Enantioselective Michael Reaction of Cyclic Î²-Ketoesters with Morita

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Enantioselective Michael Reaction of Cyclic #-Ketoesters with Morita-Baylis-Hillman Derivatives Using a Phase-Transfer Catalyst Ryukichi Takagi, Emi Fujii, and Hirotoshi Kondo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01777 • Publication Date (Web): 21 Aug 2018 Downloaded from http://pubs.acs.org on August 21, 2018

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The Journal of Organic Chemistry

Enantioselective Michael Reaction of Cyclic bKetoesters with Morita–Baylis–Hillman Derivatives Using a Phase-Transfer Catalyst Ryukichi Takagi,* Emi Fujii, and Hirotoshi Kondo Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan

AUTHOR EMAIL ADDRESS: [email protected]

ABSTRACT:

This study aims to develop a highly enantioselective Michael reaction of cyclic b-ketoesters with Morita–Baylis–Hillman (MBH) derivatives using a phase-transfer catalyst. Cyclic b-ketoesters reacted ACS Paragon Plus Environment

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with MBH derivatives to stereoselectively generate a quaternary carbon center in the presence of cinchona alkaloid-derived bulky ammonium catalyst and aqueous KOH and Michael adducts bearing an acrylate moiety were obtained in good chemical yields with good enantioselectivity.

Introduction In the field of synthetic organic chemistry, Morita–Baylis–Hillman (MBH) derivatives are versatile 1a-c

synthons used for the construction of multifunctional compounds. The ability of MBH derivatives to 1d-f

regenerate the reactive acrylic moiety by S 2 or S 2' substitution reaction with a nucleophile at the allylic N

N

position is one of the advantages of using MBH derivatives (Figure 1). Resultantly, successive nucleophilic reactions can take place at the allylic positions of MBH derivatives. When a Lewis base, 2

such as a tertiary amine or phosphine, is used as a nucleophile, MBH derivatives can act as 1,3-dipole synthons in [3+2] reactions and other types of annulation reactions. Based on these characteristics of MBH derivatives, many types of chiral Lewis base-catalyzed enantioselective reactions have been reported.

1d-f,3

Figure 1. Advanced feature of MBH derivatives

The MBH derivatives have also been utilized for the total synthesis of natural products. During our 4

previous synthetic studies based on the densely functionalized bicyclo[3.3.1]nonanes, which are a core characteristic structure of the polycyclic polyprenylated acylphloroglucinols (PPAPs) family of natural product, we focused on the features of MBH derivatives, and have developed a convenient approach for the synthesis of the frameworks by conducting successive Michael reactions of cyclic b-ketoesters with

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MBH derivatives. Similarly, on the basis of biosynthetic considerations, Porco et al. proposed an 5

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ingenious and highly instructive approach to PPAPs by alkylative dearomatization–annulation reaction of MBH derivatives with acylphloroglucinols. In their study, the methodology was elevated to 6

enantioselective synthesis of an adamantane-containing a PPAP using cinchona alkaloid-derived phasetransfer catalysts.

6b

The proposed study describes the organocatalytic enantioselective Michael reaction of cyclic bketoesters with MBH derivatives because the reaction was essential in expanding our successive Michael reaction methodology to the asymmetric synthesis of densely functionalized bicyclo[3.3.1]nonanes. Cyclic b-ketoesters have been widely applied as substrates for organocatalyzed enantioselective reactions, because they readily enolize to react with electrophiles, and can generate quaternary carbon center stereoselectively. Jørgensen et al. developed a novel cinchona alkaloid-derived phase-transfer catalyst 1 7

with a 9-anthracenylmethyl group attached to the quinuclidine nitrogen atom and a 1-adamantoyl at the 9-O position, which acts as a good catalyst in the enantioselective reactions of cyclic b-ketoesters bearing a tert-butyl ester (Figure 2). This prompted an investigation of enantioselective Michael reaction of 8.9

cyclic b-ketoesters with MBH derivatives catalyzed by phase-transfer catalyst 1.

10

Figure 2. Structure of Jørgensen’s phase-transfer catalyst 1.

Results and Discussion


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Our experiments began with the investigation on Michael reaction of b-ketoesters 2 with nonsubstituted MBH derivative 3a. Results of the enantioselective Michael reaction of b-ketoester 2a with MBH derivative 3a catalyzed by phase-transfer catalyst 1 are presented in Table 1. Initial screening of the reaction conditions in the Michael reaction of b-ketoester 2a was initiated using superior solvent systems reported by Jørgensen and co-workers: [condition A: o-xylene/CHCl (7 : 1), −20 °C or condition 3

B: toluene/CHCl (7 : 1), −40 °C]. First, the reaction conditions similar to Jørgensen’s asymmetric 8

3

conjugate addition of b-ketoester 2a with allenic ester were tested. Treatment of b-ketoester 2a with 8a

MBH derivative 3a in the presence of 50 wt% aq. K PO (10 equiv) and 5 mol% of 1 in o-xylene/CHCl 3

4

3

(7 : 1) at −20 °C (condition A) gave Michael adduct 4a in low yield and with moderate enantioselectivity (entry 1). To improve the reaction yield and the enantioselectivity, the reaction was conducted under the reaction conditions using KOH (solid or 50 wt% aq. solution, 10 equiv) as a base and 10 mol% of 1 in toluene/CHCl (7: 1) at −40 °C (condition B) (entries 2 and 3). The strong base allowed the reaction to 3

proceed moderately even at −40 °C, and it was found that using 50 wt% aq. KOH as a base achieved good enantioselectivity in comparison with the enantioselectivity obtained using solid KOH. Moreover, increasing the amount of 50 wt% aq. KOH (40 equiv) resulted in a slight decrease in the enantioselectivity (entry 4). The amount of catalyst loading was also examined, and the best result in the Michael reaction of b-ketoester 2a was obtained using 20 mol% of 1 and 50 wt% aq. KOH (10 equiv) in toluene/CHCl (7 : 3

1) at −40 °C (entry 6). Additional attempts such as decreasing the reaction temperature or using single solvent system did not afford better results (entries 7-10).


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Table 1. Enantioselective Michael reaction of b-ketoester 2a with MBH derivative 3a a

Unless otherwise noted, reactions were performed with b-ketoester 2a (0.20 mmol), 3a (0.23 mmol), 1 (20 mol%), and base (2.0 mmol) in 0.15 M solution of the solvent system. Isolated yields. Determined by chiral stationary phase HPLC. 40 equiv of aq. KOH was used. Reaction was performed at −55 °C. N.D. = not determined. a

b

c

d

e

f

Next, the Michael reaction of b-ketoester 2b with MBH derivative 3a was examined (Table 2). In the case of the Michael reaction of b-ketoester 2b, the catalyst loading of 15 mol% was enough for good enantioselectivity, however, an increased reaction temperature (−20 °C) was necessary due to a low


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reactivity of the Michael donor (entries 1 and 2). For the best result, adjustment of the base amount was also necessary to decrease non-catalytic background reactions (entry 3).

Table 2. Enantioselective Michael reaction of b-ketoester 2b with MBH derivative 3a a

Unless otherwise noted, reactions were performed with b-ketoester 2b (0.20 mmol), 3a (0.23 mmol), 1 (15 mol%), and 50 wt% aq. KOH (1.0 mmol) in 0.15 M solution of condition A or B. Isolated yields. Determined by chiral stationary phase HPLC. 10 equiv of aq. KOH was used. a

b

c

d

Further applications of this catalytic system for the reaction between cyclohexenone derivatives 2c-f and MBH derivative 3a were investigated (Table 3). In the reaction of cyclohexenone derivative 2c with MBH derivative 3a, it was noted that smaller amounts of the 50 wt% aq. KOH base (3 equiv) were necessary for good enantioselectivity in comparison with the amounts used in the reactions that are already described (entries 1 and 2). Reaction between cyclohexenone derivatives 2d-f and MBH derivative 3a proceeded under the same reaction conditions, and the corresponding adducts 4d-f were obtained in good chemical yields and excellent enantioselectivities (entries 3-5).


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Table 3. Enantioselective Michael reaction of b-ketoesters 2c-f with MBH derivative 3a a

Unless otherwise noted, reactions were performed with bketoester 2 (0.20 mmol), 3a (0.23 mmol), 1 (15 mol%), and 50 wt% aq. KOH (0.60 mmol) in 0.15 M solution of o-xylene/CHCl (7 : 1) at -20 °C. Isolated yields. Determined by chiral stationary phase HPLC. 5equiv of aq. KOH was used. Reported results are the average of two trials. a

3

b

c

d

e

To expand enantioselective Michael reaction for the preparation of more densely functionalized Michael adducts, feasibility of the reaction between b-ketoester 2a and methyl-substituted MBH derivatives 3b-e was tested (Table 4). First, Michael reaction of b-ketoester 2a with MBH derivative 3b in o-xylene/CHCl solvent was examined (entry 1). Introducing a methyl group on the MBH derivative 3

decreased the reactivity of the MBH derivative 3b in comparison with that of non-substituted MBH derivative 3a. The chemical yield of Michael adduct 4g was moderate, despite high catalyst loading (40 mol%), high reaction temperature (0 °C), and long reaction time (40 h). Replacement of the leaving group (LG) on methyl-substituted MBH derivative from acetate (OAc) to benzoate (OBz) improved the ACS Paragon Plus Environment

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reactivity of the MBH derivative 3c and made it possible to reduce the amount of catalyst loading to 20 mol% and decrease reaction temperature to −20 °C (entry 2). Resultantly, enantioselectivity of Michael adduct 4g was enhanced for every geometric isomer (E: 77% ee, Z: 86% ee). However, the reaction yield was not satisfactory (37% yield). The size of the ester group also affected the reactivity of the MBH derivative (entry 3). Even at −20 °C, Michael reaction of b-ketoester 2a with MBH derivative 3d produced Michael adduct 4h in 51% yield with moderate enantioselectivities (E: 63% ee, Z: 78% ee). In the case of n-hexyl ester 3e, the reaction yield was improved to 70% yield (entry 4). Finally, it was found that a combination of the n-hexyl ester and benzoate as a LG was the best MBH derivative for a satisfactory reaction yield (85%) and good enantioselectivities (E: 71% ee and Z: 85% ee) (entry 5). The enantioselectivity of the Michael adduct E-4i was enhanced at lower temperature reactions (entry 6). Under these reaction conditions, E-geometric isomers E-4g-i were generated selectively.


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Table 4. Enantioselective Michael reaction of b-ketoester 2a with MBH derivatives 3b-f a

Unless otherwise noted, reactions were performed with b-ketoester 2a (0.20 mmol), 3 (0.23 mmol), 1 (20 mol%), and 50 wt% aq. KOH (2.0 mmol) in 0.15 M solution of o-xylene/CHCl (7 : 1) at -20 °C. Isolated yields. E/Z ratios were determined by H NMR analysis of crude products. Determined by chiral stationary phase HPLC. 40mol% of catalyst 1 was used. Reaction was performed at 0 °C. Reaction was performed in condition B. a

3

b

c

1

d

e

f

g

Having identified the best methyl-substituted MBH derivative, Michael reaction of b-ketoester 2b with MBH derivative 3f was evaluated (Table 5). Since controlling the base amount was important for the Michael reaction of b-ketoester 2b with MBH derivative 3a to prevent non-catalytic background reactions, a small amount of base (50 wt% aq. KOH; 3 equiv) was used for the Michael reaction of b-ketoester 2b


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with methyl-substituted MBH derivative 3f (entry 1). The chemical yield of the Michael adduct 4j from the reaction was low (33%), although the Michael adduct E-4j was obtained with a high enantioselectivity rate (90% ee). Moreover, the enantioselectivity of the Michael adduct Z-4j was moderate (61% ee), although the reaction was carried out at −40 °C. An excess amount of base (20 equiv) together with an increase in the catalyst loading (20 mol%) did not improve the reaction yield (49%) and led to a decrease in the enantioselectivity of E-4j (85% ee) (entry 2). We suspected that the strong base KOH was not suitable for the Michael reaction of b-ketoester 2b with MBH derivative 3f. After examining other kinds of base on the basis of Jørgensen’s report , the conditions using solid Cs CO at 0 °C gave best results for 8a

2

3

producing a satisfactory enantioselectivity for both geometric isomers E- and Z-4j (E: 81% ee and Z: 91% ee), although the reaction yield was moderate (51%) (entry 3).

Table 5. Enantioselective Michael reaction of b-ketoester 2b with MBH derivative 3f a

Unless otherwise noted, reactions were performed with b-ketoester 2b (0.20 mmol), 3e (0.23 mmol), 1 (20 mol%), and 50 wt% aq. KOH in 0.15 M solution of toluene/CHCl (7 : 1) at −40 °C. Isolated yields. E/Z ratios were determined by H NMR analysis of crude products. Determined by chiral stationary phase HPLC. 15mol% of catalyst 1 was used. N.D. = not determined. a

b

c

3

1

d

e

f


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Michael reaction of cyclohexenone derivatives 2c-f with methyl-substituted MBH derivative 3f was also explored under condtion A (Table 6). In these reactions, a longer reaction time in comparison with the Michael reaction with MBH derivative 3a was required for the satisfactory reaction yields. Michael adducts 4k-n were obtained as a mixture of geometric isomers (E : Z = ca. 1 : 1) with high enantioselectivities. To obtain Michael adducts 4k-n with higher enantioselectivities, the lower temperature conditions (condition B) using 6 equiv of aq. KOH were subjected to Michael reaction of cyclohexenone derivatives 2c-f with methyl-substituted MBH derivative 3f (Table S3, Supporting Information). However, these enantioselectivities increased only slightly under these reaction conditions.

Table 6. Enantioselective Michael reaction of b-ketoesters 2c-f with MBH derivative 3f a

The reactions were performed with b-ketoester 2 (0.20 mmol), 3f (0.23 mmol), 1 (15 mol%), and 50 wt% aq. KOH (0.60 mmol) in 0.15 M solution of o-xylene/CHCl (7 : 1) at −20 °C. Isolated yields. E/Z ratios were determined by H NMR analysis of crude products. Determined by chiral stationary phase HPLC. Reported results are the average of three trials. a

b

c

3

1

d

e


11


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Michael reaction of b-ketoesters 2 with ethoxycarbonyl-substituted MBH derivative 3g was also investigated (Tables 7 and 8). The reactivity was improved by introducing the electron-withdrawing group on MBH derivative and, even at −40 °C, the Michael reaction of b-ketoesters 2c-f with MBH derivative 3g smoothly proceeded to afford the Michael adducts 4o-r with excellent yields (Table 7). In these reactions, the Z-isomers of the Michael adduct Z-4o-r were obtained as the major geometric isomer. Michael reaction of b-ketoesters 2c-f with MBH derivative 3g under the condition B afforded Michael adducts 4o-r with high enantioselectivities, respectively (Table 7, entries 1, 3, 5, and 7). In addition, a novel solvent system (condition C: o-xylene/toluene/CHCl = 7 : 1 : 1) was also tried for the Michael 3

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reaction at −40 °C. Because this solvent system allowed the use of o-xylene, which has superior enantioselectivity than toluene. The Michael reaction under the novel solvent system afforded Michael adducts 4o-r with slightly better enantioselectivities than those under the condition B (Table 7, entries 2, 4, 6, and 8). It is noteworthy that the Michael adducts, 4s and 4t, were readily obtained from Michael reaction of b-ketoesters 2a,b with MBH derivative 3g and resulted in moderate chemical yields, i.e., 67% and 71%, respectively, coupled with good enantioselectivies even when 3 equiv of aq. KOH was used at −40 °C (Table 8).


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Table 7. Enantioselective Michael reaction of b-ketoesters 2c-f with MBH derivative 3g a

Unless otherwise noted, reactions were performed with b-ketoester 2 (0.20 mmol), 3g (0.23 mmol), 1 (15 mol%), and 50 wt% aq. KOH (0.60 mmol) in 0.15 M solution of condition B or 0.13 M solution of condition C. Isolated yields. E/Z ratios were determined by H NMR analysis of crude products. Determined by chiral stationary phase HPLC. Reported results are the average of at minimum two trials. a

b

c

1

d

e


13


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Table 8. Enantioselective Michael reaction of b-ketoesters 2a,b with MBH derivative 3g a

Unless otherwise noted, reactions were performed with bketoester 2 (0.20 mmol), 3g (0.23 mmol), 1 (15 mol%), and 50 wt% aq. KOH (0.60 mmol) in 0.13 M solution of o-xylene/toluene/CHCl (7 : 1 : 1) at −40 °C. Isolated yields. E/Z ratios were determined by H NMR analysis of crude products. Determined by chiral stationary phase HPLC. Reported results are the average of at minimum two trials. a

3

b

c

1

d

e

Finally, the absolute stereochemistry of Michael adducts 4b and 4e were assigned based on the structure of bicyclo[3.3.1]nonanes 5a and 6, which were determined by single-crystal X-ray analysis (Figure 3).

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The Michael adduct 4b was transformed to bicyclo[3.3.1]nonane 5a by intramolecular Michael reaction under the reported conditions using tetrabutylammonium bromide (TBAB) and K CO . Intramolecular 5,13

2

3

Michael reaction of adduct 4e gave a mixture of bicyclo[3.3.1]nonanes a- and g-5b without decrease in the enantiomeric excess. Bromination of g-5b with N-Bromosuccinimide (NBS) afforded bromide 6 as a 14

crystalline solid suitable for X-ray crystallography. The single-crystal X-ray structure of 5a and 6 enabled us to estimate the absolute configuration of the Michael adducts 4a-t, which was found to be 1S. The assigned S configuration at C-1 position of the Michael adducts agrees with the Jørgensen’s model on the asymmetric direct a-alkynylation of cyclic b-ketoesters. The ion pair between the enolate derived from 8b

cyclic b-ketoester 2 and catalyst 1, which provides a very efficient shielding to the Re-face of the enolate, allowing approach of MBH derivative 3 from the Si-face (Figure 4). According to this model, the 1SACS Paragon Plus Environment

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configuration of the Michael adducts 4 might also be inferred for the Michael reaction of the other bketoesters 1 and other MBH derivatives 3.

Figure 3. Construction of bicyclo[3.3.1]nonanes 5 via intramolecular Michael reaction from the Michael adducts and determination of absolute stereochemistry of the Michael adducts.


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Figure 4. Proposed transition state model.

Conclusion In this study, enantioselective Michael reaction of cyclic b-ketoesters 2 with MBH derivative 3 catalyzed by phase-transfer catalyst 1 was accomplished. The reaction stereoselectively generated a quaternary carbon center to afford Michael adducts bearing an acrylate moiety in good chemical yields with good enantioselectivity. This study indicates that, even in a racemic mixture, not only the nonsubstituted MBH derivatives but also the substituted MBH derivatives can be used as a Michael acceptor for enantioselective Michael reactions. The investigated novel solvent system (o-xylene/toluene/CHCl = 3

7 : 1 : 1) proposes the feasibility of the solvent to be a versatile solvent that can be employed at a wide range of low temperature. In these reactions, it was essential to optimize the reaction conditions to prevent non-catalytic background reactions according to the reactivity of cyclic b-ketoester 2 and MBH derivative 3, and best results were obtained when a little amount of base at low temperatures was used. From this viewpoint, cyclic b-ketoesters 2c-f and MBH derivative 3f were suitable substrates for the enantioselective Michael reaction owing to their high reactivity. Furthermore, construction of densely functionalized bicyclo[3.3.1]nonanes from Michael adduct 4 without decrease in enantiomeric excess has also been demonstrated. ACS Paragon Plus Environment

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Experimental Section Internal references for H NMR spectra were 0.0 ppm (Me Si) for CDCl and C D (7.16 ppm). Chemical 1

4

3

6

6

shifts for C NMR spectra were referenced to CDCl (77.0 ppm) and C D (128.1 ppm). High-resolution 13

3

6

6

mass spectral (HRMS) data were recorded with a LTQ Orbitrap trap mass spectrometer using electrospray ionization (ESI) method. The enantiomeric excess (ee) of the products were determined by high performance liquid chromatography (HPLC) analysis on Chiralpak IA, IC and IC3 columns. Optical rotations were measured on a digital polarimeter with a 0.1 dm cell at room temperature. All reactions involving air- and moisture-sensitive reagents were carried out under N . All reactions were monitored by 2

analytical thin-layer chromatography (TLC), which was visualized by ultraviolet light (254 nm). Preparation of b-ketoeters 2a and 2b. b-Ketoesters 2a and 2b were prepared according to literature.

15

tert-Butyl 2-oxo-cyclopentane-1-carboxylate (2a): The title compound was prepared according to the reported procedure from di-tert-butyl adipate (4.38 g, 17.0 mmol). The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 10:1) to give 2a (1.83 g, 59% yield) as a colorless oil. tert-Butyl 2-oxo-cyclohexane-1-carboxylate (2b): The title compound was prepared according to the reported procedure from di-tert-butyl heptanedioate (8.06 g, 29.6 mmol). The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 10:1) to give 2b (4.45 g, 76% yield) as a colorless oil. General procedure for the preparation of b-ketoesters 2c-f. To a stirred solution of LDA (17.8 16

mmol, 0.5 M) in THF, prepared from i-Pr NH and n-BuLi, was added a solution of cyclohexenone (15.2 2

mmol) in THF (3 mL) at −78 °C. After 30 min, a solution of 1-(tert-butoxycarbonyl)-imidazole (17.9 17

mmol) in THF (10 mL) was added. The mixture was stirred at −78 °C to room temperature for overnight and quenched with 1 M HCl. The resulting mixture was extracted with AcOEt. The combined organic


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layer was washed with water and brine, dried over Na SO , and evaporated. The resulting residue was 2

4

purified by column chromatography on silica gel to give b-ketoesters 2c-f. tert-Butyl 2-oxo-3-cyclohexene-1-carboxylate (2c): The title compound was prepared according to the 8b

general procedure from the commercial available 2-cyclohexen-1-one (2.0 mL, 20.7 mmol). The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 5:1) to give 2c (1.18 g, 29% yield) as a colorless oil. tert-Butyl 3-methyl-2-oxo-3-cyclohexene-1-carboxylate (2d): The title compound was prepared according to the general procedure from 2-methyl-2-cyclohexen-1-one (2.03 g, 18.5 mmol). The crude 18

product was purified by column chromatography on silica gel (hexane/AcOEt = 10:1) to give 2d (1.43 g, 25% yield) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.72 (s, 1 H), 3.29 (dd, J = 9.8, 4.8 Hz, 1 H), 1

3

2.47-2.38 (m, 1 H), 2.37-2.27 (m, 2 H), 2.22-2.12 (m, 1 H), 1.80 (s, 3 H), 1.48 (s, 9 H). C NMR (125 13

MHz, CDCl ) d 195.2, 169.7, 144.9, 135.3, 81.6, 54.4, 28.0 (x3), 26.3, 24.4, 16.1. HRMS (ESI+) m/z calcd 3

for C H O Na [M+Na] 233.1148, found 233.1150. 12

18

+

3

tert-Butyl 4-methoxy-2-oxo-3-cyclohexene-1-carboxylate (2e): The title compound was prepared according to the general procedure from 3-methoxy-2-cyclohexen-1-one (1.91 g, 15.2 mmol). The crude 19

product was purified by column chromatography on silica gel (hexane/AcOEt = 5:2) to give 2e (1.70 g, 37% yield) as a colorless oil. H NMR (500 MHz, CDCl ) d 5.38 (s, 1 H), 3.70 (s, 3 H), 3.21 (dd, J = 8.6, 1

3

5.0 Hz, 1 H), 2.58-2.51 (m, 1 H), 2.44-2.36 (m, 1 H), 2.34-2.25 (m, 1 H) 2.18-2.10 (m, 1 H), 1.47 (s, 9 H). C NMR (125 MHz, CDCl ) d 194.2, 178.0, 169.5, 101.7, 81.5, 55.7, 53.1, 28.0, 27.0 (x3), 24.3. 13

3

HRMS (ESI+) m/z calcd for C H O [M+H] 227.1278, found 227.1278. +

12

19

4

tert-Butyl 3-(3’-methyl-2’-butenyl)-4-methoxy-2-oxo-3-cyclohexene-1-carboxylate (2f): The title compound was prepared according to the general procedure from 2-(3’-methyl-2’-butenyl)-3-methoxy-2cyclohexen-1-one (3.80 g, 19.5 mmol). The crude product was purified by column chromatography on 20

silica gel (hexane/AcOEt = 1:1) to give 2f (1.70 g, 30% yield) as a white solid. m.p. 64-65 °C (dec). H 1

NMR (500 MHz, CDCl ) d 5.03 (t, J = 7.2 Hz, 1 H), 3.81 (s, 3 H), 3.19 (dd, J = 8.9, 4.9 Hz, 1 H), 2.96 (d, 3


18

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J = 7.2 Hz, 2 H), 2.77-2.69 (m, 1 H), 2.56-2.48 (m, 1 H), 2.35-2.26 (m, 1 H), 2.17-2.10 (m, 1 H), 1.68 (s, 3 H), 1.64 (s, 3 H), 1.47 (s, 9 H). C NMR (125 MHz, CDCl ) d 193.0, 170.9, 169.8, 131.1, 122.5, 118.6, 13

3

81.4, 55.1, 52.5, 28.0 (x3), 25.7, 23.5, 23.1, 21.5, 17.7. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 17

26

+

4

317.1723, found 317.1719. General procedure for the preparation of MBH derivative 3. DABCO (568.5 mg, 5.07 mmol) was added to a solution of aldehyde (22.7 mmol) and acrylate (45.7 mmol). The reaction mixture was stirred at room temperature until the aldehyde was completely consumed. The resulting mixture was purified by 21

column chromatography on silica gel to give Morita-Baylis-Hillman (MBH) adduct. To a mixture of MBH adduct (1.01 mmol) and acid anhydride (1.25 mmol) in CH CN (4.0 mL) was 3

added Yb(OTf) (35.3 mg, 56.9 µmol). After being stirred at 40 °C for 2 days, the reaction mixture was 22

3

filtered through a short pad of silica gel, then the filtrate was evaporated. The residue was purified by column chromatography on silica gel to give Morita-Baylis-Hillman (MBH) derivative 3. tert-Butyl 3-acetoxy-2-methylenepropionate (3a): The title compound (6.34 g, 32% yield over 2 steps 5b

from tert-butyl acrylate, 37 wt% aq. formaldehye, and acetic anhydride) was prepared according to our reported literature. tert-Butyl 3-acetoxy-2-methylenebutanoate (3b): The title compound (2.46 g, 50% yield over 2 steps 5b

from tert-butyl acrylate, acetoaldehyde, and acetic anhydride) was prepared according to our reported literature. tert-Butyl 3-benzoxy-2-methylenebutanoate (3c): The title compound (1.04 g, 55% yield over 2 steps 23

from tert-butyl acrylate, acetoaldehyde, and benzoyl chloride) was prepared according to our reported literature.

5b

Ethyl 3-acetoxy-2-methylenebutanoate (3d): The title compound (0.97 g, 40% yield over 2 steps from 24

ethyl acrylate, acetoaldehyde, and acetic anhydride) was prepared according to our reported literature.

5b

n-Hexyl 3-hydroxy-2-methylenebutanoate (MBH-3e): The title compound was prepared according to the general procedure from n-hexyl acrylate (5.99 g, 38.3 mmol), acetaldehyde (5.0 mL, 79.7 mmol), and


19


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DABCO (0.52 g, 4.64 mmol). The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 4:1) to give MBH-3e (5.45 g, 71% yield) as a colorless oil. H NMR (500 MHz, CDCl ) 1

3

d 6.26 (s, 1 H), 5.85 (s, 1 H), 4.67 (quint, J = 6.1 Hz, 1 H), 4.23 (t, J = 6.7 Hz, 2 H), 2.76 (d, J = 6.1 Hz, 1 H), 1.77-1.70 (m, 2 H), 1.47-1.33 (m, 6 H), 1.44 (d, J = 6.1 Hz, 3 H), 0.95 (t, J = 7.1 Hz, 3 H). C NMR 13

(125 MHz, CDCl ) d 166.7, 143.7, 123.9, 67.2, 65.0, 31.4, 28.5, 25.6, 22.5, 22.0, 14.0. HRMS m/z calcd 3

for C H O Na [M+Na] 223.1305, found 223.1305. 11

20

+

3

n-Hexyl 3-acetoxy-2-methylenebutanoate (3e): The title compound was prepared according to the general procedure from MBH-3e (1.58 g, 7.90 mmol), acetic anhydride (1.0 mL, 10.6 mmol), and Yb(OTf) (252.2 mg, 0.41 mmol). The crude product was purified by column chromatography on silica 3

gel (hexane/AcOEt = 8:1) to give 3e (1.67 g, 87% yield) as a pale yellow oil. H NMR (400 MHz, CDCl ) 1

3

d 6.28 (s, 1 H), 5.80 (s, 1 H), 5.71 (q, J = 6.4 Hz, 1 H), 4.17 (t, J = 6.7 Hz, 2 H), 2.07 (s, 3 H), 1.75-1.60 (m, 2 H), 1.43-1.26 (m, 6 H), 1.40 (d, J = 6.4 Hz, 3 H), 0.89 (t, J = 6.9 Hz, 3 H). C NMR (100 MHz, 13

CDCl ) d 169.7, 165.3, 141.3, 124.4, 68.2, 65.0, 31.4, 28.5, 25.6, 22.5, 21.1, 20.1, 13.9. HRMS (ESI+) 3

m/z calcd for [M+Na] C H O Na 265.1411, found 265.1410. +

13

22

4

n-Hexyl 3-benzoxy-2-methylenebutanoate (3f): The title compound was prepared according to our reported literature from MBH-3e (6.05 g, 30.2 mmol), benzoyl chloride (4.2 mL, 36.2 mmol), and pyridine (7.0 mL, 86.7 mmol). The crude product was purified by column chromatography on silica gel 5b

(hexane/AcOEt = 10:1) to give 3f (5.96 g, 65% yield) as a pale yellow oil. H NMR (500 MHz, CDCl ) d 1

3

8.08-8.04 (m, 2 H), 7.59-7.54 (m, 1 H), 7.48-7.42 (m, 2 H), 6.32 (s, 1 H), 5.97 (q, J = 6.6 Hz, 1 H), 5.90 (s, 1 H), 4.18 (t, J = 6.6 Hz, 2 H), 1.70-1.62 (m, 2 H), 1.54 (d, J = 6.6 Hz, 3 H), 1.40-1.32 (m, 2 H), 1.321.24 (m, 4 H), 0.88 (t, J = 7.0 Hz, 3 H). C NMR (125 MHz, CDCl ) d 165.4, 165.3, 141.4, 133.0, 130.3, 13

3

129.6 (x2), 128.4 (x2), 124.6, 68.9, 65.1, 31.4, 28.5, 26.6, 22.5, 20.3, 13.9. HRMS (ESI+) m/z calcd for [M+Na] C H O Na 327.1567, found 327.1569. +

18

24

4

1-Ethyl 4-n-hexyl 2-hydroxy-3-methylene-succinate (MBH-3g): The title compound was prepared according to the general procedure from n-hexyl acrylate (5.0 mL, 45.7 mmol), and ethyl glyoxylate (50 ACS Paragon Plus Environment

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wt% in toluene, 4.5 mL, 22.7 mmol). The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 4:1) to give MBH-3g (3.28 g, 28% yield) as a colorless oil. H NMR (400 MHz, 1

CDCl ) d 6.37 (s, 1 H), 5.92 (s, 1 H), 4.84 (d, J = 6.2 Hz, 1 H). 4.25 (q, J = 7.1 Hz, 2 H), 4.17 (t, J = 6.7 3

Hz, 2 H), 3.45 (d, J = 6.2 Hz, 1 H), 1.71-1.61 (m, 2 H), 1.42-1.23 (m, 6 H), 1.27 (t, J =7.3 Hz, 3 H), 0.89 (t, J = 6.7 Hz, 3 H). HRMS m/z calcd for C H O Na [M+Na] 281.1359, found 281.1362. +

13

22

5

1-Ethyl 4-n-hexyl 2-acetoxy-3-methylene-succinate (3g): The title compound was prepared according to the general procedure from MBH-3g (3.23 g, 12.7 mmol), acetic anhydride (1.4 mL, 14.8 mmol),and Yb(OTf) (505.5 mg, 0.81 mmol). The crude product was purified by column chromatography on silica 3

gel (hexane/AcOEt = 4:1) to give 3g (3.2 g, 95% yield) as a pale yellow oil. H NMR (400 Hz, CDCl ) d 1

3

6.50 (s, 1 H), 5.98 (s, 1 H), 5.97 (s, 1 H), 4.28-4.14 (m, 4 H), 2.17 (s, 3 H), 1.74-1.60 (m, 2 H), 1.47-1.22 (m, 6 H), 1.26 (t, J = 7.1 Hz, 3 H), 0.90 (t, J = 6.9 Hz, 3 H). C NMR (100 MHz, CDCl ) d 169.7, 167.8, 13

3

164.5, 135.1, 130.3, 70.4, 65.5, 61.8, 31.3, 28.4, 25.5, 22.5, 20.6, 14.0, 13.9. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 323.1465, found 323.1467. 15

24

6

+

General procedure for the preparation of racemic Michael adduct 4. To a suspension of sodium hydride (60 wt% in mineral oil, 1.2 equiv) in THF was added a solution of b-ketoester 2 (1.0 equiv) in THF at 0 ˚C. After 30 min, MBH derivative (1.2 equiv) in THF was added. The resulting mixture was stirred at 0 °C to room temperature. After b-ketoester 2 was completely consumed, the reaction mixture was quenched with sat. NH Cl and extracted with AcOEt. The combined organic layers were washed with 4

H O and brine, dried over MgSO , filtered, and evaporated under reduced pressure. The resulting residue 2

4

was purified by column chromatography on silica gel. Typical procedure for Michael reaction of cyclic b-ketoesters 2 with Morita-Baylis-Hillman derivatives 3 catalyzed by phase-transfer catalyst 1. In a test tube equipped with a magnetic stirring bar, b-ketoester 2, MBH derivative 3 (1.2 equiv), and the stated amount of catalyst 1 were dissolved in 8b,e

0.15 M (for condition A and B) or 0.13 M (for condition C) solution of the solvent system stated. The mixture was placed at the stated temperature. When the mixture had cooled, the stated amount of 50 wt% ACS Paragon Plus Environment

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Page 22 of 43

aqueous KOH was added and the resulting biphasic mixture was vigorously stirred. After the stated reaction time, the reaction mixture was filtered through a short pad of silica gel, then the filtrate was evaporated. The residue was purified by purified by column chromatography on silica gel to give Michael adduct 4. (1S)-tert-Butyl 1-(2’-tert-butoxycarbonyl-3’-propenyl)-2-oxo-cyclopentane-1-carboxylate (4a): The title compound was obtained by the typical procedure using b-ketoester 2a (59.6 mg, 0.32 mmol), MBH derivative 3a (74.4 mg, 0.37 mmol), 1 (20 mol%), and 50 wt% KOH (10 equiv) in 0.15 M-toluene/CHCl

3

(7:1) at −40 °C for 22 h. The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 4:1) to give 4a (74.8 mg, 72% yield, 81% ee) as a colorless oil. H NMR (500 MHz, 1

CDCl ) d 6.14 (d, J = 1.7 Hz, 1 H), 5.59-5.57 (m, 1 H), 2.95 (dd, J = 14.2, 0.8 Hz, 1 H), 2.69 (dd, J = 14.2, 3

0.9 Hz, 1 H), 2.44-2.33 (m, 2 H), 2.23-2.14 (m, 1 H), 2.01-1.85 (m, 3 H), 1.49 (s, 9 H), 1.43 (s, 9 H). C 13

NMR (125 MHz, CDCl ) d 214.3, 169.9, 166.5, 138.0, 127.6, 81.9, 80.8, 61.3, 37.8, 33.8, 32.8, 28.0 (x3), 3

27.9 (x3), 19.6. HRMS (FAB+) m/z calcd for C H O [M+H] 325.2015, found 325.2030. Anal. Calcd for 18

29

5

+

C H O : C, 66.64; H, 8.70. Found: C, 66.74; H, 8.52. The ee was determined by HPLC using a Chiralpak 18

28

5

IC column (hexane/EtOH = 100:1, flow rate 1.0 mL/min, l = 230 nm), tr (minor) = 9.0 min, tr (major) = 13.7 min. [a] = −4.6 (c 7.38, CHCl , 81% ee). 27

D

3

(1S)-tert-Butyl 1-(2’-tert-butoxycarbonyl-2’-propenyl)-2-oxo-cyclohexane-1-carboxylate (4b): The title compound was obtained by the typical procedure using b-ketoester 2b (53.6 mg, 0.27 mmol), MBH derivative 3a (55.6 mg, 0.28 mmol), 1 (15 mol%), and 50 wt% KOH (5 equiv) in 0.15 M-o-xylene/CHCl

3

(7:1) at −20 °C for 16 h. The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 5:1) to give 4b (66.9 mg, 73% yield, 91% ee) as a colorless oil. H NMR (500 MHz, 1

CDCl ) d 6.11 (d, J = 1.6 Hz, 1 H), 5.50-5.47 (m, 1 H), 2.87 (d, J = 1.42 Hz, 1 H), 2.71 (d, J = 14.2 Hz, 1 3

H), 2.49-2.41 (m, 2 H), 2.37 (dq, J = 2.8, 13.6 Hz, 1 H), 2.04-1.95 (m, 1 H), 1.76-1.54 (m, 4 H), 1.47 (s, 9 H), 1.44 (s, 9 H). C NMR (125 MHz, CDCl ) d 207.1, 170.0, 166.5, 137.9, 127.4, 82.1, 80.5, 61.7, 41.1, 13

3

35.5, 34.8, 28.0 (x3), 27.9 (x3), 27.4, 22.6. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 361.1986, +

19


22

30

5

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found 361.1983. The ee was determined by HPLC using a Chiral IC column (hexane/EtOH = 100/1, flow rate 1.0 mL/min, l = 230 nm), tr (minor) = 7.4 min, tr (major) = 9.2 min. [a] = −64.0 (c 5.89, CHCl , 27

D

3

91% ee). (1S)-tert-Butyl 1-(2’-tert-butoxycarbonyl-2’-propenyl)-2-oxo-3-cyclohexene-1-carboxylate (4c): The title compound was obtained by the typical procedure using b-ketoester 2c (55.7 mg, 0.28 mmol), MBH derivative 3a (68.4 mg, 0.34 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.15 M-o-xylene/CHCl

3

(7:1) at −20 °C for 22 h. The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 5:1) to give 4c (64.0 mg, 68% yield, 92% ee) as a colorless oil. H NMR (500 MHz, 1

CDCl ) d 6.88-6.82 (m, 1 H), 6.16 (d, J = 1.8 Hz, 1 H), 6.03 (ddd, J = 10.1, 2.6, 1.4 Hz, 1 H), 5.61-5.57 3

(m, 1 H), 3.02 (d, J = 13.9 Hz, 1 H), 2.82 (d, J = 13.9 Hz 1 H), 2.52-2.43 (m, 1 H), 2.42-2.36 (m, 1 H), 2.35-2.27 (m, 1 H), 1.89-1.78 (m, 1 H), 1.49 (s, 9 H), 1.41 (s, 9 H). C NMR (125 MHz, CDCl ) d 195.3, 13

3

169.8, 166.6, 148.7, 137.8, 129.4, 128.0, 82.1, 80.5, 58.1, 33.8, 30.1, 28.0 (x3), 27.8 (x3), 23.9. HRMS (ESI+) m/z C H O Na [M+Na] 359.1829, found 359.1826. The ee was determined by HPLC using a 19

28

+

5

Chiral IC column (hexane/EtOH = 10/1, flow rate 1.0 mL/min, l = 230 nm), tr (minor) = 4.3 min, tr (major) = 9.8 min. [a] = −25.3 (c 6.05, CHCl , 92% ee). 28

(1S)-tert-Butyl

D

3

1-(2’-tert-butoxycarbonyl-2’-propenyl)-3-methyl-2-oxo-3-cyclohexene-1-carboxylate

(4d): The title compound was obtained by the typical procedure using b-ketoester 2d (43.0 mg, 0.20 mmol), MBH derivative 3a (52.6 mg, 0.25 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.15 Mo-xylene/CHCl (7:1) at −20 °C for 22 h. The crude product was purified by column chromatography on 3

silica gel (hexane/AcOEt = 10:1) to give 4d (60.0 mg, 84% yield, 91% ee ) as a colorless oil. H NMR 1

(500 MHz, CDCl ) d 6.59-6.54 (m, 1 H), 6.15 (d, J = 1.8 Hz, 1 H), 5.61-5.56 (m, 1 H), 3.03 (d, J = 14.1 3

Hz, 1 H), 2.79 (d, J = 14.1 Hz, 1 H), 2.48-2.34 (m, 2 H), 2.29-2.20 (m, 1 H), 1.87-1.80 (m, 1 H), 1.80 (s, 3 H), 1.48 (s, 9 H), 1.40 (s, 9 H). C NMR (125 MHz, CDCl ) d 196.0, 170.2, 166.7, 142.8, 138.0, 135.5, 13

3

127.9, 81.9, 80.5, 57.8, 33.8, 30.6, 28.0 (x3), 27.9 (x3), 23.6, 16.7. HRMS (ESI+) m/z calcd for C H O Na 20

30

5

[M+Na] 373.1986, found 373.1992. The ee was determined by HPLC using a Chiral IC column +


23


Page 24 of 43

(hexane/EtOH = 100/1, flow rate 1.0 mL/min, l = 230 nm), tr (major) = 14.4 min, tr (minor) = 15.8 min. [a] = −34.7 (c 6.65, CHCl , 92% ee). 28

3

D

(1S)-tert-Butyl 1-(2’-tert-butoxycarbonyl-2’-propenyl)-4-methoxy-2-oxo-3-cyclohexene-1-carboxylate (4e): The title compound was obtained by the typical procedure using b-ketoester 2e (57.6 mg, 0.25 mmol), MBH derivative 3a (63.4 mg, 0.32 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.15 M-oxylene/CHCl (7:1) at −20 °C for 20 h. The crude product was purified by column chromatography on 3

silica gel (hexane/AcOEt = 5:1) to give 4e (86.3 mg, 93% yield, 94% ee) as a colorless oil. H NMR (500 1

MHz, CDCl ) d 6.16 (d, J = 1.8 Hz, 1 H), 5.63-5.61 (m, 1 H), 5.38 (d, J = 1.3 Hz, 1 H), 3.68 (s, 3 H), 3.03 3

(d, J = 14.1 Hz, 1 H), 2.88 (d, J = 14.1 Hz, 1 H), 2.66-2.55 (m, 1 H), 2.37-2.28 (m, 2 H), 1.88-1.80 (m, 1 H), 1.88 (s, 9 H), 1.42 (s, 9 H). C NMR (125 MHz, CDCl ) d 194.8, 177.1, 170.1, 166.8, 137.9, 128.2, 13

3

101.9, 81.9, 80.5, 57.3, 55.7, 33.8, 28.3, 28.0 (x3), 27.9 (x3), 26.4. HRMS (ESI+) m/z calcd for C H O Na 20

30

6


(hexane/EtOH = 10/1, flow rate 1.0 mL/min, l = 254 nm), tr (minor) = 8.4 min, tr (major) = 13.0 min. [a] = −43.0 (c 8.19, CHCl , 94% ee). 28

D

3

(1S)-tert-Butyl

1-(2’-tert-butoxycarbonyl-2’-propenyl)-4-methoxy-3-(3’-methyl-2’-butenyl)-2-oxo-3-

cyclohexene-1-carboxylate (4f): The title compound was obtained by the typical procedure using bketoester 2f (50.9 mg, 0.17 mmol), MBH derivative 3a (45.5 mg, 0.23 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.15 M-o-xylene/CHCl (7:1) at −20 °C for 22 h. The crude product was purified by 3

column chromatography on silica gel (hexane/AcOEt = 3:1) to give 4f (53.3 mg, 71% yield, 90% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.15 (d, J = 1.8 Hz, 1 H), 5.60-5.57 (m, 1 H), 5.03 (t, J = 7.3 1

3

Hz, 1 H), 3.76 (s, 3 H), 3.05 (d, J = 13.9 Hz, 1 H), 3.02 (dd, J = 7.3, 14.1 Hz, 1 H), 2.91 (dd, J = 7.3, 14.1 Hz, 1 H), 2.81 (d, J = 13.8 Hz, 1 H), 2.72 (ddd, J = 5.3, 10.5, 18.2 Hz, 1 H), 2.51 (ddd, J = 2.3, 5.3, 18.2 Hz, 1 H), 2.37 (ddd, J = 2.3, 5.7, 13.6 Hz, 1 H), 1.77 (ddd, J = 5.7, 10.5, 13.6 Hz, 1 H), 1.69 (s, 3 H), 1.63 (s, 3 H), 1.48 (s, 9 H), 1.38 (s, 9 H). C NMR (125 MHz, CDCl ) d 193.3, 169.8, 169.6, 166.8, 138.0, 13

3

130.9, 128.0, 122.5, 118.4, 81.6, 80.5, 56.0, 54.9, 34.2, 28.0 (x3), 27.8 (x3), 27.3, 25.7, 22.6, 22.0, 17.7. ACS Paragon Plus Environment

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HRMS (ESI+) m/z calcd for C H O Na [M+Na] 457.2561, found 457.2561. The ee was determined by 25

38

+

6

HPLC using a Chiral IC column (hexane/EtOH = 100/1, flow rate 1.0 mL/min, l = 254 nm), tr (minor) = 19.7 min, tr (major) = 25.2 min. [a] = −5.5 (c 7.71, CHCl , 90% ee). 29

D

3

(1S)-tert-Butyl 1-(2’-tert-butoxycarbonyl-2’-butenyl)-2-oxo-cyclopentane-1-carboxylate (4g): The title compound was obtained by the typical procedure using b-ketoester 2a (50.9 mg, 0.28 mmol), MBH derivative 3c (93.8 mg, 0.34 mmol), 1 (20 mol%), and 50 wt% KOH (10 equiv) in 0.15 M-o-xylene/CHCl

3

(7:1) at −20 °C for 28 h. The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 20:1) to give a mixture of E- and Z-4g (35.1 mg, 37% yield, E : Z = 4 : 1, E: 77% ee, Z: 86% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.83 (q, J = 7.2 Hz, E-1 H), 5.96 (q, J = 7.2 Hz, 25 1

3

Z-1 H), 2.97 (d, J = 14.2 Hz, E-1 H), 2.85 (d, J = 14.2 Hz, 1 H), 2.68 (d, J = 14.2 Hz, Z-1 H), 2.41-2.28 (m, 2 H), 2.21-2.08 (m, 1 H), 1.96-1.85 (m, 3 H), 1.86 (d, J = 7.2 Hz, Z-3 H), 1.80 (d, J = 7.2 Hz, E-3 H), 1.61 (s, Z-9 H), 1.47 (s, E-9 H), 1.42 (s, 9 H). C NMR (125 MHz, CDCl ) d 214.8, 170.6, 167.5, 139.5, 13

3

130.8, 81.8, 80.3, 60.7, 37.8, 33.4, 29.0, 28.0 (x3), 27.8 (x3), 19.8, 14.9. HRMS (ESI+) m/z C H O Na 26

19

30

5


(hexane/EtOH = 100/1, flow rate 1.0 mL/min, l = 230 nm), E-4g: tr (minor) = 11.5 min, tr (major) = 14.6 min, Z-4g: tr (minor) = 16.7 min, tr (major) = 19.5 min. (1S)-tert-Butyl 1-(2’-ethoxylcarbonyl-2’-butenyl)-2-oxo-cyclopentane-1-carboxylate (4h): The title compound was obtained by the typical procedure using b-ketoester 2a (54.3 mg, 0.29 mmol), MBH derivative 3d (63.7 mg, 0.34 mmol), 1 (20 mol%), and 50 wt% KOH (10 equiv) in 0.15 M-o-xylene/CHCl

3

(7:1) at −20 °C for 28 h. The crude product was purified by column chromatography on silica gel (hexane/AcOEt 10:1) to give a mixture of E- and Z-4h (46.3 mg, 51% yield, E : Z = 3 : 2, E: 63% ee, Z: 78% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.93 (q, J = 7.2 Hz, E-1 H), 6.06 (q, J = 7.2 Hz, 25 1

3

Z-1 H), 4.23-4.13 (m, 2 H), 3.02 (d, J = 14.4 Hz, E-1 H), 2.90 (d, J = 14.2 Hz, Z-1 H), 2.86 (d, J = 1.4 Hz, E-1 H), 2.69 (d, J = 14.2 Hz, Z-1 H), 2.42-2.28 (m, 2 H), 2.20-2.09 (m, 1 H), 1.97-1.84 (m, 3 H), 1.92 (d, J = 7.2 Hz, Z-3 H), 1.84 (d, J = 7.2 Hz, E-3 H), 1.43 (s, E-9 H), 1.42 (s, Z-9 H), 1.31 (t, J = 6.0 Hz, Z-3 ACS Paragon Plus Environment

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H), 1.28 (t, J = 7.1 Hz, E-3 H). C NMR (125 MHz, CDCl ) d 214.8 (E), 214.6 (Z), 170.5 (E), 169.9 (Z), 13

3

168.2 (E), 168.1 (Z), 140.6 (Z), 139.8 (E), 129.5 (E), 128.9 (Z), 81.9 (E), 81.9 (Z), 61.5 (E), 60.7 (Z), 60.5 (E), 60.3 (Z), 37.8 (Z), 37.7 (E), 36.7 (Z), 33.4 (E), 32.5 (Z), 29.0 (E), 27.8 (x3), 19.8 (E), 19.6 (Z), 15.8 (Z), 14.9 (E), 14.2. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 333.1673, found 333.1674. The ee +

17

26

5

was determined by HPLC using a Chiral IC column (hexane/EtOH = 30/1, flow rate 1.0 mL/min, l = 230 nm), E-4h: tr (minor) = 11.6 min, tr (major) = 15.8 min, Z-4h: tr (minor) = 11.9 min, tr (major) = 15.7 min.

27

(1S)-tert-Butyl 1-(2’-n-hexylcarbonyl-2’-butenyl)-2-oxo-cyclopentane-1-carboxylate (4i): The title compound was obtained by the typical procedure using b-ketoester 2a (45.6 mg, 0.25 mmol), MBH derivative 3f (92.3 mg, 0.30 mmol), 1 (20 mol%), and 50 wt% KOH (10 equiv) in 0.15 M-toluene/CHCl

3

(7:1) at −40 °C for 24 h. The crude product was purified by column chromatography on silica gel (hexane/AcOEt = 10:1) to give a mixture of E- and Z-4i (65.5 mg, 71% yield, E : Z = 1.9 : 1, E: 81% ee, Z: 81% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.92 (q, J =7.2 Hz, E-1 H), 6.06 (q, J = 7.2 25 1

3

Hz, Z-1 H), 4.18-4.04 (m, 2 H), 3.03 (d, J = 14.5 Hz, E-1 H), 2.90 (d, J = 14.2 Hz, Z-1 H), 2.85 (d, J = 14.5 Hz, E-1 H), 2.69 (d, J = 14.2 Hz, Z-1 H), 2.42-2.29 (m, 2 H), 2.22-2.08 (m, 1 H), 1.98-1.80 (m, 3 H), 1.91 (d, J = 7.2 Hz, Z-3 H), 1.83 (d, J = 7.2 Hz, E-3 H), 1.73-1.61 (m, 2 H), 1.42 (s, 9 H), 1.41-1.27 (m, 6 H), 0.88 (t, J = 6.5 Hz, 3 H). C NMR (125 MHz, CDCl ) d 214.7 (E), 214.5 (Z), 170.5 (E), 169.9 (Z), 13

3

168.3, 140.5 (E), 139.7 (Z), 129.6 (E), 129.0 (Z), 81.9, 74.8 (E), 64.6 (Z, x2), 60.7 (E), 37.8 (Z), 37.7 (E), 36.6 (Z), 33.3 (E), 32.4 (Z), 31.4, 29.0 (E), 28.6 (E), 28.6 (Z), 27.9 (Z, x3), 27.8 (E, x3), 25.7 (Z), 25.6 (E), 22.5, 19.8 (E), 19.6 (Z), 15.8 (Z), 14.9 (E), 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 389.2299, +

21

34

5

found 389.2298. The ee was determined by HPLC using a Chiral IC column (hexane/EtOH = 20/1, flow rate 1.0 mL/min, l = 230 nm), E-4i: tr (minor) = 8.0 min, tr (major) = 10.5 min, Z-4i: tr (minor) = 8.1 min, tr (major) = 9.7 min.

27

(1S)-tert-Butyl 1-(2’-n-hexylcarbonyl-2’-butenyl)-2-oxo-cyclohexane-1-carboxylate (4j): The title compound was obtained by the typical procedure using b-ketoester 2b (54.5 mg, 0.27 mmol), MBH ACS Paragon Plus Environment

26

Page 27 of 43 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


derivative 3f (95.0 mg, 0.31 mmol), 1 (20 mol%), and Cs CO (3 equiv) in 0.15 M-o-xylene/CHCl (7:1) 2

3

3

at 0 °C for 84 h. The crude product was purified by column chromatography on silica gel (hexane/AcOEt 20:1) to give a mixture of E- and Z-4j (52.3 mg, 51% yield, E : Z = 1.2 : 1, E: 81% ee, Z: 91% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.87 (q, J = 7.2 Hz, E-1 H), 5.96 (q, J = 7.3 Hz, Z-1 H), 4.14 25 1

3

(t, J = 6.7 Hz, Z-2 H), 4.08 (t, J = 6.8 Hz, E-2 H), 3.15 (d, J = 14.4 Hz, E-1 H), 2.83 (d, J = 14.0 Hz, Z-1 H), 2.71 (d, J = 14.0 Hz, Z-1 H), 2.69 (d, J = 14.4 Hz, E-1 H), 2.51-2.32 (m, 3 H), 2.21 (t, J = 7.4 Hz, Z1 H), 2.03-1.96 (m, E-1 H), 1.89 (d, J = 7.3 Hz, Z-3 H), 1.78 (d, J = 7.2 Hz, E-3 H), 1.75-1.54 (m, 5 H), 1.48-1.23 (m, 7 H), 1.44 (s, 9 H), 0.88 (t, J = 7.1 Hz, 3 H). C NMR (125MHz, CDCl ) d 207.2 (Z), 207.1 13

3

(E), 170.2 (E), 170.1 (E), 168.4 (Z), 168.2 (Z), 139.6 (Z), 138.6 (E), 129.7 (E), 129.1 (Z), 82.2 (Z), 82.0 (E), 64.6 (E), 64.5 (Z), 62.1 (Z), 61.4 (E), 41.1 (Z), 41.0 (E), 38.1(Z), 36.1 (E), 35.5 (E), 35.4 (Z), 31.4 (E), 29.5 (Z), 28.6, 28.1 (Z, x3), 27.9 (E, x3), 27.4, 25.7, 22.8 (E), 22.6 (Z), 22.5, 15.7 (Z), 15.3 (E), 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 403.2455, found 403.2462. The ee was determined by 22

36

5

+

HPLC using a Chiral IC column (hexane/EtOH = 40/1, flow rate 1.0 mL/min, l = 230 nm), E-4j: tr (minor) = 11.8 min, tr (major) = 14.3 min, Z-4j: tr (minor) = 10.8 min, tr (major) = 12.2 min.

27

(1S)-tert-Butyl 1-(2’-n-hexylcarbonyl-2’-butenyl)-2-oxo-3-cyclohexene-1-carboxylate (4k): The title compound was obtained by the typical procedure using b-ketoester 2c (46.3 mg, 0.24 mmol), MBH derivative 3f (88.1 mg, 0.29 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.15 M-o-xylene/CHCl

3

(7:1) at −20 °C for 40 h. The crude product was purified by column chromatography on silica gel (hexane/AcOEt 20:1) to give a mixture of E- and Z-4k (57.6 mg, 63% yield, E : Z = 1 : 1.3, E: 95% ee, Z: 91% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.92 (q, J = 7.3 Hz, E-1 H), 6.86-6.79 (m, 1 H), 25 1

3

6.09-5.99 (m, 1 H, Z-1 H), 4.14 (t, J = 7.0 Hz, Z-2 H), 4.09 (t, J = 6.8 Hz, E-2 H), 3.29 (d, J = 14.3 Hz, E-1 H), 2.94 (d, J = 13.9 Hz, Z-1 H), 2.83 (d, J = 13.9 Hz, Z-1 H), 2.76 (d, J = 14.3 Hz, E-1 H), 2.55-2.22 (m, 3 H), 1.95-1.77 (m, 1 H), 1.91 (d, J = 7.3 Hz, Z-3 H), 1.82 (d, J = 7.2 Hz, E-3 H), 1.71-1.61 (m, 2 H), 1.49-1.23 (m, 6 H), 1.40 (s, E-9 H), 1.39 (s, Z-9 H), 0.89 (t, J = 7.1 Hz, 3 H). C NMR (125MHz, CDCl ) 13

3

d 195.7 (E), 195.5 (Z), 169.9 (Z), 169.8 (E), 168.5 (Z), 168.3 (E), 148.7 (Z), 148.4 (E), 140.1 (Z), 139.4 ACS Paragon Plus Environment

27


Page 28 of 43

(E), 129.5, (Z), 129.4 (E, x2), 128.9 (Z), 82.1 (E), 82.0 (Z), 64.7 (E), 64.5 (Z), 58.3 (Z), 57.5 (E), 37.1 (Z), 31.4, 31.1 (E), 30.1 (E), 29.0 (Z), 28.6, 27.8 (Z, x3), 27.7 (E, x3), 25.7, 24.1 (E), 24.0 (Z), 22.5, 15.8 (Z), 15.2 (E), 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 401.2299, found 401.2297. The ee was +

22

34

5

determined by HPLC using a Chiral IC3 column (hexane/EtOH = 10/1, flow rate 0.5 mL/min, l = 230 nm), E-4k: tr (minor) = 22.5 min, tr (major) = 43.6 min, Z-4k: tr (minor) = 20.4 min, tr (major) = 41.2 min. (1S)-tert-Butyl 1-(2’-n-hexylcarbonyl-2’-butenyl)-3-methyl-2-oxo-3-cyclohexene-1-carboxylate (4l): The title compound was obtained by the typical procedure using b-ketoester 2d (45.4 mg, 0.22 mmol), MBH derivative 3f (82.2 mg, 0.27 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.15 M-oxylene/CHCl (7:1) at −20 °C for 40 h. The crude product was purified by column chromatography on 3

silica gel (hexane/AcOEt 10:1) to give a mixture of E- and Z-4l (51.6 mg, 61% yield, E : Z = 1 : 1, E: 85% ee, Z: 90% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.91 (q, J = 7.2 Hz, E-1 H), 6.57-6.49 (m, 25 1

3

1 H), 6.04 (q, J = 7.2 Hz, Z-1 H), 6.05 (t, J = 6.8 Hz, Z-2 H), 6.03 (t, J = 6.8 Hz, E-2 H), 3.29 (d, J = 14.4 Hz, E-1 H), 2.95 (d, J = 13.9 Hz, Z-1 H), 2.81 (d, J = 13.9 Hz, Z-1 H), 2.73 (d, J = 14.4 Hz, E-1 H), 2.472.13 (m, 3 H), 1.91 (d, J = 7.2 Hz, Z-3 H), 1.88-1.76 (m, 1 H), 1.82 (d, J = 7.2 Hz, E-3 H), 1.81 (bs, E-3 H), 1.79 (bs, Z-3 H), 1.71-1.61 (m, 2 H), 1.41-1.26 (m, 6 H), 1.39 (s, Z-9 H), 1.37 (s, E-9 H), 0.89 (t, J = 7.0 Hz, 3 H). C NMR (125 MHz, CDCl ) d 196.4 (E), 196.2, (Z), 170.2 (Z), 169.9 (E), 168.5 (Z), 168.3 13

3

(E), 142.7 (Z), 142.4 (E), 139.8 (Z), 139.2 (E), 135.6 (E), 135.5 (Z), 129.7 (E), 129.1 (Z), 81.9 (E), 81.8 (Z), 64.6 (E), 64.5 (Z), 58.0 (Z), 57.2 (E), 37.1 (Z), 31.4 (E x2, Z), 30.5 (Z), 29.0 (E), 28.6, 27.8 (Z, x3), 27.7 (E, x3), 25.7, 23.8 (E), 23.7 (Z), 22.5 (E,Z), 16.8 (E), 16.6 (Z), 15.7 (Z), 15.2 (E), 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 415.2455, found 415.2466. The ee was determined by HPLC using a 23

36

5

+

Chiral IC column (hexane/EtOH = 10/1, flow rate 1.0 mL/min, l = 254 nm), E-4l: tr (major) = 7.1 min, tr (minor) = 9.2 min, Z-4l: tr (major) = 8.4 min, tr (minor) = 10.2 min. (1S)-tert-Butyl

1-(2’-n-hexylcarbonyl-2’-butenyl)-4-methoxy-2-oxo-3-cyclohexene-1-carboxylate

(4m): The title compound was obtained by the typical procedure using b-ketoester 2e (43.8 mg, 0.22 ACS Paragon Plus Environment

28

Page 29 of 43 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mmol), MBH derivative 3f (87.4 mg, 0.29 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.15 Mo-xylene/CHCl (7:1) at −20 °C for 40 h. The crude product was purified by column chromatography on 3

silica gel (hexane/AcOEt 3:1) to give a mixture of E- and Z-4m (66.9 mg, 74% yield, E : Z = 1 : 1.3, E: 81% ee, Z: 93% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.89 (q, J = 7.2 Hz, E-1 H), 6.07 (q, 25 1

3

J = 7.2 Hz, Z-1 H), 5.37 (d, J = 1.2 Hz, E-1 H), 5.35 (d, J = 1.1 Hz, Z-1 H), 4.12 (t, J = 6.9 Hz, Z-2 H), 4.08 (t, J = 6.8 Hz, E-2 H), 3.66 (s, 3 H), 3.28 (d, J = 14.2 Hz, E-1 H), 2.96 (d, J = 13.9 Hz, Z-1 H), 2.86 (d, J = 13.9 Hz, Z-1 H), 2.80 (d, J = 14.2 Hz, E-1 H), 2.64-2.49 (m, 1 H), 2.39-2.20 (m, 2 H), 1.91-1.76 (m, 1 H), 1.89 (d, J = 7.2 Hz, Z-3 H), 1.82 (d, J = 7.2 Hz, E-3 H), 1.70-1.58 (m, 2 H), 1.44-1.24 (m, 6 H), 1.40 (s, Z-9 H), 1.38 (s, E-9 H), 0.88 (t, J = 6.8 Hz, 3 H). C NMR (125 MHz, CDCl ) d 195.2 (Z), 194.9 13

3

(E), 177.0 (Z), 176.7 (E), 170.1, 168.6 (Z), 168.5 (E), 140.3 (Z), 140.0 (E), 129.7 (Z), 129.1 (E), 101.9 (E), 101.8 (Z), 81.9 (E), 81.8 (Z), 64.7 (E), 64.5 (Z), 57.4 (E), 56.6 (Z), 55.7, 37.2 (Z), 31.4, 29.4, 28.6, 28.3 (E), 27.9 (Z, x3), 27.8 (E, x3), 26.6 (E), 26.5 (Z), 25.7, 22.5, 15.8 (Z), 15.2 (E), 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 431.2404, found 431.2405. The ee was determined by HPLC using a Chiral +

23

36

6

IC column (hexane/EtOH = 5/1, flow rate 0.85 mL/min, l = 254 nm), E-4m: tr (minor) = 15.3 min, tr (major) = 23.8 min, Z-4m: tr (minor) = 12.8 min, tr (major) = 16.3 min.

27

(1S)-tert-Butyl

1-(2’-n-hexylcarbonyl-2’-butenyl)-4-methoxy-3-(3’-methyl-2’-butenyl)-(2-oxo-3-

cyclohexene-1-carboxylate (4n): The title compound was obtained by the typical procedure using bketoester 2f (47.3 mg, 0.16 mmol), MBH derivative 3f (58.4 mg, 0.19 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.15 M-o-xylene/CHCl (7:1) at −20 °C for 40 h. The crude product was purified by 3

column chromatography on silica gel (hexane/AcOEt 5:1) to give a mixture of E- and Z-4n (49.9 mg, 65% yield, E : Z = 1 : 1.1, E: 73% ee, Z: 87% ee) as a colorless oil. H NMR (500 MHz, CDCl ) d 6.92 25 1

3

(q, J = 7.2 Hz, E-1 H), 6.05 (q, J = 7.2 Hz, Z-1 H), 5.06 (t, J = 7.2 Hz, E-1 H), 5.02 (t, J = 7.2 Hz, Z-1 H), 4.24-4.09 (m, 2 H), 3.76 (s, Z-3 H), 3.74 (s, E-3 H), 3.34 (d, J = 14.4 Hz, E-1 H), 3.07-2.97 (m, 1 H, Z-1 H), 2.96-2.87 (m, 1 H), 2.83 (d, J = 14.0 Hz, Z-1 H), 2.73-2.59 (m, 1 H), 2.73 (d, J = 14.4 Hz, E-1 H), 2.54-2.30 (m, 2 H), 1.91 (d, J = 7.2 Hz, Z-3 H), 1.85-1.55 (m, 3 H), 1.81 (d, J = 7.2 Hz, E-3 H), 1.70 (s, ACS Paragon Plus Environment

29


Page 30 of 43

E-3 H), 1.69 (s, Z-3 H), 1.63 (s, E-3 H), 1.61 (s, Z-3 H), 1.52-1.22 (m, 6 H), 1.37 (s, Z-9 H), 1.36 (s, E-9 H), 1.30 (t, J = 7.0 Hz, Z-3 H), 1.28 (t, J = 7.2 Hz, E-3 H). C NMR (125 MHz, CDCl ) d 193.9 (E), 193.5 13

3

(Z), 169.9, 169.5 (Z), 169.3 (E), 168.2, 140.1 (E), 139.6 (Z), 130.9 (E), 130.8 (Z), 129.8 (E), 129.0 (Z), 122.5, 118.5 (Z), 118.4 (E), 81.7 (E), 81.5 (Z), 60.4 (E), 60.2 (Z), 56.1 (Z), 55.3 (E), 54.9, 37.4, 29.4, 28.4, 27.8, 27.7 (x3), 27.4, 25.7, 22.8 (E), 22.6 (Z), 22.2 (E), 22.0 (Z), 17.7, 15.7, 15.3, 14.2. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 499.30301, found 499.30252. The ee was determined by HPLC using a +

28

44

6

Chiral IC column (hexane/EtOH = 10/1, flow rate 0.95 mL/min, l = 254 nm), E-4n: tr (minor) = 13.9 min, tr (major) = 16.4 min, Z-4n: tr (minor) = 11.0 min, tr (major) = 12.9 min. (1S)-tert-Butyl

1-(3’-ethoxycarbonyl-2’-n-hexylcarbonyl-2’-propenyl)-2-oxo-3-cyclohexene-1-

carboxylate (4o): The title compound was obtained by the typical procedure using b-ketoester 2c (41.1 mg, 0.21 mmol), MBH derivative 3g (74.9 mg, 0.25 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.13 M-o-xylene/toluene/CHCl (7:1:1) at −40 °C for 23 h. The crude product was purified by column 3

chromatography on silica gel (hexane/AcOEt 10:1) to give E- and Z-4o as a colorless oil, respectively (E: 6.4 mg, Z: 80.7 mg, 90% yield, E : Z = 1 : 8.8, E: 86% ee, Z: 91% ee). E-4o: H NMR (400 MHz, 25

1

CDCl ) d 6.84-6.78 (m, 1 H), 6.76 (s, 1 H), 6.04 (ddd, J = 1.2, 2.7, 10.1 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 3

H), 4.14 (t, J = 6.8 Hz, 2 H), 3.63 (d, J = 13.3 Hz, 1 H), 3.40 (d, J = 13.3 Hz, 1 H), 2.45-2.18 (m, 3 H), 2.02-1.93 (m, 1 H), 1.73-1.63 (m, 2 H), 1.43-1.24 (m, 6 H), 1.38 (s, 9 H), 1.30 (t, J = 7.1 Hz, 3 H), 0.89 (t, J = 7.0 Hz, 3 H). C NMR (100 MHz, CDCl ) d 195.1, 169.7, 167.2, 165.6, 148.0, 144.5, 129.4, 128.4, 13

3

82.4, 65.7, 60.7, 57.3, 31.4, 31.1, 29.8, 28.4, 27.7 (x3), 25.5, 23.9, 22.5, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 459.2353, found 459.2352. The ee was determined by HPLC using a Chiral +

24

36

7

IC column (hexane/EtOH = 3/1, flow rate 1.2 mL/min, l = 254 nm), tr (minor) = 5.8 min, tr (major) = 10.4 min. Z-4o: H NMR (400 MHz, CDCl ) d 6.93-6.86 (m, 1 H), 6.05 (ddd, J = 1.1, 2.6, 10.1 Hz, 1 H), 1

3

5.92 (s, 1 H), 4.20-4.11 (m, 4 H), 3.12 (d, J = 13.8 Hz, 1 H), 2.77 (d, J = 13.8 Hz, 1 H), 2.56-2.43 (m, 1 H), 2.40-228 (m, 2 H), 2.18-2.08 (m, 1 H), 1.71-1.62 (m, 2 H), 1.52-1.22 (m, 6 H), 1.41 (s, 9 H), 1.26 (t, J = 7.0 Hz, 3 H), 0.87 (t, J = 7.0 Hz, 3 H). C NMR (100 MHz, CDCl ) d 194.4, 169.8, 168.3, 164.5, 149.0, 13

3


30

Page 31 of 43 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


145.1, 129.1, 124.6, 82.7, 65.7, 60.8, 57.4, 37.9, 31.4, 29.9, 28.2, 27.8 (x3), 25.6, 23.9, 22.5, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 459.2353, found 459.2352. The ee was determined by +

24

36

7

HPLC using a Chiral IC column (hexane/EtOH = 3/1, flow rate 1.2 mL/min, l = 254 nm), tr (minor) = 7.5 min, tr (major) = 11.3 min. [a] = −46.7 (c 5.15, CHCl , 91% ee). 29

D

3

(1S)-tert-Butyl 1-(3’-ethoxycarbonyl-2’-n-hexylcarbonyl-2’-propenyl)-3-methyl-2-oxo-3-cyclohexene1-carboxylate (4p): The title compound was obtained by the typical procedure using b-ketoester 2d (43.5 mg, 0.21 mmol), MBH derivative 3g (75.2 mg, 0.25 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.13 M-o-xylene/toluene/CHCl (7:1:1) at −40 °C for 23 h. The crude product was purified by column 3

chromatography on silica gel (hexane/AcOEt 10:1) to give E- and Z-4p as a colorless oil, respectively (E: 16.7 mg, Z: 68.6 mg, 94% yield, E : Z = 1 : 5.2, E: 82% ee, Z: 89% ee). E-4p: H NMR (400 MHz, CDCl ) 25

1

3

d 6.76 (s, 1 H), 6.54-6.48 (m, 1 H), 4.24-4.16 (m, 2 H), 4.14 (t, J = 6.8 Hz, 2 H), 3.63 (d, J = 13.2 Hz, 1 H), 3.39 (d, J = 13.2 Hz, 1 H), 2.41-2.14 (m, 3 H), 2.04-1.83 (m, 1 H), 1.81 (s, 3 H), 1.73-1.63 (m, 2 H), 1.42-1.23 (m, 6 H), 1.36 (s, 9 H), 1.29 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 7.0 Hz, 3 H). C NMR (100 MHz, 13

CDCl ) d 195.8, 170.0, 167.2, 165.6, 144.8, 142.0, 135.6, 128.2, 82.2, 65.7, 60.6, 57.1, 31.4, 31.3, 29.7, 3

28.4, 27.7 (x3), 25.6, 23.6, 22.5, 16.7, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 25

38

+

7

473.2510, found 473.2511. The ee was determined by HPLC using a Chiral IC column (hexane/EtOH = 5/1, flow rate 1.2 mL/min, l = 254 nm), tr (minor) = 5.7 min, tr (major) = 10.1 min. Z-4p: H NMR (400 1

MHz, CDCl ) d 6.62-.6.57 (m, 1 H), 5.92 (s, 1 H), 4.20-4.08 (m, 4 H), 3.14 (d, J = 13.7 Hz, 1 H), 2.75 (d, 3

J = 13.7 Hz, 1 H), 2.51-2.36 (m, 1 H), 2.34-2.23 (m, 2 H), 2.17-2.06 (m, 1 H), 1.79 (s, 3 H), 1.71-1.61 (m, 2 H), 1.44-1.22 (m, 6 H), 1.40 (s, 9 H), 1.24 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 6.7 Hz, 3 H). C NMR (100 13

MHz, CDCl ) d 195.1, 170.2, 168.3, 164.5, 145.2, 143.2, 135.3, 124.5, 82.5, 65.7, 60.7, 57.4, 38.0, 31.4, 3

30.4, 28.2, 27.8 (x3), 25.6, 23.6, 22.5, 16.5, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 25

38

7

+

473.2510, found 473.2506. The ee was determined by HPLC using a Chiral IC column (hexane/EtOH = 10/1, flow rate 1.2 mL/min, l = 254 nm), tr (minor) = 12.2 min, tr (major) = 13.4 min. [a] = −47.3 (c 29

D

5.95, CHCl , 91% ee). 3


31


(1S)-tert-Butyl

Page 32 of 43

1-(3’-ethoxycarbonyl-2’-n-hexylcarbonyl-2’-propenyl)-4-methoxy-2-oxo-3-

cyclohexene-1-carboxylate (4q): The title compound was obtained by the typical procedure using bketoester 2e (43.2 mg, 0.19 mmol), MBH derivative 3g (71.7 mg, 0.24 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.13 M-o-xylene/toluene/CHCl (7:1:1) at −40 °C for 23 h. The crude product was 3

purified by column chromatography on silica gel (hexane/AcOEt 5:1) to give E- and Z-4q as a colorless oil, respectively (E: 3.7 mg, Z: 80.9 mg, 95% yield, E : Z = >1 : 10, E: 75% ee, Z: 89% ee). H NMR (400 25 1

MHz, CDCl ) d 6.73 (s, 1 H), 5.38 (s, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.15 (t, J = 6.8 Hz, 2 H), 3.67 (s, 3 3

H), 3.64 (d, J = 13.2 Hz, 1 H), 3.39 (d, J = 13.2 Hz, 1 H), 2.54-2.43 (m, 1 H), 2.33-2.23 (m, 2 H), 2.031.91 (m, 1 H), 1.73-1.63 (m, 2 H), 1.43-1.20 (m, 6 H), 1.39 (s, 9 H), 1.31 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 6.9 Hz, 3 H). C NMR (100 MHz, CDCl ) d 194.7, 176.4, 170.0, 167.3, 165.6, 144.9, 128.3, 101.7, 82.2, 13

3

65.7, 60.7, 56.4, 55.7, 31.4, 30.2, 29.4, 28.4, 27.8 (x3), 26.4, 25.6, 22.5, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 489.2459, found 489.2462. The ee was determined by HPLC using a Chiral 25

38

8

+

IC column (hexane/EtOH = 3/1, flow rate 1.2 mL/min, l = 254 nm), tr (minor) = 8.4 min, tr (major) = 17.3 min. Z-4q: H NMR (400 MHz, CDCl ) d 5.92 (s, 1 H), 5.38 (s, 1 H), 4.22-4.10 (m, 4 H), 3.69 (s, 3 1

3

H), 3.09 (d, J = 14.0 Hz, 1 H), 2.86 (d, J = 14.0 Hz, 1 H), 2.69-2.57 (m, 1 H), 2.40-2.24 (m, 2 H), 2.152.05 (m, 1 H), 1.73-1.63 (m, 2 H), 1.49-1.21 (m, 6 H), 1.42 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H), 0.87 (t, J = 0.9 Hz, 3 H). C NMR (100 MHz, CDCl ) d 194.0, 177.2, 169.8, 168.4, 164.5, 145.5, 124.4, 101.5, 82.4, 13

3

65.7, 60.8, 56.4, 55.8, 38.0, 31.4, 28.2, 28.0, 27.8 (x3), 26.4, 25.6, 22.5, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 489.2459, found 489.2461. The ee was determined by HPLC using a Chiral +

25

38

8

IC column (hexane/EtOH = 3/1, flow rate 1.2 mL/min, l = 254 nm), tr (minor) = 11.7 min, tr (major) = 14.0 min. [a] = −30.8 (c 9.94, CHCl , 90% ee). 29

D

(1S)-tert-Butyl

3

1-(3’-ethoxycarbonyl-2’-n-hexylcarbonyl-2’-propenyl)-4-methoxy-3-(3’-methyl-2’-

butenyl)-2-oxo-3-cyclohexene-1-carboxylate (4r): The title compound was obtained by the typical procedure using b-ketoester 2f (44.6 mg, 0.15 mmol), MBH derivative 3g (60.1 mg, 0.20 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.13 M-o-xylene/toluene/CHCl (7:1:1) at −40 °C for 23 h. The 3


32

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crude product was purified by column chromatography on silica gel (hexane/AcOEt 4:1) to give E- and Z-4r as a colorless oil, respectively (E: 3.3 mg, Z: 89.7 mg, 78% yield, E : Z > 1 : 10, E: 69% ee, Z: 89% ee). E-4r: H NMR (400 MHz, CDCl ) d 6.72 (s, 1 H), 5.06 (t, J = 7.1 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 2 H), 25

1

3

4.13 (t, J = 6.7 Hz, 2 H), 3.73 (s, 3 H), 3.61 (d, J = 13.4 Hz, 1 H), 3.39 (d, J = 13.4 Hz, 1 H), 3.03 (dd, J = 7.1, 13.7 Hz, 1 H), 2.90 (dd, J = 7.1, 13.7 Hz, 1 H), 2.61-2.43 (m, 2 H), 2.36-2.27 (m, 1 H), 1.96-1.86 (m, 1 H), 1.74-1.56 (m, 2 H), 1.70 (s, 3 H), 1.63 (s, 3 H), 1.38-1.24 (m, 6 H), 1.35 (s, 9 H), 1.28 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 7.0 Hz, 3 H). C NMR (100 MHz, CDCl ) d 193.3, 167.0, 168.9, 167.2, 165.6, 145.2, 13

3

130.8, 128.1, 122.6, 118.4, 82.0, 65.6, 60.6, 55.2, 54.9, 31.4, 30.4, 28.4, 28.2, 27.7 (x3), 26.0, 25.6, 22.6, 22.5, 22.1, 17.7, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O [M+H] 535.3265, found 535.3266. The +

30

47

8

ee was determined by HPLC using a Chiral IC column (hexane/EtOH = 5/1, flow rate 1.5 mL/min, l = 254 nm), tr (minor) = 5.0 min, tr (major) = 8.0 min. Z-4r: H NMR (400 MH, CDCl ) d 5.90 (s, 1 H), 5.00 1

3

(t, J = 7.1 Hz, 1 H), 4.20-4.10 (m, 4 H), 3.78 (s, 3 H), 3.04 (d, J = 13.9 Hz, 1 H), 2.99 (dd, J = 13.3, 7.1 Hz, 1 H), 2.92 (dd, J = 13.3, 7.1 Hz, 1 H), 2.88 (d, J = 14.0 Hz, 1 H), 2.81-2.70 (m, 1 H), 2.59-2.49 (m, 1 H), 2.42-2.34 (m, 1 H), 2.04-1.95 (m, 1 H), 1.71-1.58 (m, 4 H), 1.68 (s, 3 H), 1.62 (s, 3 H), 1.45-1.21 (m, 6 H), 1.39 (s, 9 H), 1.24 (t, J = 7.0 Hz, 3 H), 0.89 (t, J = 6.9 Hz, 3 H). C NMR (100 MHz, CDCl ) d 192.4, 13

3

169.9, 169.7, 168.4, 164.5, 145.6, 131.0, 124.2, 122.4, 118.1, 82.2, 65.7, 60.7, 55.4, 55.0, 38.2, 31.4, 28.2, 27.8, 27.7 (x3), 27.1, 25.7, 25.6, 22.5, 21.9, 17.7, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O [M+H] 30

47

8

+

535.3265, found 535.3268. The ee was determined by HPLC using a Chiral IC column (hexane/EtOH = 10/1, flow rate 1.5 mL/min, l = 254 nm), tr (major) = 14.2 min, tr (minor) = 16.4 min. [a] = −39.6 (c 29

D

7.86, CHCl , 91% ee). 3

(1S)-tert-Butyl

1-(3’-ethoxycarbonyl-2’-n-hexylcarbonyl-2’-propenyl)-2-oxo-cyclopentane-1-

carboxylate (4s): The title compound was obtained by the typical procedure using b-ketoester 2a (48.8 mg, 0.26 mmol), MBH derivative 3g (99.4 mg, 0.33 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.13 M-o-xylene/toluene/CHCl (7:1:1) at −40 °C for 23 h. The crude product was purified by column 3

chromatography on silica gel (hexane/AcOEt 10:1) to give E- and Z-4s as a colorless oil, respectively (E: ACS Paragon Plus Environment

33


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7.5 mg, Z: 79.9 mg, 78% yield, E : Z = 1 : 10, E: 69% ee, Z: 87% ee). E-4s: H NMR (400 MHz, CDCl ) 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

3

d 6.71 (s, 1H), 4.22 (q, J = 6.8 Hz, 2 H), 4.16 (t, J = 6.8 Hz, 2 H), 3.51 (d, J = 13.3 Hz, 1 H), 3.22 (d, J = 13.3 Hz, 1 H), 2.43-2.30 (m, 2 H), 2.28-2.18 (m, 1 H), 1.99-1.82 (m, 3 H), 1.73-1.63 (m, 2 H), 1.49-1.22 (m, 6 H), 1.40 (s, 9 H), 1.31 (t, J = 7.3 Hz, 3 H), 0.89 (t, J = 6.8 Hz, 3 H). C NMR (100 MHz, CDCl ) d 13

3

213.6, 169.9, 167.3, 165.7, 144.2, 128.3, 82.0, 65.8, 60.8, 60.6, 37.4, 34.0, 31.4, 30.0, 28.4, 27.8 (x3), 25.5, 22.5, 19.6, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 447.2353, found 447.2359. 23

36

+

7

The ee was determined by HPLC using a Chiral IC3 column (hexane/EtOH = 5/1, flow rate 1.2 mL/min, l = 230 nm), tr (major) = 7.6 min, tr (minor) = 11.4 min. Z-4s: H NMR (400 MHz, CDCl ) d 5.86 (s, 1 1

3

H), 4.16 (q, J = 7.2 Hz, 2 H), 4.15 (t, J = 6.8 Hz, 2 H), 2.97 (d, J = 14.5 Hz, 1 H), 2.70 (d, J = 14.5 Hz, 1 H), 2.48-2.36 (m, 2 H), 2.32-2.21 (m, 1 H), 2.09-1.91 (m, 3 H), 1.74-1.63 (m, 2 H), 1.48-1.22 (m, 6 H), 1.43 (s, 9 H), 1.26 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 6.8 Hz, 3 H). C NMR (100 MHz, CDCl ) d 213.8, 13

3

169.2, 168.3, 164.4, 145.4, 123.9, 82.6, 65.8, 60.8, 60.2, 37.3, 37.2, 31.9, 31.4, 28.2, 27.8 (x3), 25.5, 22.5, 19.5, 14.1, 14.0. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 447.2353, found 447.2358. The ee was 23

36

7

+

determined by HPLC using a Chiral IC3 column (hexane/EtOH = 5/1, flow rate 1.2 mL/min, l = 230 nm), tr (minor) = 7.8 min, tr (major) = 10.0 min. [a] = +28.5 (c 3.78, CHCl , 87% ee). 29

(1S)-tert-Butyl

D

3

1-(3’-ethoxycarbonyl-2’-n-hexylcarbonyl-2’-propenyl)-2-oxo-cyclohexane-1-

carboxylate (4t): The title compound was obtained by the typical procedure using b-ketoester 2b (48.6 mg, 0.25 mmol), MBH derivative 3g (98.0 mg, 0.33 mmol), 1 (15 mol%), and 50 wt% KOH (3 equiv) in 0.13 M-o-xylene/toluene/CHCl (7:1:1) at −40 °C for 23 h. The crude product was purified by column 3

chromatography on silica gel (hexane/AcOEt 10:1) to give E- and Z-4t as a colorless oil, respectively (E: 3.8 mg, Z: 75.6 mg, 74% yield, E : Z = >1 : 10, E: 83% ee, Z: 94% ee). E-4t: H NMR (400 MHz, CDCl ) 25

1

3

d 6.71 (s, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.14 (t, J = 7.0 Hz, 2 H), 3.43 (bs, 2 H), 2.57-2.42 (m, 2 H), 2.42-2.26 (m, 1 H), 2.05-1.92 (m, 1 H), 1.74-1.49 (m, 6 H), 1.46-1.26 (m, 6 H), 1.44 (s, 9 H), 1.31 (t, J = 7.2 Hz, 3 H), 0.90 (t, J = 6.9 Hz, 3 H). C NMR (100 MHz, CDCl ) d 206.3, 170.1, 167.2, 165.5, 144.6, 13

3

128.3, 82.6, 65.7, 61.0, 60.7, 40.9, 35.3, 31.4, 30.3, 28.4, 27.8 (x3), 27.2, 25.5, 22.7, 22.5, 14.1, 14.0. ACS Paragon Plus Environment

34

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HRMS (ESI+) m/z calcd for C H O Na [M+Na] 461.2510, found 461.2510. The ee was determined by 24

38

+

7

HPLC using a Chiral IC column (hexane/EtOH = 5/1, flow rate 1.2 mL/min, l = 240 nm), tr (minor) = 5.0 min, tr (major) = 7.9 min. Z-4t: H NMR (400 MHz, CDCl ) d 5.86 (s, 1 H), 4.16 (t, J = 6.8 Hz, 2 H), 1

3

4.15 (q, J = 7.2 Hz, 2 H), 2.89 (d, J = 13.9 Hz, 1 H), 2.74 (d, J = 13.9 Hz, 1 H), 2.55-2.34 (m, 3 H), 2.071.94 (m, 1 H), 1.82-1.54 (m, 6 H), 1.46 (s, 9 H), 1.41-1.28 (m, 6 H), 1.26 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 6.8 Hz, 3 H). C NMR (100 MHz, CDCl ) d 206.2, 169.9, 168.2, 164.5, 144.9, 124.6, 82.8, 65.6, 61.4, 13

3

60.7, 40.7, 38.8, 35.4, 31.4, 28.2, 27.8 (x3), 26.9, 25.6, 22.5 (x2), 14.0 (x2). HRMS (ESI+) m/z calcd for C H O Na [M+Na] 461.2510, found 461.2507. The ee was determined by HPLC using a Chiral IC 24

38

+

7

column (hexane/EtOH = 5/1, flow rate 1.2 mL/min, l = 240 nm), tr (minor) = 5.9 min, tr (major) = 7.9 min. [a] = −54.0 (c 6.37, CHCl , 94% ee). 29

D

3

Typical procedure for the intramolecular Michael reaction. To a solution of Michael adduct 4 (0.17 mmol) in toluene (1.5 mL) were added K CO (81.7 mg, 0.59 mmol) and TBAB (171.5 mg, 0.53 mmol), 2

3

and the mixture was heated at reflux for 19 h. After cooling, the resulting mixture was filter through a short pad of silica gel, and the filtrate was condensed. The crude product was purified by column chromatography on silica gel to give bicyclo[3.3.1]nonane 5. (1S,3R,5S)-1,3-Di-tert-butoxycarbonyl-bicyclo[3.3.1]nonane-9-one (5a): The title compound was obtained by the typical procedure using Michael adduct 4b (58.9 mg, 0.17 mmol). The crude product was purified by column chromatography on silica gel (hexane/AcOEt 10:1) to give 5a (48.9 mg, 83% yield) as a white solid. m.p. 69-71 °C. H NMR (500 MHz, C D ) d 2.99 (ddd, J = 13.6, 4.6, 2.9 Hz, 1 H), 2.39 1

6

6

(dt, J = 13.6, 4.6 Hz, 1 H), 2.34 (dq, J = 14.5, 3.4 Hz, 1 H), 2.17 (td, J = 13.5, 4.6 Hz, 1 H), 2.11 (t, J = 13.6 Hz, 1 H), 2.04-1.98 (m, 1 H), 1.76 (td, J = 13.6, 4.6 Hz, 1 H), 1.72 (dquit, J = 13.6, 2.4 Hz, 1 H), 1.63-1.52 (m, 1 H), 1.32 (s, 9 H), 1.45 (s, 9 H), 1.44-1.35 (m, 1 H), 1.31-1.25 (m, 1 H), 1.05-0.98 (m, 1 H). C NMR (125 MHz, C D ) d 213.3, 173.4, 171.7, 80.8, 80.0, 57.3, 44.0, 38.4, 37.9, 35.9, 35.7, 32.4, 13

6

6

28.1 (x3), 28.0 (x3), 16.3. HRMS (ESI+) m/z calcd for C H O Na [M+Na] 361.1985, found 361.1991. +

19

30

5

[a] = −24.9 (c 3.31, CHCl ) . 27

D

3

13


35


Page 36 of 43

(1S,3R,5S)-1,3-Di-tert-butoxycarbonyl-6-methoxy-bicyclo[3.3.1]non-6-ene-9-one

(a-5b)

(g-5b):

(1S,3S,5R)-di-tert-butoxycarbonyl-6-methoxy-bicyclo[3.3.1]non-6-ene-8-one

and

The

title

compounds were obtained by the typical procedure using Michael adduct 4e (94.2 mg, 0.26 mmol). The crude product was purified by column chromatography on silica gel (hexane/AcOEt 5:1) to give a-5b (18.3 mg, 19% yield) and g-5b (43.3 mg, 45% yield) as a colorless oil, respectively. a-5b: H NMR (500 1

MHz, CDCl ) d 4.58 (dd, J = 4.7, 2.8 Hz, 1 H), 3.54 (s, 3 H), 3.05 (dd, J = 16.6, 2.8 Hz, 1 H), 2.81 (dd, J 3

= 5.3, 2.4 Hz, 1 H), 2.73 (ddd, J = 13.6, 5.3, 2.4 Hz, 1 H), 2.63-2.58 (m, 3 H), 2.55 (dd, J = 16.6, 4.7 Hz, 1 H), 2.19-2.12 (m, 1 H), 1.50 (s, 9 H), 1.47 (s, 9 H). C NMR (125 MHz, CDCl ) d 208.0, 172.4, 170.8, 13

3

152.6, 92.8, 81.7, 80.8, 57.2, 54.8, 49.0, 37.4, 37.0, 32.7, 32.2, 28.0 (x6). HRMS (ESI+) m/z calcd for C H O Na [M+Na] 389.1935, found 389.1934. The ee was determined by HPLC using a Chiral IC 20

30

+

6

column (hexane/EtOH = 20/1, flow rate 1.0 mL/min, l = 210 nm), tr (major) = 10.5 min, tr (minor) = 12.0 min. [a] = −8.4 (c 1.21, CHCl , 93% ee). g-5b: H NMR (500 MHz, C D ) d 5.17 (s, 1 H), 3.10 (s, 3 27

1

3

D

6

6

H), 3.03 (ddd, J = 14.5, 3.4, 1.5 Hz, 1 H), 2.59-2.51 (m, 1 H), 2.56-2.53 (m, 1 H), 2.26-2.23 (m, 1 H), 2.21 (d, J = 7.3 Hz, 1 H), 1.75 (dd, J = 14.5, 7.6 Hz, 1 H), 1.45 (s, 9 H), 1.34 (s, 9 H), 1.33-1.28 (m, 1 H), 1.06 (ddd, J = 13.6, 6.6, 3.7 Hz, 1 H). C NMR (125 MHz, C D ) d 196.0, 179.7, 173.1, 172.6, 104.5, 81.1, 13

6

6

80.9, 55.9, 53.6, 37.5, 37.0, 35.1, 30.5, 28.6 (x3), 28.2 (x3), 26.5. HRMS (ESI+) m/z calcd for C H O Na 20

30

6


(hexane/EtOH = 20/1, flow rate 1.0 mL/min, l = 230 nm), tr (major) = 12.6 min, tr (minor) = 22.0 min. [a] = 124.3 (c 1.74, CHCl , 92% ee). 27

3

D

(1S,3S,5R)-Di-tert-butoxycarbony-7-bromo-6-methoxy-bicyclo[3.3.1]non-6-ene-8-one

(6).

N-

Bromosuccinimide (NBS) (259.2 mg, 1.46 mmol) was added to a solution of g-5b (102.9 mg, 0.28 mmol) in CCl (1.0 mL). After the mixture was stirred for 2 days at room temperature, the solvent was evaporated. 4

The residue was purified by column chromatography (hexane/AcOEt = 2:1) on silica gel to give 6 (44.1 mg, 35% yield) as a white solid (98% ee after recrystallization from AcOEt). m.p. 172-174 °C. H NMR 1

(400 MHz, CDCl ) d 4.08 (s, 3 H), 3.17-3.10 (m, 1 H), 2.88-2.80 (m, 1 H), 2.79-2.67 (m, 2 H), 2.61-2.53 3


36

Page 37 of 43


(m, 1 H), 1.96 (dd, J = 14.8, 7.8 Hz, 1 H), 1.83-1.74 (m, 2 H), 1.45 (s, 9 H), 1.39 (s, 9 H). C NMR (100 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

MHz, CDCl ) d 189.0, 174.0, 171.9, 170.9, 103.4, 81.6 (x2), 56.3, 53.3, 36.4, 36.3, 31.4, 29.9, 28.2 (x3), 3

27.9 (x3), 25.4. HRMS (ESI+) m/z calcd for C H O Br [M+H] 445.1220, found 445.1220. The ee was +

20

30

6

determined by HPLC using a Chiral IA column (hexane/EtOH = 5/1, flow rate 1.3 mL/min, l = 254 nm), tr (major) = 4.3 min, tr (minor) = 4.9 min. [a] = 27.3 (c 2.73, CHCl , 98% ee). 23

3

D

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Copies of H and C NMR spectra for all new compounds and HPLC traces of 4 (PDF) 1

13

X-ray crystallographic data for compound 5a (CIF) X-ray crystallographic data for compound 6 (CIF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] . ORCID Ryukichi Takagi: 0000-0002-8180-6297 Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by a Grant-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (JSPS KAKENHI Grant Number JP26410121). NMR, MS, optical rotation measurements, and X-ray crystallography analysis were made at the Natural ACS Paragon Plus Environment

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Science Center for Basic Research and Development (N-BARD), Hiroshima University. Authors thank Ms. Naomi Kawata and Dr. Sayaka Hatano (Hiroshima University) for her support in X-ray crystallography analysis.

REFERENCES: (1) For reviews: for Morita-Baylis-Hillman Reactions: (a) Wei, Y.; Shi, M. Recent Advances in Organocatalytic Asymmetric Morita−Baylis−Hillman/aza-Morita−Baylis−Hillman Reactions. Chem. Rev. 2013, 113, 6659. (b) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Recent Contributions from the Baylis-Hillman Reaction to Organic Chemistry. Chem. Rev. 2010, 110, 5447. (c) Ma, G.-N.; Jiang, J.-J.; Shi, M.; Wei, Y. Recent extensions of the Morita–Baylis–Hillman reaction. Chem. Commun. 2009, 5496. for synthetic applications of MBH derivative: (d) Xie, P.; Huang, Y. Morita–Baylis–Hillman adduct derivatives (MBHADs): versatile reactivity in Lewis base-promoted annulation. Org. Biomol. Chem. 2015, 13, 8578. (e) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Organocatalytic asymmetric transformations of modified Morita–Baylis–Hillman adducts. Chem. Soc. Rev. 2012, 41, 4101. (f) Rios, R. Organocatalytic enantioselective methodologies using Morita–Baylis–Hillman carbonates and acetates. Catal. Sci. Technol. 2012, 2, 267. (2) For some papers for successive substitution reaction of MBH derivative: (a) Zheng, Y.; Cui, L.; Wang, Y.; Zhou, Z. Stereocontrolled Construction of Tetrahydropyrano[2,3-c]pyrazole Scaffold via an Organocatalyzed Formal [3 + 3] Annulation. J. Org. Chem. 2016, 81, 4340. (b) Basavaiah, D.; Lingaiah, B.; Reddy, G. C.; Sahu, B. C. Baylis–Hillman Acetates in Synthesis: Copper(I)/tert-Butyl Hydroperoxide Promoted One-Pot Oxidative Intramolecular Cyclization Protocol for the Preparation of Pyrrole-Fused Compounds and the Formal Synthesis of (±)-Crispine A. Eur. J. Org. Chem. 2016, 2398. (c) Chen, R.; Xu, S.; Fan, X.; Li, H.; Tang, Y.; He, Z. Construction of dispirocyclohexanes via aminecatalyzed [2 + 2 + 2] annulations of Morita–Baylis–Hillman acetates with exocyclic alkenes. Org. Biomol. Chem. 2015, 13, 398. (d) Cao, C.-L.; Zhou, Y.-Y.; Zhou, J.; Sun, X.-L.; Tang, Y.; Li, Y.-X.; Li, G.-Y.; Sun, J. An


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Organocatalytic Asymmetric Tandem Reaction for the Construction of Bicyclic Skeletons. Chem. Eur. J. 2009, 15, 11384 and references cited therein. (3) For some recent noteworthy papers: (a) Nishimine, T.; Taira, H.; Tokunaga, E.; Shiro, M.; Shibata, N. Enantioselective Trichloromethylation of MBH-Fluorides with Chloroform Based on Silicon-assisted C–FActivation and Carbanion Exchange Induced by a Ruppert–Prakash Reagent. Angew. Chem. Int. Ed. 2016, 55, 359. (b) Zhan, G.; Shi, M.-L.; He, Q.; Lin, W.-J.; Ouyang, Q.; Du, W.; Chen, Y.-C. CatalystControlled Switch in Chemo- and Diastereoselectivities: Annulations of Morita–Baylis–Hillman Carbonates from Isatins. Angew. Chem. Int. Ed. 2016, 55, 2147. (c) Okusu, S.; Okazaki, H.; Tokunaga, E.; Soloshonok, V. A.; Shibata, N. Organocatalytic Enantioselective Nucleophilic Alkynylation of Allyl Fluorides Affording Chiral Skipped Ene-ynes. Angew. Chem. Int. Ed. 2016, 55, 6744. (d) Chen, P.; Yue, Z.; Zhang, J.; Lv, X.; Wang, L.; Zhang, J. Phosphine-Catalyzed Asymmetric Umpolung Addition of Trifluoromethyl Ketimines to Morita–Baylis–Hillman Carbonates. Angew. Chem. Int. Ed. 2016, 55, 13316. (e) Yang, Y.; Ma, C.; Thumar, N. J.; Hu, W. Pd(II)/β-ICD-Cocatalyzed Asymmetric Route to Oxindole Scaffold via Cascade Reaction of Diazoacetamides and MBH-Carbonates. J. Org. Chem. 2016, 81, 8537. (f) Li, X.; Su, J.; Liu, Z.; Zhu, Y.; Dong, Z.; Qiu, S.; Wang, J.; Lin, L.; Shen, Z.; Yan, W.; Wang, K.; Wang, R. Synthesis of Chiral α-Trifluoromethylamines with 2,2,2-Trifluoroethylamine as a “Building Block”. Org. Lett. 2016, 18, 956. (g) Ma, J.; Yuan, Z.-z.; Kong, X.-w.; Wang, H.; Li, Y.-m.; Xiao, H.; Zhao, G. Reagent-Controlled Tandem Reactions of Vinyl Epoxides: Access to Functionalized γ-Butenolides. Org. Lett. 2016, 18, 1450. (4) For some recent papers: (a) Yoshimura, H.; Takahashi, K.; Ishihara, J.; Hatakeyama S. Unified Synthesis of Tirandamycins and Streptolydigins. Chem. Commun. 2015, 51, 17004. (b) Ilangovan, A.; Saravanakumar, S. Total Synthesis of (+)-Grandiamide D, Dasyclamide and Gigantamide A from a Baylis–Hillman Adduct: A Unified Biomimetic Approach. Beilstein J. Org. Chem. 2014, 10, 127. (c) Bhowmik, S.; Batra, S. Morita–Baylis–Hillman Approach toward Formal Total Synthesis of Tamiflu and Total Synthesis of Gabaculine. Eur. J. Org. Chem. 2013, 7145. (d) Kumar, T.; Mobin, S. M.; Namboothiri, I. N. N. Regiospecific Synthesis of Arenofurans via Cascade Reactions of Arenols with Morita-BaylisACS Paragon Plus Environment

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Hillman Acetates of Nitroalkenes and Total Synthesis of Isoparvifuran. Tetrahedron 2013, 69, 4964. (e) Krishna, P. R.; Alivelu, M.; Rao, T, P. First Stereoselective Total Synthesis of Isoaspinonene through a Baylis–Hillman/Olefin Cross-Metathesis Protocol. Eur. J. Org. Chem. 2012, 616. (5) (a) Takagi, R.; Inoue, Y.; Ohkata, K. Construction of the Adamantane Core of Plukenetione-Type Polycyclic Polyprenylated Acylphloroglucinols. J. Org. Chem. 2008, 73, 9320. (b) Takagi, R.; Miwa, Y.; Nerio, T.; Inoue, Y.; Matsumura, S.; Ohkata, K. Stereochemical Investigation on the Construction of Poly-functionalized Bicyclo[3.3.1]nonenones by Successive Michael Reactions of 2-Cyclohexenones. Org. Biomol. Chem. 2007, 5, 286. (c) Takagi, R.; Miwa, Y.; Matsumura, S.; Ohkata, K. One-Pot Synthesis of Adamantane Derivatives by Domino Michael Reactions from Ethyl 2,4-Dioxocyclohexanecarboxylate. J. Org. Chem. 2005, 70, 8587. (d) Takagi, R.; Nerio, T.; Miwa, Y.; Matsumura, S.; Ohkata, K. Construction of the Bicyclo[3.3.1]nonenone Core by Successive Michael Reactions of 2-Cyclohexenone Derivatives. Tetrahedron Lett. 2004, 45, 7401. (6) (a) Zhang, Q.; Mitasev, B.; Qi, J.; Porco, J. A. Jr. Total Synthesis of Plukenetione A. J. Am. Chem. Soc. 2010, 132, 14212. (b) Qi, J.; Beeler, A. B.; Zhang, Q.; Porco, J. A. Jr. Catalytic Enantioselective Alkylative Dearomatization-Annulation: Total Synthesis and Absolute Configuration Assignment of Hyperibone K. J. Am. Chem. Soc. 2010, 132, 13642. (c) Qi, J.; Porco, J. A. Jr. Rapid Access to Polyprenylated Phloroglucinols via Alkylative Dearomatization-Annulation: Total Synthesis of (±)Clusianone. J. Am. Chem. Soc. 2007, 129, 12682. (7) For a review: Govender, T.; Arvidsson, P. I.; Maguire, G. E. M.; Kruger, H. G.; Naicker, T. Enantioselective Organocatalyzed Transformations of β-Ketoesters. Chem. Rev. 2016, 116, 9375. (8) For Jørgensen’s pioneering papers: (a) Elsner, P.; Bernardi, L.; Salla, G. D.; Overgaard, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2008, 130, 4897. (b) Poulsen, T. B.; Bernardi, L.; Alemán, J.; Overgaard, J.; Jørgensen, K. A. Organocatalytic Asymmetric Conjugate Addition to Allenic Esters and Ketones. J. Am. Chem. Soc. 2007, 129, 441. (c) Bernardi, L.; López-Cantarero, J.; Niess, B.; Jørgensen, K. A. Organocatalytic Asymmetric 1,6-Additions of β-Ketoesters and Glycine Imine. J. Am. Chem. Soc. 2007, 129, 5772. (d) Alemán, J.; Reyes, E.; Richter, B.; Overgaard, J.; Jørgensen, K. A. Organocatalytic ACS Paragon Plus Environment

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Asymmetric ‘‘anti-Michael’’ Reaction of β-Ketoesters. Chem. Commun. 2007, 3921. (e) Poulsen, T. B.; Bernardi, L.; Bell, M.; Jørgensen, K. A. Organocatalytic Enantioselective Nucleophilic Vinylic Substitution. Angew. Chem. Int. Ed. 2006, 45, 6551. (9) For some papers using similar catalysts: (a) Moss, T. A.; Barber, D. M.; Kyle, A. F.; Dixon, D. J. Catalytic Asymmetric Alkylation Reactions for the Construction of Protected Ethylene-Amino and Propylene-Amino Motifs Attached to Quaternary Stereocentres. Chem. Eur. J. 2013, 19, 3071. (b) Luo, J.; Wu, W.; Xu, L.-W.; Meng, Y.; Lu, Y. Enantioselective Direct Fluorination and Chlorination of Cyclic β-Ketoesters Mediated by Phase-Transfer Catalysts. Tetrahedron Lett. 2013, 54, 2623. (c) Yao, H.; Lian, M.; Li, Z.; Wang, Y.; Meng, Q. Asymmetric Direct α-Hydroxylation of β-Oxo Esters Catalyzed by Chiral Quaternary Ammonium Salts Derived from Cinchona Alkaloids. J. Org. Chem. 2012, 77, 9601. (d) Moss, T. A.; Alonso, B.; Fenwick, D. R.; Dixon, D. J. Catalytic Enantio- and Diastereoselective Alkylations with Cyclic Sulfamidates. Angew. Chem. Int. Ed. 2010, 49, 568. (e) Moss, T. A.; Fenwick, D. R.; Dixon, D. J. Enantio- and Diastereoselective Catalytic Alkylation Reactions with Aziridines. J. Am. Chem. Soc. 2008, 130, 10076. (f) Kobbelgaard, S.; Bella, M.; Jørgensen, K. A. Improved Asymmetric S Ar Reaction N

of β-Dicarbonyl Compounds Catalyzed by Quaternary Ammonium Salts Derived from Cinchona Alkaloids. J. Org. Chem. 2006, 71, 4980. (10) Our preliminary investigations on the Micheal reaction catalyzed by other cinchona alkaloidderivatived ammonium catalysts also suggested phase-transfer catalyst 1 as a suitable catalyst (see Tables S1 and S2, Supporting Information). (11) The novel solvent system was created by the addition of toluene to the solvent system of condition A in order to improve solubility. (12) CCDC-1584696 (5a) and CCDC-1584697 (6) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif. (13) The enantiomeric excess of bicyclo[3.3.1]nonane 5a could not be determined due to it’s less UV activity. ACS Paragon Plus Environment

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(14)

On

the

bromination

reaction,

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(1S,3R,5R)-di-tert-butoxycarbony-7-bromo-6-methoxy-

bicyclo[3.3.1]non-6-ene-8-one, which was C3-epimer of 6, was also obtained in 33% yield. (15) Palomo, C.; Oiarbide, M.; García, J. M.; Bañuelos, P.; Odriozola, J. M.; Razkin, J.; Linden, A. Catalytic Michael Reactions of Ketoesters with a Camphor-Derived Acrylate Equivalent: Stereoselective Access to All-Carbon Quaternary Centers. Org. Lett. 2008, 10, 2637. (16) Capuzzi, M.; Perdicchia, D.; Jørgensen, K. A. Highly Enantioselective Approach to Geminal Bisphosphonates by Organocatalyzed Michael-Type Addition of β-Ketoesters. Chem. Eur. J. 2008, 14, 128. (17) 1-(tert-Butoxycarbonyl)-imidazole is hydrolyzed by moisture during storage to generate tertbutanol and imidazole. The chemical should be used after purification by column chromatography. (18) Warnhoff, E. W.; Martin, D. G.; Johnson, W. S. 2-Chloro-2-methylcyclohexanone and 2-Methyl2-cyclohexenone. Org. Synth. 1957, 37, 8. (19) Curini, M.; Epifano, F.; Genovese, S. Ytterbium Triflate Catalyzed Synthesis of β-Keto Enol Ethers. Tetrahedron Lett. 2006, 47, 4697. (20) Yu, B.; Jiang, T.; Quan, W.; Li, J.; Pan, X.; She, X. An Efficient Method for Construction of the Angularly Fused 6,3,5-Tricyclic Skeleton of Mycorrhizin A and Its Analogues. Org. Lett. 2009, 11, 629. (21) Trost, B. M.; Machacek, M. R.; Tsui, H. C. Development of Aliphatic Alcohols as Nucleophiles for Palladium-Catalyzed DYKAT Reactions: Total Synthesis of (+)-Hippospongic Acid A. J. Am. Chem. Soc. 2005, 127, 7014. (22) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. Scandium Trifluoromethanesulfonate as an Extremely Active Lewis Acid Catalyst in Acylation of Alcohols with Acid Anhydrides and Mixed Anhydrides. J. Org. Chem. 1996, 61, 4560. (23) Shimizu, M.; Kimura, M.; Tanaka, S.; Tamaru, Y. Unique Regio- and Stereoselectivity in the AIlylation of Benzaldehyde with 2-Substituted Allylzincs Generated by Umpolung of p-Allylpalladinm. Tetrahedron Lett. 1998, 39, 609.


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(24) Kalyva, M.; Zografos, A. L.; Kapourani, E.; Giambazolias, E.; Devel, L.; Papakyriakou, A.; Dive, V.; Lazarou, Y. G.; Georgiadis, D. Probing the Mechanism of Allylic Substitution of Morita–Baylis– Hillman Acetates (MBHAs) by using the Silyl Phosphonite Paradigm: Scope and Applications of a Versatile Transformation. Chem. Eur. J. 2015, 21, 3278. (25) The geometric stereochemistry of the olefin moiety was determined on the basis of the H NMR 1

chemical shift value of the vinylic proton: the vinyl proton observed at lower magnetic field was assigned to E-isomer. (26) Only peaks for E-4g were observed in the C NMR measurement due to less amount of Z-4g. 13

(27) The HPLC analysis using a chiral stationary phase was conduced after separation of the mixture of geometric isomers with HPLC using normal phase column.


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Enantioselective Michael Reaction of Cyclic Î²-Ketoesters with Morita

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