Diversity-Oriented One-Pot Synthesis to Construct Functionalized

Apr 19, 2017 - The asymmetric organocatalyzed diversity-oriented one-pot synthesis has been developed to construct chroman-2-one derivatives and other...
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Diversity-Oriented One-Pot Synthesis to Construct Functionalized Chroman-2-one Derivatives and Other Heterocyclic Compounds Ying-Han Chen,† Xue-Li Sun,† Hua-Shi Guan,†,‡ and Yan-Kai Liu*,†,‡ †

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Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China ‡ Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China S Supporting Information *

ABSTRACT: The asymmetric organocatalyzed diversity-oriented one-pot synthesis has been developed to construct chroman2-one derivatives and other heterocyclic compounds with excellent efficiency and stereoselectivity. The reactions represent a challenging issue, since it altered the inherent selectivity profiles exhibited by the substrates of 2-hydroxycinnamaldehyde 1 and trans-β-nitrostyrene 2, which was previously reported as the asymmetric oxa-Michael−Michael cascade to generate chiral chromans. It should be noted that polycyclic O,O-acetal-containing compounds, which are found in numerous natural products and biologically interesting molecules, could also be achieved in good yields with excellent enantioselectivity as a single diastereoisomer with five continuous stereogenic centers.

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INTRODUCTION Over the past decades, the demand for enantiomerically enriched compounds has gradually increased, as they are critical to developments in medicine, biology, and materials science. Consequently, one of the highly desirable but challenging goals in modern synthetic chemistry is to establish catalytic, atom-economical method to efficiently construct enantiomerically enriched compounds. Toward this, the asymmetric organocatalyzed sequential one-pot synthesis provides the possibility to reach this goal owing to their ability to rapidly assemble skeletally complex and stereochemically diverse small molecules, and thus has received much attention.1 Meanwhile, the diversity-oriented synthesis has now become another powerful tool to generate small drug-like molecules with both stereochemical and skeletal diversity.2 In this context, we envisioned that it might be possible to combine the diversity-oriented synthesis with sequential one-pot synthesis, namely, the diversity-oriented one-pot synthesis, which would be potentially more advantageous to give extremely powerful synthetic efficiency with highly atom- and step-economy. Recently, we have become interested in the application of cyclic hemiacetals as versatile reactants in the asymmetric © 2017 American Chemical Society

organocatalyzed sequential one-pot synthesis to construct multifunctionalized heterocycles,3 which might serve as templates for drug discovery and also be potentially applied in the total synthesis of natural products.3e In 2009, Wang and co-workers reported an asymmetric organocatalyzed oxaMichael−Michael cascade conducted between 2-hydroxycinnamaldehydes and trans-β-nitrostyrenes leading to facile construction of chiral chromans (Scheme 1, path a).4 Very recently, we developed one-pot, multicomponent, enantioselective domino reactions that contained a five-step sequence, in which trans-benzoylacrylic ester was chosen instead of trans-βnitrostyrene as a suitable Michael acceptor to balance the chemoselectivity and reactivity, and then reacted with 2hydroxycinnamaldehyde in the presence of Hantzsch ester leading to substituted chiral chroman-2-one derivatives in good isolated yields and excellent diastereo- and enantioselectivities.3b Chiral chroman-2-one derivatives are privileged structures that are frequently found in a large family of natural products Received: February 26, 2017 Published: April 19, 2017 4774

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783

Article

The Journal of Organic Chemistry

Obviously, the success of either path b or path c would be highly dependent on the different reaction rate of the reduction of 2-hydroxycinnamaldehyde via iminium-ion activation and trans-β-nitrostyrene via hydrogen-bond activation, and this would be the prerequisite for the asymmetric organocatalyzed diversity-oriented one-pot synthesis. Gratifyingly, in the presence of Hantzsch ester 3 at room temperature, the reduction of 2-hydroxycinnamaldehyde 1a was finished remarkably in less than 1 h catalyzed by 4a (20 mol%, TMS = trimethylsilyl) and PhCOOH (20 mol%), yielding the desired chroman-2-ol 5a in almost quantitative yield (Scheme 2, a). In

Scheme 1. Reaction Design: Asymmetric Organocatalyzed Diversity-Oriented One-Pot Synthesis

Scheme 2. Control Experiments

and biologically intriguing molecules.5 Meanwhile, the nitro group is a very important synthon owing to the potential utility as a precursor to various functionalities.6 Thus, although the reaction between 2-hydroxycinnamaldehyde and trans-β-nitrostyrene had been reported as an asymmetric organocatalyzed oxa-Michael−Michael cascade by Wang, it would be even more appealing to conduct the reaction of 2-hydroxycinnamaldehyde and trans-β-nitrostyrene based on the diversity-oriented onepot synthesis (Scheme 1), which not only provides an efficient approach to synthetically useful scaffolds containing both chroman-2-one moiety and nitro group for further formations of biologically active compounds, but also is a new addition to our continuing efforts on the application of cyclic hemiacetals in asymmetric organocatalysis. However, this is a challenging issue, since it will alter the inherent selectivity profiles exhibited by the substrates of 2-hydroxycinnamaldehyde and trans-βnitrostyrene. Herein, we wish to disclose the details of the abovementioned asymmetric organocatalyzed diversity-oriented onepot synthesis (Scheme 1), in which the Hantzsch ester 3 was used as the only hydride donor to reduce either the 2hydroxycinnamaldehyde to chroman-2-ol via iminium-ion activation or the trans-β-nitrostyrene to nitroalkane via hydrogen-bond activation, respectively. It should be noted that the asymmetric organocatalyzed diversity-oriented one-pot synthesis affords highly functionalized chiral chroman-2-one derivatives with excellent stereoselectivity under mild conditions. From the outset, we recognized that several challenges to this designed strategy must be addressed. First, an efficient catalytic system must be identified that will not participate first in the reported catalytic asymmetric oxa-Michael−Michael cascade by Wang, while selectively involved in the designed diversityoriented reduction/Michael addition/oxidation sequential process (Scheme 1, path b). Second, in path b, the reduction step induced by the Hantzsch ester 3 as the hydride donor should give priority to the 2-hydroxycinnamaldehyde 1a, while in path c, the trans-β-nitrostyrene 2a should be reduced first (Scheme 1, path c). Third, owing to the existence of several highly compatible chemoselectivity issues, the reaction system must be carefully considered to ensure that the enantioselective diversity-oriented synthesis can proceed smoothly in a one-pot sequential manner.

sharp contrast, the reduction of trans-β-nitrostyrene 2a into the nitroalkane 6a under the same conditions proved very sluggish, and indeed, more than 18 h were required to reach full conversion (Scheme 2, b). According to the results of the above control experiments, we confirmed the possibility to perform the designed diversity-oriented synthesis via an asymmetric organocatalyzed one-pot procedure.

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RESULTS AND DISCUSSION Encouraged by these considerations and also the previous work developed by Wang and co-worker and our group, we initially investigated the reaction of 2-hydroxycinnamaldehyde 1a, transβ-nitrostyrene 2a, and Hantzsch ester 3, in the presence of 4a (20 mol%) and additives (add. 20 mol%) in CH2Cl2 as the solvent at room temperature (for the full optimization studies, see the Supporting Information, Table S1, S2, and S3). As shown in Table 1, after the in situ reduction of 2hydroxycinnamaldehyde 1a via iminium-ion activation,7 the enamine activation triggered Michael addition between the reduced 1a and trans-β-nitrostyrene 2a delivered hemiacetal 10,8 followed by the pyridinium chlorochromate (PCC) introduced in situ oxidation to achieve the final chroman-2one products. To our surprise, when PhCOOH was used as the additive, the functionalized chroman-2-one 7a was isolated in 70% yield as a single diastereoisomer with 99% enantiomeric excess (ee), while path a and path c showed much lower reactivity (Table 1, entry 1). In contrast, when NaOAc was used as the cocatalyst, which was the optimized additive in Wang’s work, all these three pathways were activated, and, however, an incomplete reaction was observed even after 96 h leading to 7a as the major product in 38% yield with excellent enantioselectivity as well as 8a from path a in 20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

a

Unless otherwise noted, all reactions were carried out using 1a (0.10 mmol, 1.0 equiv), 2a (0.12 mmol, 1.2 equiv), 3 (0.12 mmol, 1.2 equiv) in CH2Cl2 (0.2 mL) with 4a (20 mol%) and additive (20 mol%) at 25 °C. After the Michael addition step, the PCC (0.3 mmol, 3.0 equiv) with Celite (64 mg) were added, and then the reaction mixture was stirred at 40 °C for another 2 h. bRefers to the total reaction time of two steps. cIsolated yield of 7a, 8a, and 9a, respectively. dDetermined by HPLC analysis on chiral stationary phases. eDetermined by 1H NMR analysis of the crude reaction mixture.

man-2-one derivative 7 was investigated with different 2hydroxycinnamaldehyde 1 and trans-β-nitrostyrenes 2 under the optimized conditions (Table 1, entry 6). As summarized in Table 2, the reaction proceeded in a highly chemoselective manner and tolerated trans-β-nitrostyrene 2 with various substituents, such as aromatic and heteroaromatic groups at β-position, affording the corresponding products 7a−7l in moderate to good yields with excellent enantioselectivities as a single diastereoisomer (Table 2, entries 1−12). To our surprise, the aliphatic trans-β-nitrostyrene turned out to have lower reactivity and chemoselectivity, that both path b and path c worked under the applied conditions leading to both enamineMichael adducts 7m−n and iminium-Michael adducts 9m−n, respectively (Table 2, entries 13−14).9 Moreover, 2-hydroxycinnamaldehydes bearing either electron-withdrawing or electron-donating substituents finished the one-pot procedure without noticeable changes in the stereoselectivity (Table 2, entries 15−17). Next, we moved toward the development of a sequential Henry-cyclization process with which to accomplish more complex chiral molecules.10 Polycyclic compounds, containing

between chemoselectivity and the additives, various acidic and basic additives were screened. As expected, all the carboxylic acids, either aromatic or aliphatic substituted, showed excellent chemoselectivity, namely, path b worked much better than both path a and path c, providing 7a in moderate to good isolated yield and in diastereo- and enantiopure form (Table 1, entries 4−12). While several phenols possessing relatively lower acidity, such as phenol, 2,4-dimethylphenol, and 4-nitrophenol, were also screened and gave 7a in moderate yield with high enantioselectivities, whereas the lower chemoselectivity and much longer reaction time were obtained in all cases, relative to the use of carboxylic acids (Table 1, entries 13−15). All these results clearly indicated that the chemoselectivity of this diversity-oriented one-pot process changed along with the property of the additives. Further optimization revealed that the best results for path b were achieved using 20 mol % of 4a in combination with an acidic cocatalyst p-MePhCOOH (p-MBA) in CH2Cl2 as the reaction media at room temperature (Table 1, entry 6). The scope of the asymmetric organocatalyzed diversityoriented one-pot synthesis to construct functionalized chro4776

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783

Article

The Journal of Organic Chemistry Table 2. Substrate Scope of Path ba

entry

R1

R2

t (h)b

7

yield (%)c

ee (%)d

Dre

1 2 3 4 5 6 7 8 9 10 11 12 13f 14f 15 16 17

H H H H H H H H H H H H H H 4-Me 4-F 5-Cl

Ph 4-FPh 4-ClPh 4-BrPh 4-MePh 4-CNPh 4-MeOPh 3-MeOPh 2,4-MeOPh 2-furan 2-thienyl 2-naphthyl phenylethyl cyclohexyl Ph Ph Ph

46 56 36 56 56 40 96 40 96 36 56 56 96 96 96 96 96

7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o 7p 7q

87 58 53 53 63 50 55 48 53 65 55 69 26 26 58 63 39

99 99 99 99 99 99 99 99 97 99 99 99 98 99 99 98 98

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

a

Unless otherwise noted, all reactions were carried out using 1 (0.30 mmol, 1.0 equiv), 2 (0.36 mmol, 1.2 equiv), 3 (0.36 mmol, 1.2 equiv) in CH2Cl2 (0.6 mL) with 4a (20 mol%) and p-MBA (20 mol%) at 25 °C. After the Michael addition step, the PCC (0.90 mmol, 3.0 equiv) with Celite (192 mg) and additional CH2Cl2 (2.0 mL) were added, and then the reaction mixture was stirred at 40 °C for another 2 h. bRefers to the total reaction time of two steps. cIsolated yield. dDetermined by HPLC analysis on chiral stationary phases. eDetermined by 1H NMR analysis of the crude reaction mixture. fThe isomer 9m (26%) and 9n (26%) were also generated as unseparated diastereoisomer mixture under our standard conditions.

functionalized aldehydes, including aromatic (Table 3, entries 1−3) and heteroaromatic (Table 3, entry 4) have been successfully applied in this Henry-cyclization sequence, leading to highly substituted heterocyclic frameworks containing polycyclic O,O-acetal skeleton with excellent outcomes. Notably, even ethyl glyoxylate worked well under this basic condition (Table 3, entry 5). It should be noted that this protocol is highly efficient affording the important polycyclic O,O-acetals that contain five continuous stereogenic centers in good yields with excellent enantioselectivity as a single diastereoisomer. As the path c delivered potentially more useful products via iminium ion triggered Michael addition, we investigated whether the reactivity of path c could be definitely enhanced and thus these derivatives were able to be synthesized in a more effective manner. The sequential one-pot process was initially conducted by treatment of trans-β-nitrostyrene 2 with Hantzsch ester 3 in the presence of (S)-diphenylprolinol tertbutyldimethylsilyl ether 4b and p-MBA. After the reduction of trans-β-nitrostyrene 2 was completed,12 the 2-hydroxycinnamaldehyde 1a was directly added to the solution for the sequential iminium ion triggered Michael addition by the same catalytic system (for the full optimization studies, see the Supporting Information, Tables S5, S6, and S7).13 To our delight, as summarized in Table 4, the sequence proceeded smoothly to provide the functionalized products with high stereoselectivity, albeit a further reduction step with NaBH4 was required to achieve two separable diastereoisomers 13 and 14 by column chromatography on silica gel. Different substituents at the aromatic moiety of trans-β-nitrostyrene 2, regardless of their electronic properties, and a naphthyl substituent were well-tolerated (Table 4, entries 1−5). Indolyl-substituted

O,O-acetal skeleton, are found in numerous natural products and biologically interesting molecules.11 Therefore, an efficient and general strategy to access such polycyclic O,O-acetalcontaining compounds would be very attractive. After a concise optimization study (see the Supporting Information, Table S4), we found that with the use of KOH as the catalyst, the Henry reaction between hemiacetal 10 and aldehyde 11 proceeded smoothly in MeOH, which is followed by BF3·Et2O catalyzed cyclization to achieve polycyclic O,O-acetal 12 in diastereomerically pure form. As summarized in Table 3, several Table 3. Synthesis of Polycyclic Compounds Containing O,O-Acetal Skeletona

entry

R

11

yield (%)b

ee (%)c

Drd

1 2 3 4 5

4-ClPh 4-NO2Ph 4-CNPh 2-thienyl −COOEt

11a 11b 11c 11d 11e

81 72 68 79 81

97 97 97 96 97

>20:1 >20:1 >20:1 >20:1 >20:1

a

Unless otherwise noted, all reactions were carried out using hemiacetal 10 (0.10 mmol, 1.0 equiv) and aldehyde 11 (0.12 mmol, 1.2 equiv), in MeOH (1.0 mL) and the pH of the reaction mixture was adjusted to 8−9 with KOH solution (3 M in MeOH) at 0 °C. After the Henry reaction step was finished, the MeOH solvent was replaced by CH2Cl2 (1.0 mL), and BF3·Et2O (0.3 mmol, 3.0 equiv) was added at 0 °C for another 0.5 h. bIsolated yield. cDetermined by HPLC analysis on chiral stationary phases. dDetermined by 1H NMR analysis of the crude reaction mixture. 4777

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783

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The Journal of Organic Chemistry Table 4. Substrate Scope of Path c

entrya

2

R1

1 2 3 4 5 6

2a 2b 2c 2d 2e 2f

Ph 4-FPh 4-MePh 3-MeOPh 2-naphthyl 3-(N-tosyl)-indolyl

yield (%)b total (13/14) 67 72 52 63 77 80

(30/37) (28/44) (23/29) (33/30) (43/34) (35/45)

ee (%)c 13/14

Drd 13/14

94/98 94/99 94/99 85/93 92/98 98/99

>20:1/>20:1 >20:1/>20:1 >20:1/>20:1 >20:1/>20:1 >20:1/>20:1 >20:1/>20:1

a

Unless otherwise noted, all reactions were carried out using 2 (0.48 mmol, 1.2 equiv), 3 (0.48 mmol, 1.2 equiv) in i-PrOH (1.0 mL) with 4b (20 mol%) and p-MBA (20 mol%) at 25 °C. After reduction, 1a (0.40 mmol, 1.0 equiv) was added for another 12 h. After Michael reaction, reaction mixture was purified by flash column affording hemiacetal intermediate. MeOH (1.0 mL) and NaBH4 (0.80 mmol, 2.0 equiv) were added, then the reaction mixture was stirred at 0 °C for 1 h. bIsolated yield. cDetermined by HPLC analysis on chiral stationary phases. dDetermined by 1H NMR analysis of the crude reaction mixture.

Scheme 3. Proposed Mechanism for Path a and Henry-Cyclization Sequence

Scheme 4. Proposed Mechanism for Path c

is generated from the catalyst 4a and the reduced 2hydroxycinnamaldehyde 1a, attacked the trans-β-nitrostyrene 2a from the Re face followed by intramolecular acetalization leading to the Michael adduct 10 containing a hemiacetal moiety in the structure. And then, in the KOH catalyzed Henry reaction, the 2-thenaldehyde approached from the Si face of the nitronate furnishing the Henry product 15. The nucleophilic attack of the hydroxy group to the Si face of the oxocarbenium ion intermediate, induced by BF3·Et2O, offers the final tricyclic

nitroolefin was also proven to be a viable substrate, leading to the corresponding adduct in good yield with excellent stereoselectivity (Table 4, entry 6). The absolute configurations of tricyclic O,O-acetal 12d were unambiguously determined by X-ray analysis (Scheme 3).14 The configurations of other products in Table 2 and Table 3 were assigned by analogy. Based on the observed stereochemistry, a proposed mechanism for the formation of 12d is shown in Scheme 3. Initially, the enamine intermediate, which 4778

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783

Article

The Journal of Organic Chemistry O,O-acetal 12d that contains five continuous stereogenic centers in a diastereomerically pure form. Unfortunately, all attempts to obtain a crystal of 13 or 14 which is suitable for X-ray crystallographic analysis were unsuccessful. The absolute configuration of 13 and 14 was thus deduced from previous investigation and NOESY spectra (see the Supporting Information, Figure S1 and S2). As shown in Scheme 4, in the iminium ion triggered Michael addition of path c, the key iminium ion intermediate 16 was achieved by condensation of 4b and 2-hydroxycinnamaldehyde 1a, and then the approach of the chiral iminium ion intermediate 16 from the Si face and Re face of the nitronate leading to the S,Sconfigured 13e and S,R-configured 14e, respectively, after NaBH4 induced in situ reduction.

General Procedure for Asymmetric Synthesis of 3-Substituted Dihydrocoumarin 7. A glass vial equipped with a magnetic stirring bar was charged with 1 (0.30 mmol, 1.0 equiv), Hantzsch ester 3 (111 mg, 0.36 mmol), 4a (19.5 mg, 0.06 mmol), and p-MePhCOOH (8.1 mg, 0.06 mmol) in CH2Cl2 (0.6 mL) at 25 °C, and then niroolefin 2 (0.36 mmol, 1.2 equiv) was added. After the specified time, PCC (192 mg, 0.90 mmol) with Celite (192 mg) and additional CH2Cl2 (2.0 mL) were added, then the reaction mixture was stirred at 40 °C for another 2 h. After the reaction was completed, the reaction mixture was filtrated through a short plug of silica gel. Solvent was removed under reduced pressure and the crude product purified by column chromatography on silica gel to provide the desired product 7. (R)-3-((S)-2-Nitro-1-phenylethyl)chroman-2-one (7a).3a White solid (78 mg, 87%); mp 119−120 °C; 1H NMR (500 MHz, CDCl3) δ 7.41−7.26 (m, 4H), 7.15 (d, J = 6.9 Hz, 2H), 7.09 (d, J = 7.2 Hz, 2H), 6.99 (d, J = 7.2 Hz, 1H), 5.13 (dd, J = 13.2, 4.9 Hz, 1H), 4.82 (dd, J = 12.8, 10.3 Hz, 1H), 3.80 (dt, J = 14.9, 7.4 Hz, 1H), 3.01 (td, J = 9.6, 6.3 Hz, 1H), 2.75 (dd, J = 15.9, 5.4 Hz, 1H), 2.55 (dd, J = 15.9, 9.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ169.0, 151.1, 135.9, 129.3, 128.7, 128.5, 128.3, 128.0, 124.8, 121.1, 116.6, 78.6, 43.2, 41.8, 27.7. ESI-HRMS: [M+H]+ calcd. For C17H16NO4+ m/z: 298.1074; found: 298.1072. [α]D20 −33.1 (c = 0.58 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 80/20, 1 mL/min), λ = 210 nm, tmajor = 14.95 min, tminor = 24.61 min, ee = 99.6%. (R)-3-((S)-1-(4-Fluorophenyl)-2-nitroethyl)chroman-2-one (7b). White solid (54 mg, 58%); mp 125−126 °C; 1H NMR (500 MHz, CDCl3) δ7.32−7.29 (m, 1H), 7.16−7.12 (m, 2H), 7.12−7.03 (m, 4H), 7.00 (d, J = 7.4 Hz, 1H), 5.12 (dd, J = 13.1, 5.0 Hz, 1H), 4.78 (dd, J = 13.1, 10.1 Hz, 1H), 3.82 (td, J = 10.1, 5.0 Hz, 1H), 2.98 (td, J = 9.7, 5.6 Hz, 1H), 2.75 (dd, J = 15.9, 5.6 Hz, 1H), 2.56 (dd, J = 15.9, 9.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ169.0, 163.8, 161.8, 151.3, 131.9, 131.9, 130.0, 129.9, 129.1, 128.5, 125.1, 121.2, 116.9, 116.7, 116.5, 78.8, 42.8, 42.0, 29.9, 27.9. The carbon spectra is splitted by fluorine. ESI-HRMS: [M+H]+ calcd. For C17H15FNO4+ m/z: 316.0980; found: 316.0983. [α]D20 −13.8 (c = 0.41 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (nhexane/i-PrOH = 80/20, 1 mL/min), λ = 210 nm, tmajor = 18.58 min, tminor = 33.91 min, ee = 99.2%. (R)-3-((S)-1-(4-Chlorophenyl)-2-nitroethyl)chroman-2-one (7c).3a White solid (54 mg, 53%); mp 115−116 °C; 1H NMR (500 MHz, CDCl3) δ7.36 (d, J = 8.0 Hz, 2H), 7.31−7.28 (m, 1H), 7.12−7.07 (m, 4H), 7.00 (d, J = 7.4 Hz, 1H), 5.12 (dd, J = 13.2, 4.8 Hz, 1H), 4.78 (dd, J = 12.5, 10.7 Hz, 1H), 3.82 (td, J = 10.0, 4.9 Hz, 1H), 2.98 (td, J = 9.8, 5.9 Hz, 1H), 2.74 (dd, J = 15.9, 5.4 Hz, 1H), 2.56 (dd, J = 15.9, 9.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ169.0, 151.3, 134.7, 134.7, 129.8, 129.6, 129.1, 128.5, 125.1, 121.2, 116.8, 78.5, 42.9, 41.8, 27.9. ESI-HRMS: [M+H]+ calcd. For C17H15ClNO4+ m/z: 332.0684; found: 332.0685. [α]D20 −16.0 (c = 0.28 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 70/30, 1 mL/min), λ = 210 nm, tmajor = 13.66 min, tminor = 24.69 min, ee = 99.7%. (R)-3-((S)-1-(4-Bromophenyl)-2-nitroethyl)chroman-2-one (7d).3a White solid (60 mg, 53%); mp 133−133 °C; 1H NMR (500 MHz, CDCl3) δ7.51 (d, J = 8.3 Hz, 2H), 7.31 (dd, J = 11.4, 4.1 Hz, 1H), 7.12−7.08 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 7.4 Hz, 1H), 5.12 (dd, J = 13.2, 4.9 Hz, 1H), 4.78 (dd, J = 13.2, 10.1 Hz, 1H), 3.81 (td, J = 10.1, 5.0 Hz, 1H), 2.98 (td, J = 9.9, 5.6 Hz, 1H), 2.74 (dd, J = 15.9, 5.6 Hz, 1H), 2.56 (dd, J = 15.9, 9.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ168.9, 151.3, 135.2, 132.7, 130.0, 129.1, 128.5, 125.1, 122.9, 121.1, 116.9, 78.5, 43.0, 41.8, 27.9. ESI-HRMS: [M+H]+ calcd. For C17H15BrNO4+ m/z: 376.0179; found: 376.0178. [α]D20 −13.7 (c = 0.42 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 80/20, 1 mL/min), λ = 210 nm, tmajor = 22.17 min, tminor = 40.25 min, ee = 99.9%. (R)-3-((S)-2-Nitro-1-(p-tolyl)ethyl)chroman-2-one (7e).3a White solid (60 mg, 63%); mp 129−130 °C; 1H NMR (500 MHz, CDCl3) δ7.30−7.27 (m, 1H), 7.17 (d, J = 7.7 Hz, 2H), 7.10−7.07 (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.99 (d, J = 7.4 Hz, 1H), 5.10 (dd, J =

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CONCLUSION In summary, unlike the previously reported asymmetric oxaMichael−Michael cascade to generate chiral chromans, the reaction between 2-hydroxycinnamaldehyde and trans-β-nitrostyrene showed different reactivity as the asymmetric organocatalyzed diversity-oriented one-pot synthesis in the presence of Hantzsch ester to construct chroman-2-one derivatives and other heterocyclic compounds with excellent stereoselectivity. This method represents a challenging issue, since it altered the inherent selectivity profiles exhibited by the same substrates. More importantly, polycyclic O,O-acetal-containing compounds, which are found in numerous natural products and biologically interesting molecules, could also be achieved in good yields with excellent enantioselectivity as a single diastereoisomer with five continuous stereogenic centers.

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EXPERIMENTAL SECTION

General Methods. The 1H and 13C NMR spectra were recorded at 500 MHz for 1H and at 125 MHz for 13C, respectively. The chemical shifts (δ) for 1H and 13C are given in ppm relative to residual signals of the solvents (CDCl3, δ = 7.26 ppm for 1H NMR, 77.16 ppm for 13C NMR). Coupling constants (J) are given in Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; brs, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet. ESI-HRMS spectrometer was obtained from the Waters Q-Tof Ultima Global. Xray data were obtained from Zhongke chemical technology service center. Optical rotations are reported as follows: [α]D20 (c in g per 100 mL, solvent). All the reactions were set up under air and using freshly distilled solvents, without any precautions to exclude moisture, unless otherwise noted, open air chemistry on the benchtop. Chromatographic purification of products was accomplished using column chromatography on silica gel (300−400 mesh). For thin layer chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm) were used, using UV light as the visualizing agent and an acidic mixture of ceric ammonium molybdate or basic aqueous potassium permanganate (KMnO4) as stain developing solutions. Organic solutions were concentrated under reduced pressure on EYELA rotary evaporator. HPLC analysis on chiral stationary phase were performed on a HITACHI Chromaster. Daicel Chiralpak IA, IB, IC, or OD-H columns with i-PrOH/n-hexane as the eluent were used. HPLC traces were compared to racemic samples prepared by mixture of two enantiomeric final products obtained by using (S) and (R) catalyst. Materials. Commercial reagents and solvents were purchased from Sigma-Aldrich, Fluka, Adamas, and Alfa Aesar used as received, without further purification. (S) and (R)-diphenylprolinol silyl ether is commercially available from Daicel Chiral Technologies. All the 2hydroxycinnamaldehyde 1 were synthesized from the corresponding salicylaldehyde via Wittig reaction. The substituted nitroolefins 2 were prepared from nitromethane and the corresponding aldehyde via Henry reaction. 4779

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783

Article

The Journal of Organic Chemistry 13.0, 5.0 Hz, 1H), 4.78 (dd, J = 12.8, 10.2 Hz, 1H), 3.75 (td, J = 10.1, 5.0 Hz, 1H), 2.98 (td, J = 9.5, 5.4 Hz, 1H), 2.82−2.70 (m, 1H), 2.55 (dd, J = 16.0, 9.2 Hz, 1H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3). δ169.3, 151.3, 138.5, 133.0, 130.2, 128.9, 128.5, 129.1, 124.9, 121.4, 116.7, 78.9, 43.1, 42.0, 27.8, 21.3. ESI-HRMS: [M+H]+ calcd. For C18H18NO4+ m/z: 312.1230; found: 312.1231. [α]D20 −19.2 (c = 0.47 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 80/20, 1 mL/min), λ = 210 nm, tmajor = 14.91 min, tminor = 22.81 min, ee = 99.5%. 4-((S)-2-Nitro-1-((R)-2-oxochroman-3-yl)ethyl)benzonitrile (7f).3a White solid (48 mg, 50%); mp 119−120 °C; 1H NMR (500 MHz, CDCl3) δ7.69 (d, J = 8.0 Hz, 2H), 7.35−7.29 (m, 3H), 7.13−7.08 (m, 2H), 7.01 (d, J = 7.4 Hz, 1H), 5.17 (dd, J = 13.5, 4.9 Hz, 1H), 4.84 (dd, J = 13.3, 10.2 Hz, 1H), 3.96 (td, J = 9.8, 4.9 Hz, 1H), 3.03 (td, J = 10.0, 5.7 Hz, 1H), 2.71 (dd, J = 15.8, 5.5 Hz, 1H), 2.57 (dd, J = 15.8, 10.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ168.6, 151.2, 141.7, 133.2, 129.3, 128.4, 125.2, 120.9, 118.2, 116.9, 113.0, 78.0, 43.52, 41.7, 27.9. ESI-HRMS: [M+H]+ calcd. For C18H15N2O4+ m/z: 323.1026; found: 323.1030. [α]D20 −21.5 (c = 0.47 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 65/35, 1 mL/min), λ = 210 nm, tmajor = 16.99 min, tminor = 29.51 min, ee = 99.6%. (R)-3-((S)-1-(4-Methoxyphenyl)-2-nitroethyl)chroman-2-one (7g). White solid (54 mg, 55%); mp 132−133 °C; 1H NMR (500 MHz, CDCl3) δ7.29−7.26 (m, 1H), 7.11−7.01 (m, 4H), 6.98 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 5.07 (dd, J = 13.0, 5.0 Hz, 1H), 4.74 (dd, J = 12.9, 10.1 Hz, 1H), 3.79 (s, 3H), 3.72 (td, J = 10.2, 5.1 Hz, 1H), 2.94 (td, J = 9.3, 5.6 Hz, 1H), 2.74 (dd, J = 16.0, 5.5 Hz, 1H), 2.53 (dd, J = 16.0, 9.1 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ169.1, 159.5, 151.1, 129.8, 129.1, 128.7, 128.3, 127.6, 124.8, 121.2, 116.6, 114.6, 78.8, 55.3, 42.5, 41.9, 27.6. ESI-HRMS: [M+H]+ calcd. For C18H18NO5+ m/z: 328.1179; found: 328.1177. [α]D20 −22.6 (c = 0.34 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/CH2Cl2 = 80/20, 1 mL/min), λ = 210 nm, tmajor = 22.39 min, tminor = 25.85 min, ee = 99.6%. (R)-3-((S)-1-(3-Methoxyphenyl)-2-nitroethyl)chroman-2-one (7h).3a White solid (48 mg, 48%); mp 98−99 °C; 1H NMR (500 MHz, CDCl3) δ7.30−7.27 (m, 2H), 7.11−7.08 (m, 2H), 7.00 (d, J = 7.4 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.80 (dd, J = 13.0, 10.1 Hz, 1H), 3.85−3.71 (m, 4H), 2.98 (td, J = 9.7, 5.8 Hz, 1H), 2.76 (dd, J = 16.0, 5.5 Hz, 1H), 2.58 (dd, J = 15.9, 9.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ169.3, 160.3, 151.4, 137.7, 130.6, 128.9, 128.6, 125.0, 121.4, 120.2, 116.8, 114.5, 113.7, 78.7, 55.5, 43.5, 42.0, 27.9. ESI-HRMS: [M +H]+ calcd. For C18H18NO5+ m/z: 328.1179; found: 328.1180. [α]D20 −26.2 (c = 0.32 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 70/30, 1 mL/min), λ = 210 nm, tmajor = 13.03 min, tminor = 19.10 min, ee = 99.5%. (R)-3-((S)-1-(2,4-Dimethoxyphenyl)-2-nitroethyl)chroman-2-one (7i). White solid (57 mg, 53%); mp 135−135 °C; 1H NMR (500 MHz, CDCl3) δ7.29−7.22 (m, 1H), 7.06−7.03 (m, 2H), 6.94 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 2.2 Hz, 1H), 6.39 (dd, J = 8.3, 2.3 Hz, 1H), 5.05−4.95 (m, 2H), 3.81−3.73 (m, 7H), 3.34−3.24 (m, 1H), 2.68 (dd, J = 16.0, 5.8 Hz, 1H), 2.51 (dd, J = 16.0, 9.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ170.0, 161.1, 158.4, 151.3, 132.2, 128.5, 128.3, 124.5, 121.7, 116.5, 115.7, 104.6, 99.3, 77.3, 55.4, 55.4, 41.6, 39.7, 28.1. ESI-HRMS: [M+H]+ calcd. For C19H20NO6+ m/z: 358.1285; found: 358.1287. [α]D20 −25.7 (c = 0.35 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 70/30, 1 mL/min), λ = 210 nm, tmajor = 22.74 min, tminor = 32.36 min, ee = 96.6%. (R)-3-((R)-1-(Furan-2-yl)-2-nitroethyl)chroman-2-one (7j). 3a White solid (57 mg, 65%); mp 133−134 °C; 1H NMR (500 MHz, CDCl3) δ7.40 (s, 1H), 7.32−7.26 (m, 1H), 7.10 (d, J = 4.2 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.35 (d, J = 0.9 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 5.03 (dd, J = 13.1, 5.5 Hz, 1H), 4.87 (dd, J = 12.8, 9.3 Hz, 1H),

4.18 (dd, J = 14.4, 8.4 Hz, 1H), 3.06 (dt, J = 11.7, 7.5 Hz, 1H), 2.77− 2.64 (m, 2H). 13C NMR (125 MHz, CDCl3) δ168.8, 151.2, 149.2, 143.2, 128.9, 128.4, 125.0, 121.7, 116.8, 110.9, 110.3, 76.3, 40.7, 37.6, 27.4. ESI-HRMS: [M+H]+ calcd. For C15H14NO5+ m/z: 288.0866; found: 288.0867. [α]D20 −22.6 (c = 0.32 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 75/25, 1 mL/min), λ = 210 nm, tmajor = 13.86 min, tminor = 25.43 min, ee = 98.5%. (R)-3-((R)-2-Nitro-1-(thiophen-2-yl)ethyl)chroman-2-one (7k).3a White solid (51 mg, 55%); mp 158−159 °C; 1H NMR (500 MHz, CDCl3) δ7.30−7.27 (m, 2H), 7.12−7.07 (m, 3H), 7.02−6.97 (m, 1H), 6.93 (d, J = 2.9 Hz, 1H), 5.09 (dd, J = 13.2, 5.5 Hz, 1H), 4.82 (dd, J = 13.1, 9.2 Hz, 1H), 4.29 (dd, J = 14.5, 8.9 Hz, 1H), 3.00 (td, J = 9.7, 5.9 Hz, 1H), 2.84 (dd, J = 15.8, 5.7 Hz, 1H), 2.73 (dd, J = 15.8, 10.6 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ168.8, 151.2, 138.4, 129.0, 128.6, 127.6, 127.5, 126.0, 125.0, 121.4, 116.8, 79.0, 42.6, 39.8, 27.5. ESIHRMS: [M+H]+ calcd. For C15H14NO4S+ m/z: 304.0638; found: 304.0637. [α]D20 −22.7 (c = 0.48 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (nhexane/CH2Cl2 = 80/20, 1 mL/min), λ = 230 nm, tmajor = 19.11 min, tminor = 22.97 min, ee = 99.5%. (R)-3-((S)-1-(Naphthalen-2-yl)-2-nitroethyl)chroman-2-one (7l).3a White solid (75 mg, 69%); mp 134−135 °C; 1H NMR (500 MHz, CDCl3) δ7.89−7.80 (m, 3H), 7.61 (s, 1H), 7.53 (dd, J = 5.9, 3.1 Hz, 2H), 7.32−7.28 (m, 2H), 7.11−7.07 (m, 2H), 6.93 (d, J = 7.4 Hz, 1H), 5.23 (dd, J = 13.1, 4.8 Hz, 1H), 4.92 (dd, J = 12.8, 10.4 Hz, 1H), 3.98 (td, J = 10.2, 4.8 Hz, 1H), 3.11 (td, J = 9.8, 5.8 Hz, 1H), 2.74 (dd, J = 16.0, 5.5 Hz, 1H), 2.57 (dd, J = 16.0, 9.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ169.3, 151.4, 133.5, 133.4, 133.3, 129.6, 129.0, 128.5, 128.2, 128.1, 128.0, 127.0, 126.9, 125.0, 124.7, 121.4, 116.8, 78.8, 43.7, 41.9, 28.0. ESI-HRMS: [M+H]+ calcd. For C21H18NO4+ m/z: 348.1230; found: 348.1233. [α]D20 −15.2 (c = 0.46 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 80/20, 1 mL/min), λ = 210 nm, tmajor = 41.35 min, tminor = 34.17 min, ee = 99.6%. (R)-3-((R)-1-Nitro-4-phenylbutan-2-yl)chroman-2-one (7m).3a White solid (27 mg, 26%); mp 79−80 °C; 1H NMR (500 MHz, CDCl3) δ7.31−7.26 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 7.19−7.16 (m, 3H), 7.13−7.10 (m, 1H), 7.05 (d, J = 8.1 Hz, 1H), 4.68 (dd, J = 12.9, 5.3 Hz, 1H), 4.57 (dd, J = 12.9, 7.0 Hz, 1H), 3.01−2.85 (m, 4H), 2.75 (t, J = 8.1 Hz, 2H), 2.10−1.93 (m, 1H), 1.86−1.70 (m, 1H). 13C NMR (125 MHz, CDCl3) δ169.1, 151.3, 140.6, 128.9, 128.9, 128.5, 128.3, 126.6, 124.9, 122.2, 116.9, 76.7, 40.9, 37.2, 33.6, 31.6, 26.2. ESIHRMS: [M+H]+ calcd. For C19H20NO4+ m/z: 326.1387; found: 326.1389. [α]D20 −12.4 (c = 0.67 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (nhexane/i-PrOH = 75/25, 1 mL/min), λ = 210 nm, tmajor = 20.45 min, tminor = 13.76 min, ee = 98.0%. (R)-3-((R)-1-Cyclohexyl-2-nitroethyl)chroman-2-one (7n).3a White solid (24 mg, 26%); mp 104−105 °C; 1H NMR (500 MHz, CDCl3) δ7.31−7.26 (m, 1H), 7.20 (d, J = 7.3 Hz, 1H), 7.13−7.10 (m, 1H), 7.05 (d, J = 8.1 Hz, 1H), 4.72 (dd, J = 14.0, 5.2 Hz, 1H), 4.51 (dd, J = 14.0, 6.1 Hz, 1H), 3.09−2.89 (m, 3H), 2.66−2.56 (m, 1H), 1.82−1.66 (m, 6H), 1.25−0.93 (m, 5H). 13C NMR (125 MHz, CDCl3) δ169.5, 151.4, 128.8, 128.2, 124.8, 122.5, 116.9, 76.1, 43.2, 40.1, 39.1, 31.7, 30.3, 28.1, 26.5, 26.4, 26.3. ESI-HRMS: [M+H]+ calcd. For C17H22NO4+ m/z: 304.1543; found: 304.1540. [α]D20 −2.7 (c = 0.47 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/CH2Cl2 = 85/15, 1 mL/min), λ = 230 nm, tmajor = 14.11 min, tminor = 13.33 min, ee = 99.1%. (R)-6-Methyl-3-((S)-2-nitro-1-phenylethyl)chroman-2-one (7o).3a White solid (54 mg, 58%); mp 98−99 °C; 1H NMR (500 MHz, CDCl3) δ7.39−7.32 (m, 3H), 7.16 (d, J = 7.0 Hz, 2H), 7.08 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.79 (s, 1H), 5.13 (dd, J = 13.1, 4.9 Hz, 1H), 4.81 (dd, J = 13.0, 10.1 Hz, 1H), 3.80 (td, J = 10.1, 5.0 Hz, 1H), 2.98 (td, J = 9.8, 5.7 Hz, 1H), 2.68 (dd, J = 16.0, 5.6 Hz, 1H), 2.51 (dd, J = 15.9, 9.4 Hz, 1H), 2.29 (s, 3H). 13C NMR (125 MHz, CDCl3) δ169.5, 149.3, 136.3, 134.7, 129.5, 129.4, 128.9, 128.7, 128.3, 121.1, 116.5, 78.9, 43.5, 42.1, 27.9, 20.9. ESI-HRMS: [M+H]+ calcd. 4780

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783

Article

The Journal of Organic Chemistry For C18H18NO4+ m/z: 312.1230; found: 312.1231. [α]D20 −31.5 (c = 0.58 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/CH2Cl2 = 80/20, 1 mL/min), λ = 230 nm, tmajor = 12.94 min, tminor = 14.92 min, ee = 99.8%. (R)-6-Fluoro-3-((S)-2-nitro-1-phenylethyl)chroman-2-one (7p).3a White solid (60 mg, 63%); mp 113−114 °C; 1H NMR (500 MHz, DMSO) δ7.42−7.31 (m, 3H), 7.16 (d, J = 6.8 Hz, 2H), 7.06 (dd, J = 8.9, 4.6 Hz, 1H), 7.01−6.97 (m, 1H), 6.72 (dd, J = 8.0, 2.7 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.81 (dd, J = 13.2, 9.8 Hz, 1H), 3.79 (td, J = 10.0, 5.1 Hz, 1H), 3.01 (td, J = 9.8, 5.7 Hz, 1H), 2.73 (dd, J = 16.1, 5.6 Hz, 1H), 2.54 (dd, J = 16.1, 9.2 Hz, 1H). 13C NMR (125 MHz, DMSO) δ168.8, 160.3, 158.4, 147.4, 136.0, 129.6, 128.9, 128.2, 123.1, 123.0, 118.2, 118.1, 115.7, 115.6, 115.3, 115.1, 78.7, 43.4, 41.6, 27.9. ESI-HRMS: [M+H]+ calcd. For C17H15FNO4+ m/z: 316.0980; found: 316.0984. [α]D20 −17.8 (c = 0.49 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 70/30, 1 mL/min), λ = 210 nm, tmajor = 12.62 min, tminor = 11.21 min, ee = 98.1%. (R)-7-Chloro-3-((S)-2-nitro-1-phenylethyl)chroman-2-one (7q). White solid (39 mg, 39%); mp 143−144 °C; 1H NMR (500 MHz, CDCl3) δ7.40−7.30 (m, 3H), 7.13 (d, J = 6.6 Hz, 2H), 7.09 (d, J = 1.6 Hz, 1H), 7.06 (dd, J = 8.1, 1.8 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.79 (dd, J = 13.2, 9.8 Hz, 1H), 3.77 (td, J = 10.0, 5.1 Hz, 1H), 2.99 (td, J = 9.5, 5.7 Hz, 1H), 2.70 (dd, J = 16.1, 5.6 Hz, 1H), 2.51 (dd, J = 16.1, 9.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ168.5, 151.7, 135.9, 134.3, 129.6, 129.4, 128.9, 128.2, 125.2, 119.9, 117.3, 78.7, 43.4, 41.8, 27.5. ESI-HRMS: [M+H]+ calcd. For C17H15ClNO4+ m/z: 332.0684; found: 332.0685. [α]D20 −21.4 (c = 0.10 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/CH2Cl2 = 80/20, 1 mL/min), λ = 230 nm, tmajor = 15.92 min, tminor = 24.86 min, ee = 98.1%. General Procedure for the Synthesis of Polycyclic O,O-Acetal 12. A glass vial equipped with a magnetic stirring bar was charged with 7a (30 mg, 0.10 mmol, 1.0 equiv), aldehyde 11 (0.12 mmol, 0.12 equiv) in MeOH (1.0 mL) at 0 °C, then KOH solution (3 M in MeOH) was added slowly until pH to 8−9. After 1 h, reduce the solvent or extract with ethyl acetate/water, then CH2Cl2 (1.0 mL) were added, BF3·Et2O (37 μL, 3.0 mmol) was added slowly under 0 °C for another 0.5 h. After the reaction was completed, the reaction mixture was purified by flash chromatography to provide the desired product 12. (2R,3S,4S,4aR,10aR)-2-(4-Chlorophenyl)-3-nitro-4-phenyl3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-b]chromene (12a). White solid (34 mg, 81%); mp 272−273 °C; 1H NMR (500 MHz, CDCl3) δ7.44−7.27 (m, 7H), 7.23 (d, J = 8.3 Hz, 1H), 7.15−7.02 (m, 3H), 6.97−6.90 (m, 2H), 5.74 (d, J = 2.7 Hz, 1H), 5.52 (d, J = 9.9 Hz, 1H), 4.85 (t, J = 10.6 Hz, 1H), 3.56 (t, J = 11.8 Hz, 1H), 2.98 (dd, J = 17.0, 5.8 Hz, 1H), 2.70−2.59 (m, 1H), 2.38 (d, J = 17.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ153.0, 135.4, 135.4, 134.0, 129.3, 129.2, 129.1, 128.5, 128.5, 128.2, 121.8, 117.6, 116.7, 95.8, 93.0, 73.3, 44.5, 37.1, 26.7. The Carbon spectral was splitted by fluorine. ESI-HRMS: [M +H]+ calcd. For C24H21ClNO4+ m/z: 422.1154; found: 422.1155. [α]D20 +16.2 (c = 0.18 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IA column (nhexane/i-PrOH/CH2Cl2 = 90/8/2, 1 mL/min), λ = 220 nm, tmajor = 8.61 min, tminor = 9.48 min, ee = 97.5%. (2R,3S,4S,4aR,10aR)-3-Nitro-2-(4-nitrophenyl)-4-phenyl3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-b]chromene (12b). White solid (31 mg, 72%); mp 207−208 °C; 1H NMR (500 MHz, CDCl3) δ8.23 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 7.38−7.19 (m, 4H), 7.15−7.01 (m, 3H), 6.98−6.88 (m, 2H), 5.76 (d, J = 2.7 Hz, 1H), 5.64 (d, J = 9.9 Hz, 1H), 4.82 (dd, J = 11.1, 10.1 Hz, 1H), 3.57 (t, J = 11.8 Hz, 1H), 2.99 (dd, J = 17.0, 5.8 Hz, 1H), 2.72−2.62 (m, 1H), 2.38 (d, J = 16.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ152.8, 148.5, 142.4, 135.0, 129.3, 128.6, 128.3, 128.0, 124.0, 122.0, 117.5, 116.7, 110.0, 95.7, 92.9, 72.9, 44.4, 37.0, 26.6. ESI-HRMS: [M+H]+ calcd. For C24H21N2O6+ m/z: 433.1394; found: 433.1391. [α]D20 +28.6 (c = 0.41 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH/

CH2Cl2 = 65/30/5, 1 mL/min), λ = 254 nm, tmajor = 6.41 min, tminor = 5.47 min, ee = 97.1%. 4-((2R,3S,4S,4aR,10aR)-3-Nitro-4-phenyl-3,4,4a,10a-tetrahydro2H,5H-pyrano[2,3-b]chromen-2-yl)benzonitrile (12c). White solid (28 mg, 68%); mp 205−205 °C; 1H NMR (500 MHz, CDCl3) δ7.68 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.33−7.23 (m, 4H), 7.15−7.02 (m, 3H), 6.99−6.90 (m, 2H), 5.76 (d, J = 2.5 Hz, 1H), 5.59 (d, J = 9.9 Hz, 1H), 4.82 (t, J = 10.6 Hz, 1H), 3.57 (t, J = 11.8 Hz, 1H), 3.00 (dd, J = 17.0, 5.8 Hz, 1H), 2.74−2.60 (m, 1H), 2.39 (d, J = 17.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ152.8, 140.6, 135.1, 132.6, 129.3, 128.6, 128.3, 127.8, 122.0, 118.2, 117.5, 116.7, 113.4, 95.8, 92.9, 73.2, 44.4, 37.1, 26.6. ESI-HRMS: [M+H]+ calcd. For C25H21N2O4+ m/z: 413.1496; found: 413.1494. [α]D20 +22.5 (c = 0.56 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH/CH2Cl2 = 70/25/5, 1 mL/min), λ = 230 nm, tmajor = 6.09 min, tminor = 5.51 min, ee = 97.6%. (2S,3S,4S,4aR,10aR)-3-Nitro-4-phenyl-2-(thiophen-2-yl)3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-b]chromene (12d). White solid (31 mg, 79%); mp 290−290 °C; 1H NMR (500 MHz, CDCl3) δ7.64 (d, J = 5.0 Hz, 1H), 7.33−7.28 (m, 4H), 7.20 (dd, J = 5.0, 4.0 Hz, 2H), 7.06−6.86 (m, 5H), 5.85 (d, J = 2.4 Hz, 1H), 5.65 (d, J = 9.8 Hz, 1H), 5.43 (t, J = 10.5 Hz, 1H), 3.25 (t, J = 11.7 Hz, 1H), 3.02 (dd, J = 16.9, 5.6 Hz, 1H), 2.89 (d, J = 12.1 Hz, 1H), 2.12 (d, J = 16.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ153.3, 138.1, 136.2, 129.8, 129.4, 128.6, 128.3, 128.2, 128.2, 127.3, 121.9, 118.7, 116.6, 96.0, 92.6, 70.3, 45.3, 35.6, 26.4. ESI-HRMS: [M+H]+ calcd. For C22H20NO4S+ m/z: 394.1108; found: 394.1110. [α]D20 +20.5 (c = 0.63 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH/CH2Cl2 = 70/25/5, 1 mL/ min), λ = 230 nm, tmajor = 4.96 min, tminor = 4.51 min, ee = 96.3%. Ethyl (2S,3S,4S,4aR,10aR)-3-Nitro-4-phenyl-3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-b]chromene-2-carboxylate (12e). White solid (31 mg, 81%); mp 143−144 °C; 1H NMR (500 MHz, CDCl3) δ7.33 (d, J = 5.5 Hz, 3H), 7.24−7.21 (m, 1H), 7.08 (brs, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.97−6.87 (m, 2H), 5.70 (d, J = 2.3 Hz, 1H), 5.23 (d, J = 10.3 Hz, 1H), 5.01 (t, J = 10.9 Hz, 1H), 3.82 (s, 3H), 3.39 (t, J = 11.9 Hz, 1H), 2.94 (dd, J = 17.0, 5.7 Hz, 1H), 2.61−2.51 (m, 1H), 2.33 (d, J = 17.1 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ167.7, 152.6, 135.0, 129.3, 128.6, 128.3, 122.0, 117.4, 116.8, 95.3, 87.19, 70.0, 53.1, 44.1, 36.5, 26.5. ESI-HRMS: [M+H]+ calcd. For C21H22NO6+ m/ z: 384.1442; found: 384.1440. [α]D20 +5.3 (c = 0.22 in CHCl3). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH/CH2Cl2 = 75/22/3, 1 mL/ min), λ = 220 nm, tmajor = 5.76 min, tminor = 5.24 min, ee = 97.8%. General Procedure for the Asymmetric Conjugate Addition of Nitroalkane to 2-Hydroxycinnamaldehyde 1. A glass vial equipped with a magnetic stirring bar was charged with nitroolefin 2 (0.24 mmol, 1.2 equiv), Hantzsch ester 3 (72 mg, 0.24 mmol), cat. 4b (15 mg, 0.04 mmol), and p-MePhCOOH (5.4 mg, 0.04 mmol) in i-PrOH (0.4 mL) at 25 °C for 18 h. Then 1 (30 mg, 0.2 mmol, 0.10 equiv) was added at 25 °C for another 12 h. Hemiacetal intermediate was purified by flash column (petroleum ether−ethyl acetate = 7:1). The intermediate was dissolved in MeOH (1.0 mL) at 0 °C, then NaBH4 (0.6 mmol, 3.0 equiv) was added. Reaction was carried out at 0 °C for 1 h, then extracted with ethyl acetate and water. Crude product was purified by flash chromatography to provide the diastereoisomers 13 and 14. 2-((2S,3S)-5-Hydroxy-2-nitro-1-phenylpentan-3-yl)phenol (13a). Colorless oil (36 mg, 30%); 1H NMR (500 MHz, CDCl3) δ7.25− 7.16 (m, 4H), 7.17−7.12 (m, 1H), 7.02−6.98 (m, 3H), 6.88 (d, J = 8.0 Hz, 1H), 6.79 (brs, 1H), 5.20 (brs, 1H), 3.80 (brs, 1H), 3.69−3.57 (m, 1H), 3.35 (dd, J = 14.1, 10.6 Hz, 1H), 3.05 (dd, J = 14.6, 11.3 Hz, 1H), 2.83 (dd, J = 14.7, 2.5 Hz, 1H), 2.19 (brs, 1H), 2.00−1.84 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ154.5, 135.9, 128.9, 128.7, 128.5, 127.2, 124.6, 121.7, 117.1, 94.4, 60.1, 38.7, 34.1, 27.0. ESI-HRMS: [M +H]+ calcd. For C17H20NO4+ m/z: 302.1387; found: 302.1385. [α]D20 −27.4 (c = 0.35 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH 4781

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783

Article

The Journal of Organic Chemistry = 85/15, 1 mL/min), λ = 227 nm, tmajor = 9.11 min, tminor = 8.25 min, ee = 93.7%. 2-((2R,3S)-5-Hydroxy-2-nitro-1-phenylpentan-3-yl)phenol (14a). Colorless oil (44 mg, 37%); 1H NMR (500 MHz, CDCl3) δ7.30− 7.22 (m, 3H), 7.15 (d, J = 7.1 Hz, 2H), 7.13−7.07 (m, 2H), 6.90−6.87 (m, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.35 (brs, 1H), 5.22 (td, J = 10.9, 3.2 Hz, 1H), 3.95−3.83 (m, 1H), 3.74−3.60 (m, 1H), 3.44−3.31 (m, 2H), 3.30−3.15 (m, 1H), 2.25−2.13 (m, 1H), 2.01−1.70 (m, 2H). 13C NMR (125 MHz, CDCl3) δ153.9, 135.7, 128.8, 128.8, 128.7, 127.4, 124.4, 121.4, 116.4, 93.3, 60.2, 38.2, 33.4, 27.0. ESI-HRMS: [M+H]+ calcd. For C17H20NO4+ m/z: 302.1387; found: 302.1386. [α]D20 +35.0 (c = 0.45 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 88/12, 1 mL/min), λ = 227 nm, tmajor = 17.13 min, tminor = 16.34 min, ee = 98.2%. 2-((2S,3S)-1-(4-Fluorophenyl)-5-hydroxy-2-nitropentan-3-yl)phenol (13b). Colorless oil (18 mg, 28%); 1H NMR (500 MHz, CDCl3) δ7.23−7.18 (m, 1H), 7.14 (d, J = 6.7 Hz, 1H), 7.04−6.82 (m, 6H), 6.63 (brs, 1H), 5.16 (brs, 1H), 3.78 (brs, 1H), 3.69−3.57 (m, 1H), 3.34 (dd, J = 13.9, 10.6 Hz, 1H), 3.02 (dd, J = 14.6, 11.3 Hz, 1H), 2.79 (dd, J = 14.7, 2.2 Hz, 1H), 1.97−1.81 (m, 2H). 13C NMR (125 MHz, CDCl3) δ163.0, 161.0, 154.5, 131.6, 130.1, 130.1, 129.0, 124.4, 121.7, 117.0, 115.6, 115.5, 94.4, 60.1, 37.9, 34.1, 27.0. The Carbon spectral was splitted by fluorine. ESI-HRMS: [M+H]+ calcd. For C17H19FNO4+ m/z: 320.1293; found: 320.1296. [α]D20 −24.7 (c = 0.53 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 85/15, 1 mL/min), λ = 227 nm, tmajor = 7.59 min, tminor = 6.91 min, ee = 93.7%. 2-((2R,3S)-1-(4-Fluorophenyl)-5-hydroxy-2-nitropentan-3-yl)phenol (14b). Colorless oil (28 mg, 44%); 1H NMR (500 MHz, CDCl3) δ7.17−7.05 (m, 4H), 6.98−6.94 (m, 2H), 6.90−6.87 (m, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.34 (brs, 1H), 5.19 (td, J = 11.0, 3.1 Hz, 1H), 3.94−3.82 (m, 1H), 3.73−3.61 (m, 1H), 3.45−3.28 (m, 2H), 3.17 (dd, J = 14.5, 11.1 Hz, 1H), 2.04−1.69 (m, 2H). 13C NMR (125 MHz, CDCl3) δ163.0, 161.1, 154.0, 131.4, 131.4, 130.3, 130.3, 128.8, 128.8, 124.2, 121.3, 116.3, 115.8, 115.6, 93.3, 60.1, 37.3, 33.3, 27.0. The Carbon spectral was splitted by fluorine. ESI-HRMS: [M+H]+ calcd. For C17H19FNO4+ m/z: 320.1293; found: 320.1295. [α]D20 +52.4 (c = 0.17 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak AD-H column (n-hexane/iPrOH = 90/10, 1 mL/min), λ = 225 nm, tmajor = 22.30 min, tminor = 23.30 min, ee = 99.7%. 2-((2S,3S)-5-Hydroxy-2-nitro-1-(p-tolyl)pentan-3-yl)phenol (13c). Colorless oil (14 mg, 23%); 1H NMR (500 MHz, CDCl3) δ7.22−7.19 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.07−6.97 (m, 3H), 6.90−6.85 (m, 3H), 6.53 (brs, 1H), 5.16 (brs, 1H), 3.79 (brs, 1H), 3.68−3.56 (m, 1H), 3.33 (dd, J = 14.1, 10.5 Hz, 1H), 3.01 (dd, J = 14.6, 11.3 Hz, 1H), 2.78 (dd, J = 14.7, 2.2 Hz, 1H), 2.27 (s, 3H), 1.97−1.87 (m, 2H). 13C NMR (125 MHz, CDCl3) δ154.5, 136.8, 132.8, 129.4, 128.9, 128.3, 124.7, 121.8, 117.2, 94.5, 60.1, 38.3, 34.2, 27.0, 21.0. ESI-HRMS: [M +H]+ calcd. For C18H22NO4+ m/z: 316.1543; found: 316.1542. [α]D20 −11.4 (c = 0.54 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 85/15, 1 mL/min), λ = 227 nm, tmajor = 8.59 min, tminor = 7.72 min, ee = 94.3%. 2-((2R,3S)-5-Hydroxy-2-nitro-1-(p-tolyl)pentan-3-yl)phenol (14c). Colorless oil (18 mg, 29%); 1H NMR (500 MHz, CDCl3) δ7.14−7.01 (m, 6H), 6.90−6.87 (m, 1H), δ 6.74 (d, J = 8.4 Hz, 1H), 6.27 (brs, 1H), 5.19 (td, J = 10.6, 3.1 Hz, 1H), 3.94−3.81 (m, 1H), 3.72−3.59 (m, 1H), 3.45−3.30 (m, 2H), 3.16 (dd, J = 14.4, 11.0 Hz, 1H), 2.30 (s, 3H), 2.22 (s, 1H), 1.94−1.75 (m, 2H). 13C NMR (125 MHz, CDCl3) δ153.9, 137.0, 132.6, 129.5, 128.8, 128.7, 128.6, 124.5, 121.4, 116.4, 93.5, 60.2, 37.9, 33.4, 27.0, 21.0. ESI-HRMS: [M+H]+ calcd. For C18H22NO4+ m/z: 316.1543; found: 316.1546. [α]D20 +46.3 (c = 0.43 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IA column (n-hexane/i-PrOH = 90/10, 1 mL/min), λ = 227 nm, tmajor = 16.01 min, tminor = 14.50 min, ee = 98.8%. 2-((2S,3S)-5-Hydroxy-1-(3-methoxyphenyl)-2-nitropentan-3-yl)phenol (13d). Colorless oil (22 mg, 33%); 1H NMR (500 MHz,

CDCl3) δ7.22−7.11 (m, 3H), 7.00−6.97 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.74 (dd, J = 8.2, 2.2 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 6.55 (s, 1H), 5.20 (brs, 1H), 3.78−3.74 (m, 4H), 3.62 (dd, J = 10.3, 5.1 Hz, 1H), 3.34 (dd, J = 14.2, 10.6 Hz, 1H), 3.03 (dd, J = 14.6, 11.2 Hz, 1H), 2.80 (dd, J = 14.7, 2.4 Hz, 1H), 2.12 (brs, 1H), 2.02−1.74 (m, 3H). 13 C NMR (125 MHz, CDCl3) δ159.6, 154.5, 137.5, 129.7, 128.9, 124.6, 121.7, 120.8, 117.1, 114.5, 112.4, 94.2, 60.1, 55.1, 38.7, 34.1, 27.0. ESI-HRMS: [M+H]+ calcd. For C18H22NO5+ m/z: 332.1492; found: 332.1490. [α]D20 −19.0 (c = 0.63 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IC column (n-hexane/i-PrOH = 70/30, 1 mL/min), λ = 227 nm, tmajor = 10.72 min, tminor = 10.07 min, ee = 83.0%. 2-((2R,3S)-5-Hydroxy-1-(3-methoxyphenyl)-2-nitropentan-3-yl)phenol (14d). Colorless oil (20 mg, 30%); 1H NMR (500 MHz, CDCl3) δ7.21−7.18 (m, 1H), 7.12−7.09 (m, 2H), 6.90−6.87 (m, 1H), 6.78 (dd, J = 8.3, 2.1 Hz, 1H), 6.74 (d, J = 7.9 Hz, 2H), 6.69 (s, 1H), 6.34 (brs, 1H), 5.22 (td, J = 10.8, 3.2 Hz, 1H), 3.94−3.83 (m, 1H), 3.76 (s, 3H), 3.71−3.59 (m, 1H), 3.44−3.28 (m, 2H), 3.18 (dd, J = 14.4, 11.0 Hz, 1H), 2.20 (s, 1H), 2.00−1.72 (m, 2H). 13C NMR (125 MHz, CDCl3) δ159.7, 153.9, 137.3, 129.8, 128.8, 124.4, 121.3, 121.0, 116.4, 114.6, 112.6, 93.2, 60.2, 55.2, 38.1, 33.4. ESI-HRMS: [M+H]+ calcd. For C18H22NO5+ m/z: 332.1492; found: 332.1495. [α]D20 +53.9 (c = 0.23 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 80/20, 1 mL/min), λ = 227 nm, tmajor = 13.23 min, tminor = 10.20 min, ee = 93.3%. 2-((2S,3S)-5-Hydroxy-1-(naphthalen-2-yl)-2-nitropentan-3-yl)phenol (13e). White solid (30 mg, 43%); mp 143−144 °C; 1H NMR (500 MHz, CDCl3) δ7.80−7.74 (m, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.49−7.39 (m, 3H), 7.22−7.19 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.02−6.99 (m, 1H), 6.89 (d, overlap, J = 7.9 Hz, 2H), 5.31 (brs, 1H), 3.86 (brs, 1H), 3.69−3.59 (m, 1H), 3.36 (dd, J = 13.9, 10.6 Hz, 1H), 3.23 (dd, J = 14.6, 11.3 Hz, 1H), 2.99 (dd, J = 14.7, 2.3 Hz, 1H), 2.04− 1.69 (m, 3H). 13C NMR (125 MHz, CDCl3) δ154.6, 133.4, 133.4, 132.5, 129.0, 128.4, 127.7, 127.6, 127.4, 126.4, 126.1, 125.8, 124.6, 121.6, 117.0, 94.2, 60.1, 38.9, 34.2, 27.0. ESI-HRMS: [M+H]+ calcd. For C21H22NO4+ m/z: 352.1543; found: 352.1540. [α]D20 −9.0 (c = 0.73 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH/CH2Cl2 = 88/10/2, 1 mL/min), λ = 225 nm, tmajor = 11.60 min, tminor = 9.96 min, ee = 91.7%. 2-((2R,3S)-5-Hydroxy-1-(naphthalen-2-yl)-2-nitropentan-3-yl)phenol (14e). White solid (24 mg, 34%); mp 142−143 °C; 1H NMR (500 MHz, CDCl3) δ7.80−7.75 (m, 3H), 7.61 (s, 1H), 7.48−7.41 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.14−7.11 (m, 2H), 6.92−6.89 (m, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.06 (brs, 1H), 5.40−5.31 (m, 1H), 3.98−3.87 (m, 1H), 3.75−3.65 (m, 1H), 3.52 (dd, J = 14.6, 3.0 Hz, 1H), 3.44−3.36 (m, 2H), 2.30−2.24 (m, 1H), 2.06−2.00 (m, 1H). 13C NMR (125 MHz, CDCl3) δ153.9, 133.4, 133.2, 132.5, 128.8, 128.5, 127.7, 127.6, 126.5, 126.2, 125.9, 124.4, 121.4, 116.4, 93.1, 60.1, 38.3, 33.4, 27.0. ESI-HRMS: [M+H]+ calcd. For C21H22NO4+ m/z: 352.1543; found: 352.1546. [α]D20 +43.5 (c = 0.33 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 85/15, 1 mL/min), λ = 225 nm, tmajor = 11.52 min, tminor = 12.98 min, ee = 98.2%. 2-((2S,3S)-5-Hydroxy-2-nitro-1-(1-tosyl-1H-indol-3-yl)pentan-3yl)phenol (13f). Colorless oil (34 mg, 35%); 1H NMR (500 MHz, CDCl3) δ7.89 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.30 (s, 1H), 7.27−7.24 (m, 1H), 7.23−7.12 (m, 6H), 7.01−6.99 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.78 (brs, 1H), 5.21 (brs, 1H), 3.83 (brs, 1H), 3.70−3.57 (m, 1H), 3.35 (dd, J = 14.2, 10.6 Hz, 1H), 3.19 (dd, J = 15.3, 11.2 Hz, 1H), 2.87 (dd, J = 15.4, 1.7 Hz, 1H), 2.30 (s, 3H), 2.02−1.71 (m, 3H). 13C NMR (125 MHz, CDCl3) δ154.5, 144.9, 135.1, 134.7, 130.0, 129.8, 129.1, 126.7, 124.9, 124.6, 124.4, 123.3, 121.7, 118.7, 117.1, 117.0, 113.8, 92.4, 77.3, 77.0, 76.8, 60.1, 34.0, 28.3, 27.0, 21.5. ESI-HRMS: [M+H]+ calcd. For C26H27N2O6S+ m/z: 495.1584; found: 495.1582. [α]D20 +9.2 (c = 0.45 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IA column (n-hexane/i-PrOH = 83/17, 1 mL/min), λ = 227 nm, tmajor = 12.87 min, tminor = 12.18 min, ee = 97.6%. 4782

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783

Article

The Journal of Organic Chemistry 2-((2R,3S)-5-Hydroxy-2-nitro-1-(1-tosyl-1H-indol-3-yl)pentan-3yl)phenol (14f). Colorless oil (44 mg, 45%); 1H NMR (500 MHz, CDCl3) δ7.92 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.30−7.27 (m, 1H), 7.21−7.18 (m, 1H), 7.15 (d, J = 8.1 Hz, 2H), 7.12−7.07 (m, 2H), 6.89−6.86 (m, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.34 (brs, 1H), 5.28−5.24 (m, 1H), 3.99−3.84 (m, 1H), 3.74−3.63 (m, 1H), 3.48−3.31 (m, 3H), 2.26 (s, 3H), 2.24−2.06 (m, 2H), 1.78 (s, 1H). 13C NMR (125 MHz, CDCl3) δ154.0, 144.9, 135.1, 134.7, 130.0, 129.8, 128.9, 126.7, 125.0, 124.8, 124.1, 123.4, 121.3, 118.7, 116.9, 116.3, 113.9, 91.2, 60.1, 33.1, 27.4, 21.5. ESI-HRMS: [M+H]+ calcd. For C26H27N2O6S+ m/z: 495.1584; found: 495.1587. [α]D20 +23.1 (c = 0.22 in MeOH). The enantiomeric excess was determined by HPLC analysis on Daicel Chiralpak IB column (n-hexane/i-PrOH = 85/15, 1 mL/min), λ = 227 nm, tmajor = 16.91 min, tminor = 20.59 min, ee = 99.3%.

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P.; Liu, Y.-K. Catalysts 2016, 6, 65. (g) Li, J.-Y.; Yu, K.-W.; Xie, C.-C.; Liu, Y.-K. Org. Biomol. Chem. 2017, 15, 1407. (4) Zu, L.; Zhang, S.; Xie, H.; Wang, W. Org. Lett. 2009, 11, 1627. (5) (a) Amantini, D.; Fringuelli, F.; Pizzo, F. J. Org. Chem. 2002, 67, 7238. (b) Brun, M. P.; Bischoff, L.; Garbay, C. Angew. Chem., Int. Ed. 2004, 43, 3432. (c) Kontogiorgis, C. A.; Hadjipavlou-Litina, D. J. J. Med. Chem. 2005, 48, 6400. (d) Soltau, M.; Göwert, M.; Margaretha, P. Org. Lett. 2005, 7, 5159. (e) Robert, S.; Bertolla, C.; Masereel, B.; Dogné, J.-M.; Pochet, L. J. Med. Chem. 2008, 51, 3077. (f) Gallagher, B. D.; Taft, B. R.; Lipshutz, B. H. Org. Lett. 2009, 11, 5374. (g) Pisani, L.; Muncipinto, G.; Miscioscia, T. F.; Nicolotti, O.; Leonetti, F.; Catto, M.; Caccia, C.; Salvati, P.; Soto-Otero, R.; Mendez-Alvarez, E.; Passeleu, C.; Carotti, A. J. Med. Chem. 2009, 52, 6685. (6) For selected reviews, see: (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, NY, 2001;. (b) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017. (c) Ballini, R.; Barboni, L.; Fringuelli, F.; Palmieri, A.; Pizzo, F.; Vaccaro, L. Green Chem. 2007, 9, 823. (7) (a) Yang, J. W.; Fonseca, M. T. H.; List, B. Angew. Chem., Int. Ed. 2004, 43, 6660. (b) Yang, J. W.; Fonseca, M. T. H.; Vignola, N.; List, B. Angew. Chem., Int. Ed. 2005, 44, 108. (c) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32. (d) Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 12662. (e) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368. (f) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (8) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (b) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4722. (9) See the Supporting Information for the structural characterization of compounds 9m and 9n. (10) Ishikawa, H.; Sawano, S.; Yasui, Y.; Shibata, Y.; Hayashi, Y. Angew. Chem., Int. Ed. 2011, 50, 3774. (11) (a) Rhode, O.; Hoffmann, H. M. R. Tetrahedron 2000, 56, 6479. (b) Kawagishi, H.; Masui, A.; Tokuyama, S.; Nakamura, T. Tetrahedron 2006, 62, 8463. (c) Ghosh, A. K.; Chapsal, B. D.; Baldridge, A.; Steffey, M. P.; Walters, D. E.; Koh, Y.; Amano, M.; Mitsuya, H. J. Med. Chem. 2011, 54, 622. (d) Ghosh, A. K.; Parham, G. L.; Martyr, C. D.; Nyalapatla, P. R.; Osswald, H. L.; Agniswamy, J.; Wang, Y. F.; Amano, M.; Weber, I. T.; Mitsuya, H. J. Med. Chem. 2013, 56, 6792. (e) Ghosh, A. K.; Martyr, C. D.; Kassekert, L. A.; Nyalapatla, P. R.; Steffey, M.; Agniswamy, J.; Wang, Y. F.; Weber, I. T.; Amano, M.; Mitsuya, H. Org. Biomol. Chem. 2015, 13, 11607. (12) (a) Martin, N. J. A.; Ozores, L.; List, B. J. Am. Chem. Soc. 2007, 129, 8976. (b) Martin, N. J. A.; Cheng, X.; List, B. J. Am. Chem. Soc. 2008, 130, 13862. (13) For seminal work of organocatalyzed asymmetric Michael reaction between α,β-unsaturated aldehydes and nitroalkanes, see: (a) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307. (b) Gotoh, H.; Okamura, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 4056. (c) Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S. Angew. Chem., Int. Ed. 2007, 46, 8431. (d) Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Adv. Synth. Catal. 2007, 349, 2660. (14) CCDC 1532853 (12d) contains the supplementary crystallographic data for this compound. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_request/cif.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b00461. Full optimization studies for path a, b, and c; 1H NMR and 13C NMR for all new compounds (DOCX) X-ray crystallographic data for compound 12d (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Yan-Kai Liu: 0000-0002-6559-2348 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NSFC-Shandong Joint Fund for Marine Science Research Centers (NO. U1606403), the Scientific and Technological Innovation Project Financially Supported by Qingdao National Laboratory for Marine Science and Technology (NO. 2015ASKJ02-06), and the Fundamental Research Funds for the Central Universities (NO. 201562031).

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REFERENCES

(1) For selected reviews, see: (a) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2011, 50, 8492. (b) Marson, C. M. Chem. Soc. Rev. 2012, 41, 7712. (c) Hayashi, Y. Chem. Sci. 2016, 7, 866. For selected, recent examples, see: (d) Yin, X.-P.; Zeng, X.-P.; Liu, Y.-L.; Liao, F.-M.; Yu, J.-S.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53, 13740. (e) Hayashi, Y.; Sakamoto, D.; Okamura, D. Org. Lett. 2016, 18, 4. (f) Dochain, S.; Vetica, F.; Puttreddy, R.; Rissanen, K.; Enders, D. Angew. Chem., Int. Ed. 2016, 55, 16153. (g) Xiao, Y.; Lin, J.B.; Zhao, Y.-N.; Liu, J.-Y.; Xu, P.-F. Org. Lett. 2016, 18, 6276. (2) For selected reviews, see: (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (b) Doveston, R.; Marsden, S.; Nelson, A. Drug Discovery Today 2014, 19, 813. (c) Urabe, D.; Asaba, T.; Inoue, M. Chem. Rev. 2015, 115, 9207. (d) Devi, N.; Rawal, R. K.; Singh, V. Tetrahedron 2015, 71, 183. For leading example, see: (e) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int. Ed. 2006, 45, 3635. (3) (a) Liu, Y.-K.; Li, Z.-L.; Li, J.-Y.; Feng, H.-X.; Tong, Z.-P. Org. Lett. 2015, 17, 2022. (b) Sun, X.-L.; Chen, Y.-H.; Zhu, D.-Y.; Zhang, Y.; Liu, Y.-K. Org. Lett. 2016, 18, 864. (c) You, Z.-H.; Chen, Y.-H.; Liu, Y.-K. Org. Biomol. Chem. 2016, 14, 6316. (d) Li, J.-Y.; Li, Z.-L.; Zhao, W.-W.; Liu, Y.-K.; Tong, Z.-P.; Tan, R. Org. Biomol. Chem. 2016, 14, 2444. (e) Cai, P.-W.; You, Z.-H.; Xie, L.-H.; Tan, R.; Tong, Z.-P.; Liu, Y.-K. Synthesis 2016, 48, 2581. (f) Li, Z.-L.; Liu, C.; Tan, R.; Tong, Z.4783

DOI: 10.1021/acs.joc.7b00461 J. Org. Chem. 2017, 82, 4774−4783