; Inoue, K.; Inoue, S.; Kakehi, A. J. Am. Chem. Soc. 2002, 124, 14836; (c) Sibi, Mukund P.; Stanley, Levi M.; Jasperse, Craig P. J. Am. Chem. Soc. 2005, 127, 8276; For the Michael addition of organozinc reagents, see: (d) Hird, A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 1276. 9. (a) Orimoto, K.; Oyama, H.; Namera, Y.; Niwa, T.; Nakada, M. Org. Lett. 2013, 15, 768; A similar concept can be found in the use of 2-alkenoyl-pyridine-N-oxides, see: (b) Livieri, A.; Boiocchi, M.; Desimoni, G.; Faita, G. Chem. Eur. J. 2012, 18, 11662; (c) George, J.; Reddy, B. V. S. Adv. Synth. Catal. 2013, 355, 383; (d) Rout, S.; Ray, S. K.; Singh, V. K. Org. Biomol. Chem. 2013, 11, 4537; Also for the use of a,b-unsaturated 2-acylimidazole, see: Xu, X.; Hu, W.-H.; Doyle, M. P. Angew. Chem., Int. Ed. 2011, 50, 6392. 10. Sakakura, A.; Kondo, R.; Matsumura, Y.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2009, 131, 17762. 11. (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959; (b) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442; (c) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204. 12. Although L4–Cu(OTf)2 is soluble in CH2Cl2/toluene = 1/5 (see Scheme 2), the reaction of 4a with 7 (5.0 equiv) in CH2Cl2/toluene = 1/5 under the same conditions as those in entry 2 afforded 8a in 90% yield with 73% ee. 13. (a) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223; For Lewis acid catalyzed asymmetric Mukaiyama–Michael reaction, see: (b) Bernardi, A.;

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H. Oyama et al. / Tetrahedron: Asymmetry 26 (2015) 262–270 Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996, 37, 8921–8924; (c) Bernardi, A.; Karamfilova, K.; Sanguinetti, S.; Scolastico, C. Tetrahedron 1997, 53, 13009– 13026; (d) Kitajima, H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53, 17015–17028; (e) Kitajima, H.; Katsuki, T. Synlett 1997, 568–750; (f) Nishikiori, H.; Ito, K.; Katsuki, T. Tetrahedron: Asymmetry 1998, 9, 1165–1170; (g) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc. 1999, 121, 1994–1995; (h) Evans, D. A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1, 865–868; (i) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635–1649; (j) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134–9142; (k) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480–4491; (l) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A. Org. Lett. 2001, 3, 2101–2103; (m) Desimoni, G.; Faita, G.; Filippone, S.; Mella, M.; Zampori, M. G.; Zema, M. Tetrahedron 2001, 57, 10203–10212; (n) Wang, X.; Harada, T.; Iwai, H.; Oku, A. Chirality 2003, 15, 28–30; (o) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046–10057; (p) Suga, H.; Kitamura, T.; Kakehi, A.; Baba, T. Chem. Commun. 2004, 1414–1415; (q) Harada, T.; Adachi, S.; Wang, X. Org. Lett. 2004, 6, 4877–4879; (r) van

14. 15. 16. 17. 18.

Lingen, H. L.; van Delft, F. L.; Storcken, R. P. M.; Hekking, K. F. W.; Klaassen, A.; Smits, J. J. M.; Ruskowska, P.; Frelek, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2005, 4975–4987; (s) Desimoni, G.; Faita, G.; Guala, M.; Laurenti, A.; Mella, M. Chem. -Eur. J. 2005, 11, 3816–3824; (t) Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921–1924; (u) Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 742; (v) Yang, H.; Kim, S. Synlett 2008, 555; (w) Zhang, Q.; Xiao, X.; Lin, L.; Liu, X.; Feng, X. Org. Biomol. Chem. 2011, 9, 5748; (x) Livieri, A.; Boiocchi, M.; Desimoni, G.; Faita, G. Chem. Eur. J. 2012, 18, 11662. The conditions of transformations were not optimized. Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve, Y.; Beaudoin, S. J. Org. Chem. 1993, 58, 5032. Minato, H.; Kodama, H.; Miura, T.; Kobayashi, M. Chem. Lett. 1977, 413. Siirola, E.; Mutti, F. G.; Grischek, B.; Hoefler, S. F.; Fabian, W. M. F.; Grogan, G.; Kroutil, W. Adv. Synth. Catal. 2013, 355, 1703. Hua, D. H.; Chan-Yu-King, R.; Mckie, J. A.; Myer, L. J. Am. Chem. Soc. 1987, 109, 5026. Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D. Angew. Chem., Int. Ed. 2008, 47, 8100.