Asymmetric Organocatalytic One-Pot, Two-Step Sequential Process to

Article pubs.acs.org/joc

Asymmetric Organocatalytic One-Pot, Two-Step Sequential Process to Synthesize Chiral Acetal-Containing Polycyclic Derivatives from Cyclic Hemiacetals and Enones Chao Liu† and Yan-Kai Liu*,†,‡ †

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: We have developed an efficient one-pot, two-step sequential process to synthesize biologically and synthetically important chiral acetal-containing polycyclic derivatives. This novel protocol had been proved to proceed via Michael-lactolizationoxocarbenium ion ring-closing sequence, which was initiated by a key reactive enamine intermediate and interrupted the previously established reaction pathway of two different enones used in this work, and generated the corresponding cycloadducts with excellent stereoselectivity bearing up to seven continuous stereocenters. Both chiral and racemic starting cyclic hemiacetals worked well in this strategy. The synthetic applications of the obtained polycyclic products have also been demonstrated.

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INTRODUCTION

aforementioned chiral acetal-containing polycyclic frameworks remains scarce.7 Recently, we focused on the chemistry of cyclic hemiacetal which could be directly used to construct chiral heterocycles with high stereoselectivities through the asymmetric organocatalytic one-pot sequential processes.8 In this work, we became interested in employing γ-lactam-derived cyclic enone 19 and 2arylideneindane-1,3-dione 210 in an asymmetric organocatalytic one-pot sequential process to react with cyclic hemiacetal 3, respectively, in the presence of aminocatalyst (S)-4 (TMS = trimethylsilyl) providing densely functionalized chiral acetalcontaining polycyclic molecules (Scheme 1, bottom). It should be noted that this novel sequential process is challenging, since it potentially interrupted the previously established reaction pathway (Scheme 1, top), such as oxo-Diels−Alder process9b of enone 1 and [2 + 2 + 2] annulation process10a of enone 2, and thus is expected to proceed via a novel Michael-lactolizationoxocarbenium ion ring-closing sequence, which is initiated by the enamine-based Michael reaction between cyclic hemiacetal 3 and activated enones 1 and 2, respectively. Herein, we report our initial findings in developing this one-pot sequential process.

The densely functionalized chiral polycyclic frameworks, especially the ones containing acetal moiety, are often found in many compounds that have broad applications in both synthetic organic chemistry and medicinal chemistry.1 Thus, the strategies that could effectively form chiral acetal-containing polycyclic frameworks are clearly highly desirable but challenging goals, which attribute to the production of continuous multiple chiral centers with high chemo-, regio-, and stereocontrol.2 In the research field of asymmetric organocatalysis,3 the enamine-based Michael reaction between aldehydes and electron-deficient alkenes has emerged as a highly valuable C−C bond-formation strategy,4 providing versatile building blocks with high to excellent stereoselectivity for further useful transformations. Meanwhile, the asymmetric organocatalytic one-pot sequential processes,5 which could be performed under operationally simple and environmentally friendly reaction conditions, have received considerable attention due to their various synthetic utilities and extremely powerful synthetic efficiency for the construction of chiral polycyclic frameworks with high structural and stereochemical complexity. Indeed, in the past decade, remarkable progress has been described toward the asymmetric organocatalytic one-pot sequential processes initiated by the enamine-based Michael reaction to access biologically and synthetically important polycycles.6 However, expansion of this promising strategy to efficiently synthesize © 2017 American Chemical Society

Received: July 30, 2017 Published: September 15, 2017 10450

DOI: 10.1021/acs.joc.7b01915 J. Org. Chem. 2017, 82, 10450−10460

The Journal of Organic Chemistry

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Scheme 1. Designed Asymmetric Organocatalytic One-Pot, Two-Step Sequential Process

Article

RESULTS AND DISCUSSION

We began the optimization studies with 1a and (S)-3a11 as the starting substrates and the commercially available diphenylprolinol trimethylsilyl ether (S)-4 as the catalyst (for the full optimization studies, see the Supporting Information, Table S1 and S2). As shown in Table 1, the first step of this one-pot, two-step sequential process occurred by using p-NO2PhCOOH (p-NBA) as the cocatalyst in the solvent of toluene at 25 °C and was followed by BF3·Et2O catalyzed ring closure reaction at 0 °C in CH2Cl2, yielding the target chiral acetal-containing polycyclic product 5a in 68% isolated yield with >99:1 diastereoselectivity bearing four stereocenters (Table 1, entry 1). Further solvent screening revealed that solvents have a remarkable effect on the reactivity of the first step but little effect on the final diastereoselectivity of this protocol (Table 1, entries 2−6). To our delight, toluene is also a good choice for the second ring closure step, both reactivity and stereoselectivity were maintained (Table 1, entry 7). Thus, the whole process of this one-pot, two-step sequence could be carried out in one-pot conditions, thereby saving time, effort, and production costs. Additionally, compared with BF3·Et2O, neither PTSA nor TFA gave better results (Table 1, entries 8−9). Unsurprisingly, when the reaction was catalyzed by the racemic catalyst (±)-4, compounds 5a and 5′a could be isolated as an inseparable mixture of diastereoisomers (Table 1, entry 10, 5a:5′a = 50:50). Consequently, with the optimized conditions in hand (Table 1, entry 7), the scope and generality of this highly stereocontrolled one-pot, two-step sequential process was then studied by varying the substituents of both cyclic enones 1 and cyclic hemiacetals (S)-3. The results are listed in Table 2. Enones 1 with electron-deficient, electron-rich, and heterocyclic

Table 1. Optimization Studies for the One-Pot, Two-Step Sequential Processa

solvent entry

step 1

step 2

acid

t (h)b

yield (%)c

drd 5a:5′a

1 2 3 4 5 6 7 8 9 10e

toluene CH2Cl2 EtOH CH3CN DMF THF toluene toluene toluene toluene

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene toluene toluene toluene

BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O BF3·Et2O PTSA TFA BF3·Et2O

12 20 48 48 48 48 24 24 24 24

68 57 45 34 52 33 66 45 63 66

>99:1 >99:1 97:3 93:7 92:8 98:2 >99:1 97:3 97:3 50:50

a

Unless otherwise noted, all reactions were carried out using 1a (0.20 mmol, 1.0 equiv) and (S)-3a (0.24 mmol, 1.2 equiv) in solvent (0.2 mL) with (S)-4 (20 mol%) and p-NBA (20 mol%) at 25 °C. After full conversion of the first step, the solvent was then replaced by a new solvent (0.2 mL) for the second steps and the acid (0.40 mmol, 2.0 equiv) were added to the reaction mixture slowly at 0 °C, and then stirred at this temperature for another 24 h. bRefers to the first step. cIsolated yield of 5a. dDetermined by chiral HPLC analysis of the isolated products. e(±)-4 was used in the reaction. PTSA = p-toluene sulfonic acid. DMF = N,N-dimethylformamide. THF = tetrahydrofuran. TFA = trifluoroacetic acid. 10451


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The Journal of Organic Chemistry Table 2. Substrate Scope of Cyclic Enones 1 and Cyclic Hemiacetals (S)-3a

entry

5/n

R1

R2

R3

yieldb

drc

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18d

5a/1 5b/1 5c/1 5d/1 5e/1 5f/1 5g/1 5h/1 5i/1 5j/1 5k/1 5l/1 5m/1 5n/1 5o/2 5p/1 5q/1 5a/1

Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-BrPh 4-ClPh 4-MePh Ph Ph Ph Ph

Ph 4-NO2Ph 4-ClPh 4-MePh 2-FPh 3-BrPh 3-MePh 3-MeOPh 2-thienyl cinnamyl 2-naphthyl Ph Ph Ph Ph Ph Ph Ph

Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn 2-MeOBn 4-FBn Bn

68 62 64 69 54 65 63 62 35 52 64 64 65 30 32 64 60 70

>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 >20:1

Scheme 2. Chirality Match Relationship between Precursors, Catalyst and the Stereochemical Outcome

acetals 3 and the catalyst (R)-4 (Scheme 2, c and d). These results suggested that the chirality of (R)- and (S)-3 had no influence on both the diastereoselectivity and reactivity, and thus this one-pot sequential process is catalyst-controlled rather than substrate-controlled stereoselective reaction process. With these results in hand, we next focused on the scope of the reaction between enones 2 and cyclic hemiacetals (S)-3a under the same optimized conditions. As shown in Table 3, several substituted enones 2 containing electron-withdrawing and electron-donating groups on the aromatic ring as well as heteroaromatic substituent generated polycyclic products 7a− 7h in acceptable yield with excellent diastereoselectivity.

a

Unless otherwise noted, all reactions were carried out using 1 (0.20 mmol, 1.0 equiv) and (S)-3 (0.24 mmol, 1.2 equiv) in toluene (0.2 mL) with (S)-4 (20 mol%) and p-NBA (20 mol%) at 25 °C. After full conversion of the first step, BF3·Et2O (0.40 mmol, 2.0 equiv) were added dropwise to the reaction mixture at 0 °C, and then stirred for another 24 h. bIsolated yield of 5. cDetermined by 1H NMR spectroscopy on the isolated products. dReaction was performed on a 2 mmol scale.

substituents on the aromatic ring, as well as 2-naphthyl and cinnamyl, were all well tolerated, affording the corresponding polycyclic products 5a−5k in moderate to good yield with excellent diastereoselectivity (Table 2, entries 1−11). Pleasingly, a series of aryl substituted cyclic hemiacetals (S)-3 and also the one containing a six-membered ring proved to be suitable for this sequence (Table 2, entries 12−15).12 Additionally, both the reactivity and efficiency remained excellent when changing the substituent on the N atom of enone 1 (Table 2, entries 16 and 17). To our delight, the reaction could be performed on a 2 mmol scale (Table 2, entry 18), and the desired product 5a was obtained in slightly higher yield with excellent diastereoselectivity. To understand the excellent diastereoselectivity observed in this one-pot, two-step sequential process, we investigated the effect of both starting cyclic hemiacetal 3 and catalyst 4 (Scheme 2). Starting from racemic cyclic hemiacetal (±)-3a, polycyclic products 5a and 6 were formed as two readily separable epimers (1:1) at O-benzyl position (Scheme 2, a) and each with excellent diastereoselectivity. This result indicates that it is possible to explore this one-pot, two-step sequential process with racemic cyclic hemiacetal 3 to deliver products with high stereoselectivity and suggests that this process is highly atom economic pathway. As expected, product 6 could be further formed with similar diastereoselectivity using cyclic hemiacetal (R)-3a and catalyst (S)-4 (Scheme 2, b). Moreover, epimers 5′a and 6′ were obtained, respectively, with excellent diastereoselectivity regardless of the chirality of cyclic hemi-

Table 3. Substrate Scope of Cyclic Enones 2 and Cyclic Hemiacetals (S)-3aa

entry

7

R

yieldb

drc

1 2 3 4 5 6 7 8

7a 7b 7c 7d 7e 7f 7g 7h

Ph 2-NO2Ph 3-BrPh 4-ClPh 2-MeOPh 3-MeOPh 4-MePh 2-thienyl

47 43 40 45 40 51 53 33

>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 (0.20 mmol, 1.0 equiv) and (S)-3a (0.24 mmol, 1.2 equiv) in toluene (0.2 mL) with (S)-4 (20 mol%) and p-NBA (20 mol%) at 25 °C. After full conversion of the first step, BF3·Et2O (0.40 mmol, 2.0 equiv) were added dropwise to the reaction mixture at 0 °C, and then stirred for another 24 h. bIsolated yield of 7. cDetermined by 1H NMR spectroscopy on the isolated products. 10452


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The relative and absolute configurations of 5a and 7a were unambiguously determined by X-ray analysis,14 and the configuration of all the other examples were assigned by NOE experiments and analogy. To explain the observed absolute stereochemical outcome, a proposed mechanism for the generation of 5a is rationalized in Scheme 4. The asymmetric organocatalytic one-pot, two-step sequential process is initiated by the formation of the enamine intermediate between the catalyst (S)-4 and the cyclic hemiacetal (S)-3a, which attacked the cyclic enone 1a from the Re face thus affording the Michael adduct 12 and followed by intramolecular acetalization yielding the intermediate 8 containing a hemiacetal moiety in the structure. The subsequent nucleophilic attack of the hydroxy group of the enol to the Si face of the oxocarbenium ion intermediate, induced by BF3·Et2O, offers the target chiral acetal-containing polycyclic product 5a in a diastereomerically pure form. Accordingly, compound 7a is proposed to be formed via a similar stereocontrolled pathway. Next, selected transformations were performed to illustrate the synthetic potential of the corresponding chiral acetalcontaining polycyclic products 5 and 7 (Scheme 5). Starting from 5a, the cyclic hemiacetal 13, which was easily achieved by Pd/C catalyzed debenzylation, could be reduced to fused oxygen-containing heterocycle 14 in the presence of Et3SiH and BF3·Et2O. Interestingly, 5a did not generate any product 9 in the presence of Et3SiH and BF3·Et2O (Scheme 3, a), while the use of TiCl4, instead of BF3·Et2O, led to the desired 9 in good yield with high diastereoselectivity. A reduction of 7a triggered by NaBH4 in MeOH lead to the polycycle 15, which subsequently underwent a three-step sequence involving one olefin hydrogenation and two reductive debenzylation at 40 °C to afford fully substituted pyran derivative 16 bearing five continuous stereocenters, and the absolute configuration of the product 16 was assigned by a single-crystal X-ray analysis.13 We also found that the reduction of 15 working at a lower temperature (25 °C versus 40 °C) led to 17 with excellent diastereoselectivity containing six continuous stereocenters and a preserved hydroxy group. Additionally, by treating 15 with Et3SiH and BF3·Et2O, the O,O-acetal moiety could be chemoselectively opened to afford the oxocarbenium ion intermediate, which was smoothly transformed to enone 18 via a domino process involving reduction and dehydroxylation sequence. Moreover, compound 19, which contained five continuous stereogenic centers, was easily accessed via simple reduction conditions at 25 °C. Finally, tetracyclic 20, one of the epimers of 17, could be obtained in good isolated yield under mild reduction conditions. It should be noted that cyclic

In order to demonstrate the possible reaction pathway, several control experiments were conducted to obtain more mechanistic details (Scheme 3). Generally, there are two Scheme 3. Control Experiments

possible intermediates 8 and 8′ could be involved in this onepot, two-step sequential process. Starting from the reactoin of cyclic hemiacetal (S)-3a and enone 1a catalyzed by (S)-4, intermediate 8 was proposed to be formed via Michaellactolization sequence, while intermediate 8′ might be obtained by a Michael-enolization-lactolization sequence.13 However, in the presence of BF3·Et2O and Et3SiH, the subsequent reduction reaction lead to 9 as the unique product, and neither 10 nor 5a was obtained (Scheme 3, a). Moreover, no reaction occurred when compound 5a was subjected to the same reduction conditions. Additionally, similar behavior was observed in the reaction between (S)-3a and enone 2a, resulting in the formation of compound 11 as the only product by the Michael-lactolization-reduction sequence (Scheme 3, b). All these results suggested that this novel one-pot, two-step sequential process proceeded via Michael-lactolization-oxocarbenium ion ring-closing sequence.

Scheme 4. Proposed Mechanism for the Asymmetric Organocatalytic One-Pot, Two-Step Sequential Process

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The Journal of Organic Chemistry Scheme 5. Useful Transformations

center and collected on a Bruker Smart-1000 CCD diffractometer equipped with a graphite-monochromatized Mo Kα radiation (0.71073 Å) at 291(2) K. 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, and Alfa Aesar used as received, without further purification. (S)- and (R)-diphenylprolinol silyl ether is commercially available from Daicel chiral Technologies. The γ-lactam-derived cyclic enone15 1, 2-arylideneindane-1,3-dione16 2, and chiral hemiacetals11 3, were prepared according to the literature procedures. General Procedure for the Synthesis of Chiral Cyclic Hemiacetal 3. In an oven-dried, 100 mL round-bottom flask equipped with a magnetic stirring bar in a stream of nitrogen, (−)-DIP-Chloride (7.7 mmol) was dissolved in THF (50 mL) at −25 °C. After the addition of the corresponding keto ester (7.0 mmol), the solution was stirred for 2 h, and then the mixture was warmed to 0 °C before quenched by 2.2 equiv of diethanolamine. This mixture was

compounds 9 and 13−20 were formed with multiple stereogenic centers with good to excellent diastereoselectivities.

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CONCLUSION In conclusion, we have developed a novel asymmetric organocatalytic one-pot, two-step sequential process to synthesize biologically and synthetically important chiral acetal-containing polycyclic frameworks with excellent stereoselectivities bearing multiple stereocenters. On the basis of some initial control experiments, this one-pot sequential process had been proved to be challengeable, as it interrupted the previously established reaction pathway, such as oxo-Diels− Alder process of enone 1 and [2 + 2 + 2] annulation process of enone 2, and proceeded via a Michael-lactolization-oxocarbenium ion ring-closing sequence, which was initiated by a key reactive enamine intermediate. Moreover, selected transformations demonstrated that the results present herein have a potential utility on the synthesis of related functionalized chiral heterocycles.

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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 10454


Article

The Journal of Organic Chemistry filtered through a silica gel and purified by flash chromatography affording the pure hydroxy ester. The hydroxy ester prepared as described above was dissolved in CH2Cl2 (10 mL), and the solution was cooled to 0 °C, followed by the addition of 4 drops of trifluoroacetic acid. Stirring for 6 h at room temperature completed the lactonization, and the reaction mixture was worked up with aqueous sodium bicarbonate. The organic layer was washed with water, dried (MgSO4), and concentrated to get the lactone without further purification. A solution of DIBAL-H (1.5 M in toluene, 7.5 mmol) was added dropwise to a solution of the obtained lactone (5.0 mmol) in dry toluene (50 mL) maintained at −78 °C over a period of 1.5 h. The reaction mixture was stirred for another 4.5 h at −78 °C, then quenched by the dropwise addition of methanol (3.3 mL). The mixture was allowed to warm to 0 °C and diluted with water (8.8 mL). After mechanically stirring for 30 min, the brown slurry was filtered and washed thoroughly with distilled diethyl ether (5 × 100 mL). The filtrate was concentrated at reduced pressure to afford crude product as a colorless oil that was purified by flash column chromatography on silica gel to give the desired starting cyclic hemiacetal 3. General Procedure for Asymmetric Synthesis of 5. A glass vial equipped with a magnetic stirring bar was charged with 1 (0.20 mmol, 1.0 equiv), and (S)-3 (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (S)-4 (13.0 mg, 0.04 mmol) and p-NO2PhCOOH (6.7 mg, 0.04 mmol) at 25 °C. After the Michael addition had been completed, BF3· Et2O (0.40 mmol, 2.0 equiv) was added dropwise at 0 °C. The reaction was stirred at this temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the desired product 5. ( 2S , 3 aR , 4S , 8a S) - 6- B e n z yl- 2 , 4- d ip h e n yl - 2, 3 , 3a , 5, 6 , 8a hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (5a). White solid (57 mg, 68%); mp 210−211 °C; 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 7.4 Hz, 2H), 7.35 (dd, J = 13.0, 7.1 Hz, 4H), 7.29 (d, J = 6.7 Hz, 2H), 7.28−7.24 (m, 3H), 7.22 (d, J = 7.3 Hz, 2H), 7.15 (d, J = 7.3 Hz, 2H), 5.74 (d, J = 3.3 Hz, 1H), 5.16 (dd, J = 10.2, 6.1 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 3.61 (s, 1H), 3.53 (d, J = 2.4 Hz, 2H), 2.70−2.62 (m, 1H), 2.56 (dt, J = 12.4, 6.3 Hz, 1H), 1.83 (dd, J = 23.6, 12.1 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.1, 147.0, 142.9, 142.8, 141.6, 137.0, 129.4, 128.8, 128.6, 128.3, 127.8, 127.7, 127.6, 127.2, 126.3, 118.5, 100.0, 83.0, 47.9, 47.8, 46.7, 40.1,38.3. ESI-HRMS [M + H]+ calcd. For C28H26NO3 m/z 424.1907, found 424.1908. [α] D 20 +12.4 (c = 0.12 in CHCl 3 ). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-4-(4-nitrophenyl)-2-phenyl2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5b). White solid (58 mg, 62%); mp 139−140 °C; 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 9.0 Hz, 4H), 7.28 (ddd, J = 7.0, 5.5, 4.6 Hz, 4H), 7.23−7.19 (m, 2H), 5.72 (d, J = 3.4 Hz, 1H), 5.18 (dd, J = 10.5, 5.5 Hz, 1H), 4.71 (d, J = 14.9 Hz, 1H), 4.52 (d, J = 14.9 Hz, 1H), 3.74 (s, 1H), 3.60− 3.43 (m, 2H), 2.66−2.57 (m, 2H), 1.85 (dd, J = 22.0, 10.8 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 164.7, 149.9, 147.4, 143.7, 141.2, 136.7, 128.9, 128.9, 128.3, 128.2, 128.0, 127.9, 126.3, 124.7, 116.5, 99.7, 83.0, 47.6, 47.2, 46.8, 39.8, 38.1. ESI-HRMS [M + H]+ calcd. For C28H25N2O5 m/z 469.1758, found 469.1756. [α]D20 +10.4 (c = 0.60 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-4-(4-chlorophenyl)-2-phenyl2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5c). White solid (57 mg, 64%); mp 225−226 °C; 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.3 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.33−7.30 (m, 3H), 7.29−7.23 (m, 3H), 7.21 (d, J = 6.8 Hz, 2H), 7.08 (t, J = 5.5 Hz, 2H), 5.71 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 10.4, 6.0 Hz, 1H), 4.73 (d, J = 14.9 Hz, 1H), 4.50 (d, J = 14.9 Hz, 1H), 3.59 (s, 1H), 3.53 (s, 1H), 3.50 (s, 1H), 2.61 (ddd, J = 13.0, 6.6, 3.8 Hz, 1H), 2.58− 2.52 (m, 1H), 1.81 (dd, J = 24.0, 11.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 164.9, 143.1, 141.4, 141.2, 136.9, 133.5, 129.6, 128.9, 128.6, 128.5, 128.3, 127.9, 127.8, 126.3, 117.9, 99.9, 83.0, 47.8, 47.7, 46.8, 39.5, 38.2. ESI-HRMS [M + H]+ calcd. For C28H25ClNO3 m/z

458.1517, found 458.1518. [α]D20 +9.1 (c = 0.25 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-2-phenyl-4-(p-tolyl)-2,3,3a,5,6,8ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (5d). White solid (60 mg, 69%); mp 203−204 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.33−7.24 (m, 4H), 7.21 (d, J = 7.0 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.9 Hz, 2H), 5.73 (d, J = 3.5 Hz, 1H), 5.16 (dd, J = 10.3, 6.1 Hz, 1H), 4.74 (d, J = 14.9 Hz, 1H), 4.49 (d, J = 14.9 Hz, 1H), 3.57 (s, 1H), 3.52 (d, J = 11.2 Hz, 2H), 2.67−2.59 (m, 1H), 2.54 (dt, J = 12.4, 6.3 Hz, 1H), 2.33 (s, 3H), 1.81 (dd, J = 23.6, 12.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.2, 142.7, 141.6, 139.8, 137.3, 137.0, 130.0, 128.8, 128.6, 128.3, 127.8, 127.7, 127.0, 126.4, 118.8, 100.1, 82.9, 48.1, 47.8, 46.8, 39.7, 38.3, 21.1. ESI-HRMS [M + H]+ calcd. For C29H28NO3 m/z 438.2064, found 438.2066. [α]D20 +28.8 (c = 0.44 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4R,8aS)-6-Benzyl-4-(2-fluorophenyl)-2-phenyl2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5e). White solid (48 mg, 54%); mp 216−217 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.33−7.20 (m, 7H), 7.15−7.03 (m, 3H), 5.70 (d, J = 3.5 Hz, 1H), 5.19 (dd, J = 10.3, 6.1 Hz, 1H), 4.74 (d, J = 14.9 Hz, 1H), 4.52 (d, J = 14.9 Hz, 1H), 4.00 (s, 1H), 3.57 (s, 2H), 2.72−2.64 (m, 1H), 2.60 (dt, J = 12.5, 6.3 Hz, 1H), 1.83 (d, J = 11.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.0, 161.2, 159.2, 143.7, 141.5, 136.9, 129.3, 129.2, 128.9, 128.7, 128.3, 127.9, 127.8, 126.3, 125.0, 124.9, 117.0, 116.1, 115.9, 100.0, 83.1, 47.8, 46.8, 38.1, 32.3. ESI-HRMS [M + H]+ calcd. For C28H25FNO3 m/z 442.1813, found 442.1814. [α]D20 +10.1 (c = 0.80 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-4-(3-bromophenyl)-2-phenyl2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5f). White solid (65 mg, 65%); mp 210−212 °C; 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.3 Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.33−7.29 (m, 3H), 7.28−7.25 (m, 2H), 7.22 (t, J = 7.4 Hz, 3H), 7.08 (d, J = 7.7 Hz, 1H), 5.72 (d, J = 3.6 Hz, 1H), 5.17 (dd, J = 10.3, 6.1 Hz, 1H), 4.75 (d, J = 15.0 Hz, 1H), 4.50 (d, J = 14.9 Hz, 1H), 3.57 (s, 1H), 3.53 (d, J = 5.7 Hz, 2H), 2.63 (dd, J = 14.4, 4.9 Hz, 1H), 2.55 (dt, J = 12.5, 6.3 Hz, 1H), 1.81 (dd, J = 23.5, 12.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 164.9, 145.0, 143.3, 141.4, 136.9, 131.0, 130.8, 130.4, 128.9, 128.7, 128.3, 127.9, 127.8, 126.3, 125.8, 123.5, 117.5, 99.8, 83.0, 47.7, 47.6, 46.8, 39.7, 38.2. ESI-HRMS [M + H]+ calcd. For C28H25BrNO3 m/z 502.1012, found 502.1013. [α]D20 +14.3 (c = 0.46 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-2-phenyl-4-(m-tolyl)-2,3,3a,5,6,8ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (5g). White solid (55 mg, 63%); mp 204−205 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.33−7.18 (m, 7H), 7.08 (d, J = 7.5 Hz, 1H), 6.94 (s, 2H), 5.74 (d, J = 3.5 Hz, 1H), 5.16 (dd, J = 10.3, 6.1 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.49 (d, J = 14.9 Hz, 1H), 3.57 (s, 1H), 3.53 (s, 2H), 2.69−2.60 (m, 1H), 2.55 (dt, J = 12.4, 6.3 Hz, 1H), 2.34 (s, 3H), 1.82 (dd, J = 23.6, 12.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.2, 142.8, 142.8, 141.6, 139.2, 137.0, 129.3, 128.8, 128.6, 128.3, 128.3, 127.8, 127.8, 127.7, 126.4, 124.2, 118.7, 100.1, 83.0, 47.9, 47.8, 46.8, 40.0, 38.3, 21.6. ESI-HRMS [M + H]+ calcd. For C29H28NO3 m/z 438.2064, found 438.2065. [α]D20 +16.2 (c = 1.67 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-4-(3-methoxyphenyl)-2-phenyl2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5h). White solid (56 mg, 62%); mp 187−188 °C; 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.27 (dt, J = 7.9, 7.3 Hz, 5H), 7.21 (d, J = 7.2 Hz, 2H), 6.80 (d, J = 9.6 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 5.73 (d, J = 3.3 Hz, 1H), 5.15 (dd, J = 10.2, 6.1 Hz, 1H), 4.73 (d, J = 14.9 Hz, 1H), 4.49 (d, J = 14.9 Hz, 1H), 3.78 (s, 3H), 3.58 (s, 1H), 3.54 (s, 2H), 2.69−2.61 (m, 1H), 2.55 (dt, J = 12.3, 6.3 Hz, 1H), 1.81 (dd, J = 23.6, 12.1 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 165.1, 160.3, 144.3, 142.8, 141.6, 136.9, 130.4, 128.8, 128.6, 128.2, 127.8, 127.7, 126.3, 119.4, 118.5, 113.1, 112.5, 100.0, 82.9, 55.4, 47.8, 47.7, 46.7, 40.0, 38.2. ESI-HRMS 10455


Article

The Journal of Organic Chemistry [M + H]+ calcd. For C29H28NO4 m/z 454.2013, found 454.2014. [α]D20 +9.1 (c = 0.27 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4R,8aS)-6-Benzyl-2-phenyl-4-(thiophen-2-yl)2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5i). White solid (29 mg, 35%); mp 215−216 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 7.34 (s, 1H), 7.33−7.28 (m, 2H), 7.28−7.24 (m, 2H), 7.25−7.16 (m, 3H), 6.97−6.91 (m, 1H), 6.82 (d, J = 2.3 Hz, 1H), 5.78 (d, J = 3.1 Hz, 1H), 5.20 (dd, J = 10.1, 6.3 Hz, 1H), 4.73 (d, J = 15.0 Hz, 1H), 4.52 (d, J = 14.9 Hz, 1H), 3.91 (s, 1H), 3.68 (d, J = 17.8 Hz, 1H), 3.57 (d, J = 17.8 Hz, 1H), 2.79−2.73 (m, 1H), 2.55 (dt, J = 12.3, 6.3 Hz, 1H), 1.79 (dd, J = 23.8, 12.1 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.0, 146.4, 142.3, 141.5, 136.9, 128.9, 128.7, 128.3, 127.9, 127.8, 127.4, 126.3, 124.9, 124.5, 118.2, 100.1, 83.3, 48.3, 47.7, 46.8, 37.6, 34.8. ESI-HRMS [M + H]+ calcd. For C26H23NO3S m/z 430.1471, found 430.1474. [α]D20 +37.2 (c = 0.50 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4R,8aS)-6-Benzyl-2-phenyl-4-((E)-styryl)-2,3,3a,5,6,8ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (5j). White solid (47 mg, 52%); mp 199−200 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 7.35−7.29 (m, 5H), 7.30−7.23 (m, 4H), 6.38 (d, J = 15.7 Hz, 1H), 6.15 (dd, J = 15.7, 8.3 Hz, 1H), 5.73 (d, J = 3.5 Hz, 1H), 5.55 (s, 1H), 5.21 (dd, J = 10.3, 6.2 Hz, 1H), 4.70 (d, J = 14.9 Hz, 1H), 4.57 (d, J = 14.9 Hz, 1H), 3.74 (d, J = 17.9 Hz, 1H), 3.57 (d, J = 17.9 Hz, 1H), 3.21 (d, J = 8.2 Hz, 1H), 2.70−2.59 (m, 1H), 2.48 (dt, J = 12.4, 6.4 Hz, 1H), 1.76 (dd, J = 23.4, 12.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.1, 142.3, 141.6, 137.0, 136.2, 131.4, 130.1, 128.9, 128.8, 128.6, 128.3, 128.1, 127.8, 127.8, 126.4, 126.3, 118.2, 100.0, 83.1, 47.8, 46.8, 45.5, 37.4, 37.0. ESIHRMS [M + H]+ calcd. For C30H28NO3 m/z 450.2064, found 450.2065. [α]D20 +8.5 (c = 0.27 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-4-(naphthalen-2-yl)-2-phenyl2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5k). White solid (60 mg, 64%); mp 230−231 °C; 1H NMR (500 MHz, CDCl3) δ 7.85 (t, J = 7.6 Hz, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.57 (s, 1H), 7.50 (t, J = 7.4 Hz, 4H), 7.37 (t, J = 7.6 Hz, 2H), 7.33−7.25 (m, 4H), 7.23 (dd, J = 6.5, 5.3 Hz, 2H), 5.81 (d, J = 3.6 Hz, 1H), 5.18 (dd, J = 10.3, 6.1 Hz, 1H), 4.77 (d, J = 14.9 Hz, 1H), 4.49 (d, J = 14.9 Hz, 1H), 3.79 (s, 1H), 3.57 (q, J = 18.0 Hz, 2H), 2.77−2.70 (m, 1H), 2.61 (dt, J = 12.4, 6.4 Hz, 1H), 1.89 (dd, J = 23.6, 12.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.1, 142.98, 141.6, 140.0, 136.9, 133.6, 132.6, 129.4, 128.8, 128.6, 128.2, 127.8, 127.8, 127.8, 127.7, 126.8, 126.3, 126.3, 125.7, 125.2, 118.6, 100.1, 83.0, 47.8, 46.7, 40.1, 38.3. ESI-HRMS [M + H]+ calcd. For C32H28NO3 m/z 474.2064, found 474.2065. [α]D20 +9.9 (c = 0.27 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-2-(4-bromophenyl)-4-phenyl2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5l). White solid (64 mg, 64%); mp 149−150 °C; 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 2H), 7.38−7.31 (m, 4H), 7.31− 7.24 (m, 4H), 7.21 (d, J = 7.3 Hz, 2H), 7.13 (d, J = 7.4 Hz, 2H), 5.72 (d, J = 3.5 Hz, 1H), 5.12 (dd, J = 10.2, 6.2 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 3.60 (s, 1H), 3.53 (d, J = 2.6 Hz, 2H), 2.65 (dt, J = 13.0, 5.0 Hz, 1H), 2.56 (dt, J = 12.4, 6.4 Hz, 1H), 1.76 (dd, J = 23.5, 12.1 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.0, 142.8, 142.6, 140.8, 136.9, 131.7, 129.4, 128.9, 128.3, 128.1, 127.8, 127.7, 127.2, 121.7, 118.6, 100.0, 82.3, 47.9, 47.8, 46.8, 40.1, 38.2. ESI-HRMS [M + H]+ calcd. For C28H25BrNO3 m/z 502.1012, found 502.1013. [α]D20 +35.1 (c = 0.65 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-2-(4-chlorophenyl)-4-phenyl2,3,3a,5,6,8a-hexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)one (5m). White solid (59 mg, 65%); mp 218−219 °C; 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 2H), 7.38−7.24 (m, 8H), 7.21 (d, J = 7.0 Hz, 2H), 7.14 (d, J = 7.2 Hz, 2H), 5.72 (d, J = 3.5 Hz, 1H), 5.13 (dd, J = 10.2, 6.2 Hz, 1H), 4.74 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 3.61 (s, 1H), 3.54 (d, J = 3.6 Hz, 2H), 2.70−2.51 (m, 2H), 1.76 (dd, J = 23.4, 12.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.0, 142.8, 142.6, 140.3, 136.9, 133.5, 129.4, 128.9, 128.8, 128.3,

127.8, 127.7, 127.6, 127.1, 118.6, 100.0, 82.2, 47.9, 47.8, 46.8, 40.0, 38.2. ESI-HRMS [M + H]+ calcd. For C28H25ClNO3 m/z 458.1517, found 458.1516. [α]D20 +12.5 (c = 0.34 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-Benzyl-4-phenyl-2-(p-tolyl)-2,3,3a,5,6,8ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (5n). White solid (26 mg, 30%); mp 171−172 °C; 1H NMR (500 MHz, CDCl3) δ 7.43−7.31 (m, 4H), 7.29 (d, J = 7.5 Hz, 2H), 7.27−7.24 (m, 2H), 7.21 (d, J = 7.3 Hz, 2H), 7.15 (dd, J = 11.5, 7.9 Hz, 4H), 5.73 (d, J = 3.3 Hz, 1H), 5.13 (dd, J = 10.2, 6.1 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 3.60 (s, 1H), 3.53 (d, J = 2.3 Hz, 2H), 2.68− 2.61 (m, 1H), 2.53 (dt, J = 12.3, 6.3 Hz, 1H), 2.34 (s, 3H), 1.81 (dd, J = 23.6, 12.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.2, 142.9, 142.8, 138.6, 137.54, 137.0, 129.4, 129.3, 128.9, 128.3, 127.8, 127.6, 127.2, 126.4, 118.5, 100.0, 82.9, 77.2, 47.9, 47.8, 46.8, 40.1, 38.3, 21.3. HRMS [M + H]+ calcd. For C29H28NO3 m/z 438.2064, found 438.2065. [α]D20 +10.4 (c = 0.45 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,4aR,5S,9aS)-7-Benzyl-2,5-diphenyl-3,4,4a,6,7,9a-hexahydro2H-pyrano[3′,2′:5,6]pyrano[2,3-c]pyrrol-8(5H)-one (5o). White solid (28 mg, 32%); mp 196−197 °C; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 7.4 Hz, 3H), 7.32 (d, J = 5.8 Hz, 4H), 7.28 (d, J = 10.8 Hz, 3H), 7.27−7.21 (m, 3H), 7.14 (d, J = 7.4 Hz, 2H), 5.54 (s, 1H), 5.12 (d, J = 11.6 Hz, 1H), 4.83 (d, J = 14.9 Hz, 1H), 4.51 (d, J = 14.9 Hz, 1H), 3.68 (d, J = 17.9 Hz, 1H), 3.59 (d, J = 18.0 Hz, 1H), 3.39 (s, 1H), 2.14 (t, J = 7.7 Hz, 1H), 1.97 (dd, J = 13.1, 2.2 Hz, 1H), 1.87 (dd, J = 9.2, 7.1 Hz, 2H), 1.77 (dd, J = 19.6, 11.7 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.1, 144.7, 142.8, 141.7, 137.1, 129.2, 128.9, 128.4, 128.3, 127.8, 127.6, 127.5, 127.4, 126.2, 119.3, 96.5, 72.6, 48.0, 46.8, 44.9, 41.7, 33.4, 25.7. ESI-HRMS [M + H]+ calcd. For C29H28NO3 m/ z 438.2064, found 438.2063. [α]D20 +9.3 (c = 0.53 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-(2-Methoxybenzyl)-2,4-diphenyl-2,3,3a,5,6,8ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (5p). White solid (58 mg, 64%); mp 184−184 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.3 Hz, 2H), 7.35 (t, J = 6.5 Hz, 4H), 7.27 (dd, J = 11.4, 3.7 Hz, 2H), 7.22 (dd, J = 17.5, 8.6 Hz, 2H), 7.16 (d, J = 7.2 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.72 (d, J = 3.5 Hz, 1H), 5.15 (dd, J = 10.3, 6.1 Hz, 1H), 4.73 (d, J = 14.9 Hz, 1H), 4.57 (d, J = 14.9 Hz, 1H), 3.77 (s, 3H), 3.62 (s, 1H), 3.58 (s, 2H), 2.69− 2.61 (m, 1H), 2.55 (dt, J = 12.4, 6.3 Hz, 1H), 1.82 (dd, J = 23.6, 12.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.1, 157.5, 143.0, 141.7, 130.2, 129.3, 129.0, 128.6, 127.8, 127.5, 127.2, 126.4, 125.1, 120.8, 118.2, 110.5, 99.9, 83.0, 55.4, 48.3, 47.9, 41.4, 40.0, 38.3. ESI-HRMS [M + H]+ calcd. For C29H28NO4 m/z 454.2013, found 454.2012. [α]D20 +32.6 (c = 0.62 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,8aS)-6-(4-Fluorobenzyl)-2,4-diphenyl-2,3,3a,5,6,8ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (5q). White solid (53 mg, 60%); mp 208−209 °C; 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 4H), 7.31−7.24 (m, 2H), 7.23−7.16 (m, 2H), 7.14 (d, J = 7.4 Hz, 2H), 6.97 (t, J = 8.5 Hz, 2H), 5.73 (d, J = 3.4 Hz, 1H), 5.16 (dd, J = 10.2, 6.1 Hz, 1H), 4.69 (d, J = 14.9 Hz, 1H), 4.44 (d, J = 15.0 Hz, 1H), 3.62 (s, 1H), 3.52 (d, J = 5.4 Hz, 2H), 2.69−2.62 (m, 1H), 2.56 (dt, J = 12.4, 6.3 Hz, 1H), 1.84− 1.77 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 165.1, 163.4, 161.4, 142.8, 142.7, 141.60, 132.8, 129.9, 129.9, 129.4, 128.6, 127.8, 127.6, 127.1, 126.3, 118.6, 115.8, 115.6, 100.1, 83.0, 47.9, 47.7, 46.0, 40.1, 38.3. ESI-HRMS [M + H]+ calcd. For C28H25FNO3 m/z 442.1813, found 442.1815. [α]D20 +12.7 (c = 0.22 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for Asymmetric Synthesis of 5′a. A glass vial equipped with a magnetic stirring bar was charged with 1 (0.20 mmol, 1.0 equiv), and (S)-3a (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (R)-4 (13.0 mg, 0.04 mmol) and p-NO2PhCOOH (6.7 mg, 0.04 mmol) and at 25 °C. After the Michael addition had been completed, BF3·Et2O (0.40 mmol, 2.0 equiv) was added dropwise at 0 °C. The reaction was stirred at this temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the desired product 5′a. 10456


Article

The Journal of Organic Chemistry ( 2S ,3 aS, 4 R, 8aR )- 6- Be n zy l -2 ,4 -d iph e n y l -2 ,3 , 3a, 5, 6 ,8 ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (5′a). White solid (53 mg, 62%); mp 114−115 °C; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 7.1 Hz, 3H), 7.29−7.25 (m, 3H), 7.24 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.3 Hz, 1H), 5.84 (d, J = 3.4 Hz, 1H), 5.48 (dd, J = 9.2, 2.1 Hz, 1H), 4.80 (d, J = 14.8 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 3.66−3.47 (m, 2H), 2.62 (ddd, J = 11.6, 8.4, 3.1 Hz, 1H), 2.34 (dd, J = 21.7, 12.1 Hz, 1H), 2.24−2.12 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 165.1, 143.8, 142.7, 142.5, 137.0, 129.4, 128.9, 128.6, 128.3, 127.8, 127.7, 127.6, 127.3, 125.6, 118.3, 100.6, 80.0, 77.2, 47.9, 46.8, 45.6, 40.1, 36.7. ESI-HRMS [M + H]+ calcd. For C28H26NO3 m/z 424.1907, found 424.1908. [α]D20 −20.4 (c = 1.0 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for Asymmetric Synthesis of 6. A glass vial equipped with a magnetic stirring bar was charged with 1 (0.20 mmol, 1.0 equiv), and (R)-3a (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (S)-4 (13.0 mg, 0.04 mmol) and p-NO2PhCOOH (6.7 mg, 0.04 mmol) and at 25 °C. After the Michael addition had been completed, BF3·Et2O (0.40 mmol, 2.0 equiv) was added dropwise at 0 °C. The reaction was stirred at this temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the desired product 6. ( 2R,3 aR,4S ,8aS )-6-Benzyl -2 ,4-diphenyl-2,3,3a,5,6,8 ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (6). White solid (52 mg, 63%); mp 105−106 °C; 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 7.2 Hz, 3H), 7.26 (d, J = 7.4 Hz, 3H), 7.23 (d, J = 7.6 Hz, 2H), 7.11 (d, J = 7.4 Hz, 2H), 5.84 (d, J = 3.3 Hz, 1H), 5.47 (d, J = 10.6 Hz, 1H), 4.80 (d, J = 14.9 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 3.69−3.41 (m, 3H), 2.72−2.54 (m, 1H), 2.34 (dd, J = 21.7, 12.0 Hz, 1H), 2.19 (dd, J = 14.2, 5.4 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 165.1, 143.8, 142.7, 142.5, 137.0, 129.4, 128.9, 128.6, 128.3, 127.8, 127.7, 127.6, 127.3, 125.6, 118.3, 100.6, 80.0, 77.2, 47.9, 46.8, 45.6, 40.1, 36.7. ESI-HRMS [M + H]+ calcd. For C28H26NO3 m/z 424.1907, found 424.1912. [α]D20 +29.7 (c = 1.0 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for Asymmetric Synthesis of 6′. A glass vial equipped with a magnetic stirring bar was charged with 1 (0.20 mmol, 1.0 equiv), and (R)-3a (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (R)-4 (13.0 mg, 0.04 mmol) and p-NO2PhCOOH (6.7 mg, 0.04 mmol) and at 25 °C. After the Michael addition had been completed, BF3·Et2O (0.40 mmol, 2.0 equiv) was added dropwise at 0 °C. The reaction was stirred at this temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the desired product 6′. ( 2R,3 aS,4 R,8 aR)-6 -Benzyl-2 ,4-diphenyl-2,3,3a ,5,6,8ahexahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (6′). White solid (55 mg, 65%); mp 215−216 °C; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.5 Hz, 2H), 7.35 (dd, J = 14.4, 7.3 Hz, 3H), 7.32−7.24 (m, 4H), 7.21 (d, J = 7.1 Hz, 2H), 7.15 (d, J = 7.3 Hz, 2H), 5.74 (d, J = 3.5 Hz, 1H), 5.16 (dd, J = 10.3, 6.1 Hz, 1H), 4.75 (d, J = 14.9 Hz, 1H), 4.48 (d, J = 14.9 Hz, 1H), 3.61 (s, 1H), 3.53 (d, J = 2.3 Hz, 2H), 2.70−2.61 (m, 1H), 2.56 (dt, J = 12.4, 6.3 Hz, 1H), 1.83 (dd, J = 23.6, 12.1 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 165.2, 142.9, 142.8, 141.6, 136.9, 129.4, 128.9, 128.6, 128.3, 127.8, 127.8, 127.6, 127.2, 126.3, 118.6, 100.0, 83.0, 77.2, 47.9, 47.8, 46.8, 40.1, 38.3. ESI-HRMS [M + H]+ calcd. For C28H26NO3 m/z 424.1907, found 424.1908. [α]D20 −22.4 (c = 1.20 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for the Synthesis of 7. A glass vial equipped with a magnetic stirring bar was charged with 2 (0.20 mmol, 1.0 equiv), and (S)-3a (0.24 mmol, 1.2 equiv) in toluene (0.4 mL) with (S)-4 (13.0 mg, 0.04 mmol) and p-NO2PhCOOH (6.7 mg, 0.04 mmol) at 25 °C. After the Michael addition had been completed, BF3· Et2O (0.40 mmol, 2.0 equiv) was added dropwise at 0 °C. The reaction was stirred at this temperature for 24 h. The mixture was purified by column chromatography on silica gel to provide the desired product 7.

(2S,3aR,4S,10aS)-2,4-Diphenyl-2,3,3a,10a-tetrahydrofuro[2,3-b]indeno[2,1-e]pyran-5(4H)-one (7a). Yellow solid (36 mg, 47%); mp 155−156 °C; 1H NMR (500 MHz, CDCl3) δ 7.40 (t, J = 6.9 Hz, 4H), 7.37−7.31 (m, 6H), 7.29 (d, J = 7.6 Hz, 3H), 7.25 (dd, J = 10.3, 3.6 Hz, 1H), 5.93 (d, J = 3.7 Hz, 1H), 5.26 (dd, J = 10.4, 6.3 Hz, 1H), 3.97 (s, 1H), 2.87−2.80 (m, 1H), 2.63 (dt, J = 12.8, 6.5 Hz, 1H), 1.87 (dd, J = 23.6, 12.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 192.8, 171.6, 142.9, 141.2, 137.7, 133.5, 132.3, 130.4, 129.1, 128.7, 128.1, 127.2, 126.1, 121.4, 118.3, 105.9, 102.8, 83.8, 47.6, 37.3, 35.3. ESI-HRMS [M + H]+ calcd. For C26H21O3 m/z 381.1485, found 381.1486. [α]D20 −33.9 (c = 0.30 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,10aS)-4-(2-Nitrophenyl)-2-phenyl-2,3,3a,10atetrahydrofuro[2,3-b]indeno[2,1-e]pyran-5(4H)-one (7b). Yellow solid (37 mg, 43%); mp 160−161 °C; 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.44 (dd, J = 10.8, 6.8 Hz, 4H), 7.41−7.38 (m, 3H), 7.35 (t, J = 7.5 Hz, 4H), 7.31−7.26 (m, 1H), 5.83 (d, J = 3.4 Hz, 1H), 5.30 (dd, J = 10.4, 5.9 Hz, 1H), 4.55 (s, 1H), 2.96−2.90 (m, 1H), 2.87 (dd, J = 12.5, 6.2 Hz, 1H), 1.88 (dd, J = 22.6, 11.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 192.3, 173.1, 148.4, 141.1, 138.1, 137.5, 134.0, 133.3, 132.6, 130.8, 129.4, 128.7, 128.4, 128.1, 126.2, 126.0, 121.6, 118.6, 104.4, 102.7, 83.9, 47.2, 37.1, 31.3. ESI-HRMS [M + H]+ calcd. For C26H20NO5 m/ z 426.1336, found 426.1335. [α]D20 −34.3 (c = 0.23 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,10aS)-4-(3-Bromophenyl)-2-phenyl-2,3,3a,10atetrahydrofuro[2,3-b]indeno[2,1-e]pyran-5(4H)-one (7c). Yellow solid (37 mg, 40%); mp 77−79 °C; 1H NMR (500 MHz, CDCl3) δ 7.45−7.37 (m, 6H), 7.34 (dd, J = 8.5, 4.4 Hz, 4H), 7.29 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 6.7 Hz, 2H), 5.90 (d, J = 3.7 Hz, 1H), 5.26 (dd, J = 10.4, 6.3 Hz, 1H), 3.94 (s, 1H), 2.83−2.75 (m, 1H), 2.63 (dt, J = 12.9, 6.6 Hz, 1H), 1.86 (dd, J = 23.5, 12.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 192.6, 171.9, 145.3, 141.1, 137.5, 137.5, 133.4, 132.5, 130.7, 130.6, 130.5, 130.4, 128.7, 128.1, 126.2, 126.0, 121.5, 118.5, 105.1, 102.6, 83.8, 47.4, 37.3, 35.1. ESI-HRMS [M + H]+ calcd. For C26H20BrO3 m/z 459.0590, found 459.0591. [α]D20 −45.4 (c = 1.27 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,10aS)-4-(4-Chlorophenyl)-2-phenyl-2,3,3a,10atetrahydrofuro[2,3-b]indeno[2,1-e]pyran-5(4H)-one (7d). Yellow solid (37 mg, 45%); mp 83−84 °C; 1H NMR (500 MHz, CDCl3) δ 7.43−7.37 (m, 4H), 7.34 (t, J = 7.4 Hz, 4H), 7.30 (t, J = 8.8 Hz, 3H), 7.23 (d, J = 8.4 Hz, 2H), 5.89 (d, J = 3.7 Hz, 1H), 5.26 (dd, J = 10.4, 6.3 Hz, 1H), 3.94 (s, 1H), 2.82−2.75 (m, 1H), 2.63 (dt, J = 12.9, 6.6 Hz, 1H), 1.90−1.81 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 192.7, 171.7, 141.5, 141.1, 137.6, 133.4, 133.1, 132.4, 130.6, 129.2, 128.7, 128.6, 128.1, 126.2, 121.5, 118.5, 105.4, 102.7, 83.8, 47.5, 37.3, 34.8. ESI-HRMS [M + H]+ calcd. For C26H20ClO3 m/z 415.1095, found 415.1093. [α]D20 −98.7 (c = 0.80 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,10aS)-4-(2-Methoxyphenyl)-2-phenyl-2,3,3a,10atetrahydrofuro[2,3-b]indeno[2,1-e]pyran-5(4H)-one (7e). Yellow solid (33 mg, 40%); mp 85−86 °C; 1H NMR (500 MHz, CDCl3) δ 7.47−7.39 (m, 4H), 7.34 (dd, J = 11.3, 6.2 Hz, 4H), 7.29 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 5.78 (d, J = 3.1 Hz, 1H), 5.27 (dd, J = 10.1, 6.5 Hz, 1H), 4.32 (s, 1H), 3.92 (s, 3H), 2.84 (d, J = 4.8 Hz, 1H), 2.66 (dt, J = 12.7, 6.4 Hz, 1H), 1.86 (dd, J = 23.9, 12.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 192.9, 172.6, 156.7, 141.5, 137.9, 133.6, 132.2, 130.6, 130.3, 128.6, 128.3, 127.9, 127.7, 126.2, 121.3, 120.7, 118.1, 110.8, 105.4, 103.2, 83.9, 55.6, 46.3, 37.2, 27.0. ESIHRMS [M + H]+ calcd. For C27H23O4 m/z 411.1591, found 411.1592. [α]D20 −29.3 (c = 1.16 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,10aS)-4-(3-Methoxyphenyl)-2-phenyl-2,3,3a,10atetrahydrofuro[2,3-b]indeno[2,1-e]pyran-5(4H)-one (7f). Yellow solid (42 mg, 51%); mp 90−91 °C; 1H NMR (500 MHz, CDCl3) δ 7.40 (t, J = 7.2 Hz, 4H), 7.34 (dd, J = 7.3, 2.1 Hz, 3H), 7.32 (s, 1H), 7.30−7.23 (m, 3H), 6.88 (d, J = 7.7 Hz, 1H), 6.84 (s, 1H), 6.79 (d, J = 10.0 Hz, 1H), 5.93 (d, J = 3.7 Hz, 1H), 5.26 (dd, J = 10.4, 6.3 Hz, 1H), 10457


Article


General Procedure for the Synthesis of 11. A glass vial equipped with a magnetic stirring bar was charged with 2 (0.20 mmol), and (S)-3a (0.24 mmol) in toluene (0.4 mL) with (S)-4 (20 mol %) and p-NO2PhCOOH (20 mol %) and at 25 °C. After full conversion of the first step, the crude product purified by column chromatography on silica gel and concentrated under reduced pressure, and it was dissolved in the anhydrous CH2Cl2 (2 mL), then triethylsilane (47 μL, 0.3 mmol) and trifluoroborane diethyl etherate (25 μL, 0.4 mmol) were added at 0 °C. After it was stirred at 0 °C for 1 h, the completion of the reaction indicated by TLC, the reaction mixture was slowly raised to room temperature, the resulting mixture was quenched with saturated aqueous NaHCO3 solution (5 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phase was combined and dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography to afford 11. 2-((1R)-Phenyl((5S)-5-phenyltetrahydrofuran-3-yl)methyl)-1H-indene-1,3(2H)-dione (11). Yellow oil (33 mg, 84% yield; 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 7.4 Hz, 1H), 7.73−7.64 (m, 2H), 7.29 (d, J = 4.4 Hz, 4H), 7.22 (dd, J = 8.8, 4.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 2H), 7.05 (t, J = 7.5 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 4.97 (dd, J = 10.1, 5.7 Hz, 1H), 4.43 (t, J = 7.8 Hz, 1H), 3.99 (t, J = 8.2 Hz, 1H), 3.78−3.69 (m, 1H), 3.46 (dd, J = 11.6, 3.8 Hz, 1H), 3.15 (d, J = 3.8 Hz, 1H), 2.16 (dt, J = 12.5, 6.3 Hz, 1H), 1.35 (dd, J = 22.9, 10.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 200.1, 199.5, 142.9, 142.9, 142.5, 139.26, 135.6, 135.6, 128.7, 128.4, 127.4, 127.2, 125.6, 123.1, 123.0, 81.9, 73.1, 57.4, 49.4, 42.3, 42.2. HRMS [M + H]+ calcd. For C26H23O3 m/z 383.1642, found 383.1644. [α]D20 + 32.9 (c = 1.27 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for the Synthesis of 13. To a solution of 5a (42 mg, 0.1 mmol) in methanol (4 mL) was added 10% Pd/C (6 mg). The resulting mixture was hydrogenated with H2 from a balloon at 25 °C. After 12 h, the reaction mixture was then filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 13. (2S,3aR,4S,8aS)-6-Benzyl-2,4-diphenyloctahydrofuro[3′,2′:5,6]pyrano[2,3-c]pyrrol-7(4H)-one (13). White solid (32 mg, 77%); mp 97−98 °C; 1H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 6.7 Hz, 3H), 7.27−7.22 (m, 4H), 7.19 (dd, J = 15.3, 7.6 Hz, 4H), 7.15−7.11 (m, 1H), 7.08 (d, J = 7.0 Hz, 2H), 7.00 (d, J = 7.3 Hz, 2H), 6.56 (s, 1H), 5.94 (s, 1H), 4.71 (d, J = 15.0 Hz, 1H), 4.43 (d, J = 15.0 Hz, 1H), 3.61 (d, J = 11.6 Hz, 1H), 3.47 (d, J = 18.7 Hz, 1H), 3.32 (d, J = 18.3 Hz, 1H), 2.75−2.67 (m, 1H), 2.48−2.39 (m, 1H), 2.08 (t, J = 9.9 Hz, 1H), 1.98−1.89 (m, 1H), 1.65−1.57 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 167.0, 142.3, 141.7, 140.4, 136.9, 128.9, 128.8, 128.4, 128.4, 128.2, 127.7, 127.3, 125.9, 124.6, 94.9, 48.1, 46.6, 43.6, 40.9, 33.2, 27.0. ESI-HRMS [M + H]+ calcd. For C28H28NO3 m/z 426.2064, found 426.2066. [α]D20 +48.3 (c = 0.46 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for the Synthesis of 14. To an anhydrous CH2Cl2 solution (2 mL) of 13 (20 mg 0.05 mmol) and triethylsilane (25 μL, 0.15 mmol) was added trifluoroborane diethyl etherate (12 μL, 0.1 mmol) at 0 °C. After it was stirred at 0 °C for 2 h, the reaction mixture was slowly raised to room temperature. The resulting mixture was quenched with saturated aqueous NaHCO3 solution (5 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phase was combined and dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 14. (3R,4S)-6-Benzyl-3-phenethyl-4-phenyl-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (14). White solid (16 mg, 82%); mp 75−76 °C; 1H NMR (500 MHz, CDCl3) δ 7.32−7.26 (m, 4H), 7.27−7.21 (m, 4H), 7.19 (d, J = 7.2 Hz, 2H), 7.15 (d, J = 5.9 Hz, 1H), 7.06 (d, J = 4.3 Hz, 3H), 4.78 (d, J = 15.0 Hz, 1H), 4.41 (d, J = 14.9 Hz, 1H), 4.30 (d, J = 11.4 Hz, 1H), 4.02−3.92 (m, 1H), 3.43 (q, J = 18.0 Hz, 2H), 3.32 (d, J = 6.3 Hz, 1H), 2.70 (dd, J = 16.9, 12.0 Hz,

3.94 (s, 1H), 3.80 (s, 3H), 2.87−2.80 (m, 1H), 2.61 (dd, J = 12.7, 6.4 Hz, 1H), 1.86 (dd, J = 23.6, 12.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 192.8, 171.6, 160.1, 144.6, 141.2, 137.7, 133.5, 132.3, 130.4, 130.1, 128.9, 128.7, 128.1, 126.2, 125.4, 121.4, 119.5, 118.3, 113.6, 112.0, 105.8, 102.9, 83.8, 55.4, 47.5, 37.3, 35.3. ESI-HRMS [M + H]+ calcd. For C27H23O4 m/z 411.1591, found 411.1592. [α]D20 −41.6 (c = 1.25 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4S,10aS)-2-Phenyl-4-(p-tolyl)-2,3,3a,10a-tetrahydrofuro[2,3-b]indeno[2,1-e] pyran-5(4H)-one (7g). Yellow solid (42 mg, 53%); mp 81−82 °C; 1H NMR (500 MHz, CDCl3) δ 7.43−7.37 (m, 4H), 7.37−7.24 (m, 7H), 7.16 (dd, J = 18.7, 8.0 Hz, 4H), 5.92 (d, J = 3.6 Hz, 1H), 5.25 (dd, J = 10.5, 6.3 Hz, 1H), 5.05−5.00 (m, 1H), 3.93 (s, 1H), 2.81 (ddd, J = 11.2, 6.5, 3.8 Hz, 1H), 2.62 (dt, J = 12.8, 6.5 Hz, 1H), 2.32 (s, 3H), 1.86 (dd, J = 23.6, 12.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 192.9, 171.5, 141.3, 134.0, 137.8, 136.8, 133.5, 132.3, 130.4, 129.8, 128.7, 128.1, 127.1, 126.2, 121.4, 118.3, 106.2, 102.9, 83.8, 47.8, 37.4, 34.9, 21.2. ESI-HRMS [M + H]+ calcd. For C27H23O3 m/z 395.1642, found 395.1640. [α]D20 −38.4 (c = 0.36 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. (2S,3aR,4R,10aS)-2-Phenyl-4-(thiophen-2-yl)-2,3,3a,10atetrahydrofuro[2,3-b]indeno[2,1-e]pyran-5(4H)-one (7h). Yellow solid (26 mg, 33%); mp 97−98 °C; 1H NMR (500 MHz, CDCl3) δ 7.42 (t, J = 5.3 Hz, 1H), 7.39 (d, J = 7.7 Hz, 3H), 7.33 (dd, J = 12.9, 7.0 Hz, 5H), 7.28 (d, J = 7.3 Hz, 1H), 7.17 (dd, J = 4.0, 2.3 Hz, 1H), 6.96−6.93 (m, 2H), 6.01 (d, J = 3.6 Hz, 1H), 5.30 (dd, J = 10.3, 6.4 Hz, 1H), 4.23 (s, 1H), 3.03−2.94 (m, 1H), 2.62 (dt, J = 12.9, 6.6 Hz, 1H), 1.84 (dd, J = 23.6, 12.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 192.5, 171.0, 146.9, 141.1, 137.5, 133.4, 132.4, 130.6, 128.1, 127.4, 124.5, 124.2, 121.5, 118.6, 106.2, 103.0, 84.0, 47.8, 36.7, 30.3. ESIHRMS [M + H]+ calcd. For C24H19O3S m/z 387.1049, found 387.1050. [α]D20 −86.2 (c = 0.44 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for the Synthesis of 9. The synthesis of 9 from 8: to an anhydrous CH2Cl2 solution (2 mL) of 8 (44 mg 0.1 mmol) and triethylsilane (47 μL, 0.3 mmol) was added trifluoroborane diethyl etherate (25 μL, 0.4 mmol) at 0 °C. After stirred at this temperature for 2 h, the reaction mixture was slowly raised to room temperature. The resulting mixture was quenched with saturated aqueous NaHCO3 solution (5 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phase was combined and dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether−ethyl acetate 5:1) to afford 9. The synthesis of 9 from 5a: to an anhydrous CH2Cl2 solution (2 mL) of 5a (44 mg 0.1 mmol) and triethylsilane (47 μL, 0.3 mmol) was added titanium tetrachloride (40 μL, 0.4 mmol) at −78 °C. It was stirred at −78 °C for 1 h, after the completion of the reaction indicated by TLC, the reaction mixture was slowly raised to room temperature, and was quenched with H2O (5 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phase was combined and dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography to afford 9. 1-Benzyl-3-hydroxy-4-((S)-phenyl((3R,5S)-5-phenyltetrahydrofuran-3-yl)methyl)-1,5-dihydro-2H-pyrrol-2-one (9). White solid (38 mg, 90%; 33 mg, 77%); mp 219−220 °C; 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.35−7.30 (m, 2H), 7.28 (d, J = 5.6 Hz, 4H), 7.25 (d, J = 6.8 Hz, 2H), 7.20 (dd, J = 16.2, 8.0 Hz, 5H), 4.87 (dd, J = 9.7, 5.9 Hz, 1H), 4.58 (q, J = 15.1 Hz, 2H), 4.19 (t, J = 8.1 Hz, 1H), 3.87 (t, J = 7.9 Hz, 1H), 3.60−3.47 (m, 3H), 3.37 (dd, J = 16.5, 8.9 Hz, 1H), 2.15 (dt, J = 12.8, 6.6 Hz, 1H), 1.38 (dt, J = 19.8, 9.9 Hz, 1H). 13 C NMR (125 MHz, CDCl3) δ 167.9, 142.8, 142.3, 141.30, 136.5, 129.0, 128.9, 128.4, 128.1, 128.0, 127.9, 127.4, 127.1, 125.6, 122.7, 81.6, 73.4, 48.7, 48.5, 47.0, 43.8, 41.6. ESI-HRMS [M + H]+ calcd. For C28H27NO3 m/z 426.2064, found 426.2065. [α]D20 +22.9 (c = 0.45 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. 10458


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(47 μL, 0.3 mmol) was added trifluoroborane diethyl etherate (25 μL, 0.2 mmol) at 0 °C. After it was stirred at 0 °C for 3 h, the reaction mixture was slowly raised to room temperature and quenched with saturated aqueous NaHCO3 solution (5 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The organic phase was combined and dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 18. 2-((S)-Phenyl((3R,5S)-5-phenyltetrahydrofuran-3-yl)methyl)-1Hinden-1-one (18). Yellow solid (31 mg, 81%); mp 75−76 °C; 1H NMR (500 MHz, CDCl3) δ 7.37−7.31 (m, 3H), 7.29 (d, J = 7.2 Hz, 6H), 7.25 (dd, J = 9.4, 4.6 Hz, 3H), 7.21−7.16 (m, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 4.90 (dd, J = 9.8, 5.8 Hz, 1H), 4.18 (t, J = 8.2 Hz, 1H), 3.80 (t, J = 8.2 Hz, 1H), 3.67 (d, J = 11.3 Hz, 1H), 3.23 (dd, J = 17.9, 10.3 Hz, 1H), 2.21−2.14 (m, 1H), 1.50 (dd, J = 22.4, 10.2 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 197.2, 144.3, 142.6, 141.8, 141.5, 133.9, 130.5, 128.7, 128.5, 128.3, 128.0, 127.3, 126.8, 125.5, 122.9, 121.8, 81.5, 72.9, 46.2, 44.4, 41.6. ESI-HRMS [M + H]+ calcd. For C26H23O2 m/z 367.1693, found 367.1691. [α]D20 −78.3 (c = 0.64 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for the Synthesis of 19. Methanol (4 mL) was mixed with 10% palladium on charcoal (6 mg, 20%) and 7a (20 mg, 0.05 mmol). The mixture was hydrogenated with H2 from a balloon at 25 °C for 12 h. The reaction mixture was then filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 19. (2S,3aR,4R,4aS,9bR,10aS)-2,4-Diphenyl-2,3,3a,4a,9b,10ahexahydrofuro[2,3-b]indeno[2,1-e]pyran-5(4H)-one (19). White solid (16 mg, 78%); mp 84−85 °C; 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 1H), 7.74 (dd, J = 12.0, 7.6 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.35 (dd, J = 14.1, 7.0 Hz, 4H), 7.28 (t, J = 7.9 Hz, 3H), 7.24 (t, J = 6.1 Hz, 3H), 5.59 (d, J = 5.4 Hz, 1H), 5.40 (d, J = 6.4 Hz, 1H), 4.99 (dd, J = 10.2, 5.7 Hz, 1H), 3.03 (dd, J = 11.5, 6.4 Hz, 1H), 2.72−2.59 (m, 2H), 2.47−2.26 (m, 1H), 1.68−1.59 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 202.0, 151.0, 141.0, 140.7, 135.3, 129.8, 128.7, 128.3, 128.2, 127.6, 127.18, 126.9, 125.8, 125.5, 123.8, 103.5, 81.9, 73.1, 51.4, 47.8, 46.5, 39.7. ESI-HRMS [M + H]+ calcd. For C26H23O3 m/z 383.1642, found 383.1641. [α]D20 −23.8 (c = 0.69 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for the Synthesis of 20. To a solution of 19 (15 mg, 0.04 mmol) in MeOH (2 mL) was added NaBH4 (4.0 mg, 0.1 mmol) at 0 °C. After the completion of the reaction indicated by TLC, the solvent was evaporated and the residue was purified by column chromatography on silica gel to give product 20. (2S,3aR,4S,4aR,5S,9bR,10aS)-2,4-Diphenyl-2,3,3a,4,4a,5,9b,10aoctahydrofuro[2,3-b]indeno[2,1-e]pyran-5-ol (20). White solid (13 mg, 86%); mp 102−103 °C; 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 7.0 Hz, 1H), 7.42 (t, J = 5.6 Hz, 3H), 7.38 (d, J = 7.6 Hz, 3H), 7.31 (dt, J = 11.1, 7.6 Hz, 5H), 7.24 (dd, J = 12.6, 7.5 Hz, 5H), 5.61 (d, J = 5.9 Hz, 1H), 5.06 (d, J = 6.3 Hz, 2H), 5.03−4.98 (m, 1H), 3.01−2.89 (m, 2H), 2.56−2.47 (m, 1H), 2.40−2.32 (m, 1H), 1.78−1.72 (m, 1H). 13 C NMR (125 MHz, CDCl3) δ 144.2, 143.6, 141.7, 139.9, 129.6, 129.2, 128.8, 128.2, 128.2, 127.4, 126.7, 126.1, 125.7, 125.2, 103.9, 80.4, 77.5, 75.1, 48.2, 46.6, 42.2, 39.3. ESI-HRMS [M + H]+ calcd. For C26H25O3 m/z 385.1798, found 385.1794. [α]D20 +24.3 (c = 0.12 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr = 6:1.

1H), 2.58−2.48 (m, 1H), 2.00 (s, 1H), 1.75 (dd, J = 14.5, 5.5 Hz, 1H), 1.64−1.57 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 165.2, 145.8, 141.4, 141.1, 137.0, 128.8, 128.6, 128.4, 128.2, 128.0, 128.0, 127.5, 127.1, 126.0, 121.9, 69.2, 47.8, 46.5, 44.18, 40.3, 33.3, 31.8. ESI-HRMS [M + H]+ calcd. For C28H28NO2 m/z 410.2115, found 410.2117. [α]D20 +12.7 (c = 1.67 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr >20:1. General Procedure for the Synthesis of 15. To a solution of 7a (76 mg, 0.2 mmol) in MeOH (5 mL) was added NaBH4 (16 mg, 0.4 mmol) at 0 °C. Then, the reaction mixture was stirred for 3 h. After the completion of the reaction indicated by TLC, the solvent was evaporated and the residue was purified by column chromatography on silica gel to give product 15. (2S,3aR,4S,10aS)-2,4-Diphenyl-2,3,3a,4,5,10a-hexahydrofuro[2,3-b]Indeno[2,1-e]pyran-5-ol (15). White solid (70 mg, 94%); mp 133−133 °C; 1H NMR (500 MHz, CDCl3) δ 7.47−7.42 (m, 5H), 7.39−7.34 (m, 3H), 7.34−7.30 (m, 5H), 7.29−7.26 (m, 2H), 7.26− 7.23 (m, 2H), 5.85 (d, J = 3.8 Hz, 1H), 5.30 (s, 1H), 5.19 (dd, J = 10.4, 6.3 Hz, 1H), 5.09 (d, J = 8.9 Hz, 1H), 3.84 (s, 1H), 2.65 (ddt, J = 11.4, 8.5, 4.3 Hz, 1H), 2.61−2.54 (m, 1H), 1.88 (td, J = 12.7, 10.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 150.9, 145.0, 144.5, 141.8, 136.9, 129.2, 129.0, 128.5, 128.4, 127.7, 127.4, 127.2, 127.0, 126.4, 123.2, 117.9, 111.4, 99.9, 83.1, 76.3, 48.2, 39.9, 38.0. ESI-HRMS [M + H]+ calcd. For C26H23O3 m/z 383.1642, found 383.1641. [α]D20 −34.6 (c = 1.35 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr = 6:1. General Procedure for the Synthesis of 16. Methanol (4 mL) was mixed with 10% Pd/C (8 mg) and 15 (40 mg, 0.105 mmol). The mixture was hydrogenated with H2 from a balloon at 40 °C for 20 h. The reaction mixture was then filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography on silica gel to give product 16. (2R,3R,4S,4aS,9bR)-3-Phenethyl-4-phenyl-2,3,4,4a,5,9bhexahydroindeno[1,2-b]pyran-2-ol (16). White solid (22 mg, 56%); mp 141−142 °C; 1H NMR (500 MHz, CDCl3) δ 7.49−7.46 (m, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.30−7.26 (m, 3H), 7.23−7.16 (m, 6H), 7.12 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 7.3 Hz, 2H), 5.58 (d, J = 7.0 Hz, 1H), 5.39 (d, J = 6.7 Hz, 1H), 5.15 (dd, J = 6.3, 4.1 Hz, 1H), 2.90 (d, J = 4.0 Hz, 1H), 2.88−2.82 (m, 1H), 2.73 (dt, J = 8.9, 5.4 Hz, 2H), 2.59 (ddd, J = 13.9, 11.0, 4.8 Hz, 1H), 2.45−2.35 (m, 2H), 1.98−1.91 (m, 1H), 1.57−1.51 (m, 1H), 1.49−1.41 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 142.9, 142.4, 142.3, 141.4, 128.7, 128.7, 128.4, 128.2, 126.9, 126.8, 125.7, 125.3, 125.2, 97.6, 77.1, 76.5, 48.1, 45.9, 45.3, 36.6, 32.8, 32.5. ESI-HRMS [M + H]+ calcd. For C26H27O2 m/z 371.2006, found 371.2009. [α]D20 −13.5 (c = 1.27 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr = 5:1. General Procedure for the Synthesis of 17. Methanol (4 mL) was mixed with 10% palladium on charcoal (6 mg) and 15 (30 mg, 0.08 mmol). The mixture was hydrogenated with H2 from a balloon at 25 °C for 20 h. The reaction mixture was then filtered through a pad of Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 17. (2S,3aR,4S,4aR,5R,9bR,10aS)-2,4-Diphenyl-2,3,3a,4,4a,5,9b,10aoctahydrofuro[2,3-b]indeno[2,1-e]pyran-5-ol (17). White solid (19 mg, 62%); mp 127−128 °C; 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.40−7.36 (m, 2H), 7.36−7.32 (m, 3H), 7.30 (dd, J = 13.1, 5.9 Hz, 3H), 7.24 (t, J = 7.6 Hz, 3H), 5.56 (d, J = 7.2 Hz, 1H), 5.49 (d, J = 5.6 Hz, 1H), 4.96 (dd, J = 10.2, 5.7 Hz, 1H), 4.79 (s, 1H), 2.72 (dd, J = 12.7, 7.3 Hz, 1H), 2.56−2.47 (m, 1H), 2.47−2.40 (m, 1H), 2.37−2.25 (m, 1H), 1.64 (dd, J = 22.4, 10.2 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 142.5, 142.0, 141.7, 141.5, 129.7, 129.4, 129.0, 128.3, 128.2, 127.5, 127.1, 126.3, 125.9, 125.2, 102.8, 81.7, 78.7, 78.3, 52.2, 48.4, 46.6, 39.9. ESI-HRMS [M + H]+ calcd. For C26H25O3 m/z 385.1798, found 385.1794. [α]D20 −17.2 (c = 0.54 in CHCl3). The diastereomeric ratio was determined by 1H NMR analysis, dr = 6:1. General Procedure for the Synthesis of 18. To an anhydrous CH2Cl2 solution (2 mL) of 15 (40 mg, 0.1 mmol) and triethylsilane

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01915. Full optimization studies, 1H NMR and 13C NMR for all new compounds (PDF) X-ray crystallographic data for compound 5a (CIF) X-ray crystallographic data for compound 7a (CIF) 10459


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X-ray crystallographic data for compound 16 (CIF)

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 The authors thank one of the reviewers for the constructive and pertinent comments. 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; 201762011).

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Asymmetric Organocatalytic One-Pot, Two-Step Sequential Process to

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