Synthesis of Chiral Tetrahydrofurans and Pyrrolidines by Visible-Light-Mediated Deoxygenation.

The synthesis of chiral tetrahydrofurans and pyrrolidines starting from 1,2-diols or β-amino alcohols, respectively, by visible-light-mediated deoxygenation is described. Easily accessible monoallylated/propargylated substrates were activated either as inexpensive ethyl oxalates or as recyclable 3,5-bis(trifluoromethyl)benzoates to generate alkyl radicals suitable for 5-exo-trig/5-exo-dig cyclizations under visible-light irradiation.

Introduction

Tetrahydrofurans and pyrrolidines represent important classes of heterocycles due to their diverse biological activities, and numerous natural products and pharmaceuticals incorporate chiral tetrahydrofuran1 and pyrrolidine2 rings. Many synthetic routes have been developed to these compound classes, among them methodologies making use of visible‐light photocatalysis (Scheme 1).3

Scheme 1

Strategies towards photochemical tetrahydrofurans and pyrrolidines by visible‐light‐mediated transformations3

These routes involve the formation of a C–X (X = O, NPg; Pg = protecting group) bond in the cyclization step starting from appropriately substituted alcohols or amines, in contrast to the approach reported here that features cyclization through C–C bond‐forming reactions starting from monoallylated 1,2‐diols or N‐allylated amino alcohols, being readily available either from the chiral pool or by various synthetic routes such as the Sharpless asymmetric aminohydroxylation or dihydroxylation or epoxide ring‐opening reactions.

Results and Discussion

Following our interest in the catalytic conversion of renewable resources,4 we recently reported a photoredox‐catalyzed radical deoxygenation of alcohols via 3,5‐bis(trifluoromethyl)benzoates.[5a] In the current study, we additionally evaluated ethyl oxalate as activating group, being pioneered by Utley and co‐workers for electrochemical deoxygenations,6 and which we find also allows efficient C–O bond activation under photochemical conditions (Scheme 2). However, rather than performing just simple reductive deoxygenations, we investigated horizontal functionalizations aiming at the synthesis of chiral tetrahydrofurans and pyrrolidines.

Scheme 2

Activation groups for the photoredox‐catalyzed deoxygenation reaction of alcohols.

We started our investigation by exploring the deoxygenative, intramolecular cyclization reactions of modified tartrate derivatives, readily available in either enantiomerically pure form (Scheme 3). A 5‐exo‐trig cyclization to a tetrahydrofuran would be conceivable if one of the hydroxy groups is allylated and the other is activated for deoxygenation. Testing 1a, in which deoxygenative radical formation was envisioned with 3,5‐bis(trifluoromethyl)benzoate as activating group, indeed gave rise to tetrahydrofuran 2a, albeit only in moderate yield.7 As an alternative, we tested 3a, in which radical deoxygenation was envisioned to occur with ethyl oxalate as activating group.8 Indeed, 2a could be obtained in considerably improved yields under optimized reaction conditions. The transformations of both 1a and 3a can be carried out in either the presence of a sacrificial amine (Scheme 3, top part: reductive quenching cycle) or in the absence of such an agent (Scheme 3, bottom part: oxidative quenching cycle). Although longer irradiation times are required when amines are omitted, the cyclizations typically proceed much more cleanly. Also, from an economic point of view, it is more attractive to avoid the use of relatively costly amines (iPr2NEt).

Scheme 3

Activation groups and reaction conditions tested for the construction of tetrahydrofurans through deoxygenative cyclization.

Low‐priced ethyl oxalate activation9 without sacrificial amines (conditions B) therefore seemed to be the parameters of choice for this transformation. However, ethyl oxalate esters are sometimes unstable and tend to decompose or hydrolyze quite easily, making the employment of 3,5‐bis(trifluoromethyl)benzoyl derivatives a valid alternative (see below). In combination with sacrificial electron donors, very short reaction times for challenging substrates were achieved in this manner (conditions A). Cost aspects with respect to the benzoate group are mitigated as the auxiliary can easily be recycled and reused after activation and deoxygenation.5 The highly reductive photocatalyst fac‐[Ir(ppy)3] [E Red(Ir4+/Ir3+*) = –1.73 V vs. SCE]10 was crucial for transforming ethyl oxalate activated 3a into cyclized compound 2a (Table 1, Entry 1) without employing a sacrificial amine. Less‐reducing iridium‐based photocatalysts, such as [Ir(ppy)2(dtb‐bpy)]PF6 [(dtb‐bpy) = 2‐(2,4‐difluorophenyl)‐5‐(trifluoromethyl)pyridine, E Red(Ir3+/Ir2+) = –1.51 V vs. SCE] or [Ir{dF(CF3)ppy}2(dtb‐bpy)]PF6 {dF(CF3)ppy = 3,5‐difluoro‐2‐[5‐(trifluoromethyl)‐2‐pyridyl]phenyl} [E Red(Ir4+/Ir3+*) = –1.21 V vs. SCE]11 were not capable of reducing oxalate tartrate 3a (E Red = –1.65 V vs. SCE) and yielded only negligible amounts of product (Entries 2 and 3)7 Likewise, [Ru(bpy)3]Cl2 [E Red(Ru2+/Ru+) = –1.28 V vs. SCE]12 and [Cu(dap)2]Cl [dap = 2,9‐bis(4‐anisyl)‐1,10‐phenanthroline, E Red(Cu2+/Cu+*) = –1.43 V vs. SCE]13 were not suitable catalysts for promoting the formation of 2a (Entries 4 and 5). Attempts to perform the reaction at ambient temperature or at 40 °C (Entry 6) gave no conversion of starting material 3a at all. Applying higher temperatures was key for the photoinduced cyclization; higher temperatures should increase the rotational freedom in the substrate and thus may lead to a more favorable conformation for cyclization. Indeed, 89 % conversion and 51 % yield were achieved at 60 °C (Entry 7) and 100 % conversion and 70 % yield at 80 °C (Entry 1).14

Table 1

Catalyst screening, temperature dependence, and control experiments for the cyclization of compound 3a a

John Wiley & Sons, Ltd.
Entry	Modifications to conditions	Conversion [%]b	Yield [%]b
1	none	100	70
2	[Ir(ppy)2(dtb‐bpy)]PF6	22	0
3	[Ir{dF(CF3)ppy}2(dtb‐bpy)]PF6	44	5
4	[Ru(bpy)3]Cl2	6	0
5	[Cu(dap)2]Cl	2	0
6	room temperature or 40 °C	0	0
7	60 °C	89	51
8	no light or no catalyst	< 5	0

Reagents and conditions: Oxalate ester 3a (0.1 mmol), fac‐[Ir(ppy)3] (2.0 mol‐%), and DMF (0.1 m) at 80 °C and 455 nm LED irradiation under N2 for 20 h.

Determined by GC‐FID integration over all diastereomers with an internal standard.

Control experiments corroborated our assumption that the deoxygenation of 3a is nevertheless a photochemically induced process; when either light or the photocatalyst (Entry 8) was absent, no reaction was observed (for full optimization of oxalates as well as benzoates, see the Supporting Information).

Because the reaction time for the batch setup on a 0.1 mmol scale was in the range of 1 d, it would take considerably longer to reach full conversion on a larger scale. Indeed, when we scaled up the reaction to 1.0 mmol keeping the substrate concentration constant, a prolonged reaction time of 7 d was required to achieve full conversion and 54 % isolated yield of 2a with a batch setup (Table 2, Entry 1). Setting up the reaction in a microreactor should therefore be advantageous, as demonstrated previously for photoredox processes15

Table 2

Comparison of yield and reaction time for the cyclization of 3a in a batch reaction and microreactora

Entry	Setup	Time	Conversion [%]b	Yield [%]c
1	batch	7 d	100	54
2	flowd	28 h	100	73

Reagents and conditions: Oxalate ester 3a (1.0 mmol), fac‐[Ir(ppy)3] (1.0 mol‐%), and DMF (0.1 m) at 80 °C and 455 nm LED irradiation under N2.

Determined by GC‐FID with an internal standard.

Isolated yield.

Flow rate 0.35 mL/h, 35 µmol/h.

Owing to the higher surface/volume ratio in the microreactor and improved miscibility, the continuous‐flow mode typically offers shorter reaction times, higher yields, lower catalyst loadings, and facile upscaling. This was also true for the cyclization reaction of 3a. By using a microreactor, full conversion was achieved after only 28 h and gave 2a in 73 % yield (Entry 2).

To explore the scope of the synthesis of tetrahydrofurans by deoxygenative cyclization, a number of tartrate derivatives were synthesized and subjected to the optimized reaction conditions (Table 3). Reactions with 3,5‐bis(trifluoromethyl)benzoate‐activated substrates 1 were allowed to react in a batch setup (conditions A), and substrates with ethyl oxalate as the activation group 3 were performed in a flow setup (see above, conditions B). Procedure B generally gave cleaner reactions and higher yields than procedure A, for which often minor amounts of simple reductive deoxygenation products were formed5 The diastereomeric ratios are typically similar for both procedures, because the reactions were run at identical temperatures. In all cases, high anti selectivity was obtained with respect to the stereocenters in the diol backbone, whereas the new stereocenter formed through the cyclization involving the allyl side‐chain gave rise to epimers (see below). The asymmetric center at the allylated hydroxy center during the photoredox process is preserved, as is evident from the comparison between 2a and ent‐2a (Entries 1 and 2). A switch from the diethyl tartrate 3a to the more bulky isopropyl derivative 3b resulted in a slightly decreased product yield; however, a higher diastereomeric ratio of the products could not be achieved (Entries 1 and 3). The introduction of an additional methyl group at the γ position of the allyl system had only a minor influence on both the reaction yield and the diastereomeric ratio (dr; Entry 4). A further increase in the steric bulk at the γ position with a second methyl group (Entry 6) diminished the product yield from 38 to 31 % under conditions A and from 75 to 53 % under conditions B, but exclusively gave rise to the all‐trans‐configured tetrahydrofuran derivative 2e. In the case of oxalate activation using 3e, major amounts of the alkene were also observed that originate from elimination of a hydrogen atom from one of the methyl groups rather than reduction by abstraction from an external hydrogen source after cyclization. This mixture could be hydrogenated with H2 and Pd/C to give 2e in 53 % overall yield. Methyl substitution at the β position in 1f and 3f again gave good yields of the cyclization product with excellent diastereomeric induction (Entry 7). By employing cyclohexenyl‐substituted 1h and 3h as substrates, the synthesis of cyclohexyl‐annulated tetrahydrofuran 2h was possible in acceptable yields but with high stereoselectivity (Entry 9); the product diastereomeric ratio mirrors the ratio in the starting materials (1:1). Neither procedure A nor B tolerates α,β‐unsaturated esters (Entries 5 and 8); decomposition of the starting materials was observed. Attempting the cyclization with oxalyl‐containing 3i gave no conversion, but the corresponding 3,5‐bis(trifluoromethyl)benzoate‐activated derivative 1i resulted in the formation of benzyl‐substituted tetrahydrofuran 2i (Entry 10) in 48 % yield. Tetrahydrofuran products were also obtained when either only one or both of the ester groups in the tartrate backbone were substituted with phenyl groups (Entries 11 and 12).

Table 3

Substrate scope of the photoredox‐catalyzed synthesis of chiral tetrahydrofurans 2 a

E = CO2Et unless otherwise noted. Reagents and conditions A: 3,5‐bis(trifluoromethyl)benzoate ester (0.2–0.5 mmol), Et3N (2.0 equiv.), fac‐[Ir(ppy)3] (2.0 mol‐%), H2O (100 equiv.), and MeCN (0.04 m) at 80 °C under 455 nm LED irradiation under N2 for 1 h in a batch setup. Reagents and conditions B: Oxalate ester (0.4–1.0 mmol), fac‐[Ir(ppy)3] (1.0 mol‐%), and DMF (0.1 m) at 80 °C under 455 nm LED irradiation under N2 in a flow setup (flow rate 0.30–0.35 mL/h, 29–33 h).

Isolated yield and dr determined by 1H NMR integration.

Decomposition of the starting material.

An alkane/alkene mixture (25:75) was initially formed, which was quantitatively hydrogenated (H2, Pd/C).

A series of pyrrolidines were also synthesized by using this methodology by switching from 1,2‐diols to the corresponding amino alcohol derivatives 4 and 5 (Table 4). Optimizing the reaction conditions (conditions B) for the pyrrolidine synthesis revealed that the oxidative quenching cycle was the best choice for both activation groups. The yields and diastereomeric ratios are typically similar for both benzoates 4 and oxalates 5, and for the cases in which diastereomers are formed, they can be readily separated. Using (±)‐4a or (±)‐5a as substrate led to the formation of two separable diastereomers (±)‐6a and (±)‐6a′ in yields of 61–62 % (Entry 1). The introduction of an additional methyl group at the γ position of the allyl system had a significant influence on the yield and diastereoselectivity. Although the yield dropped from 62 to 47 % for the oxalates and from 61 to 52 % for the benzoates, a higher diastereoselectivity was observed (Entry 2). A further increase in the steric bulk at the γ position with a second methyl group (Entry 3) caused no further decrease in the reaction yield but a reduction in the stereocontrol at the isopropyl‐bearing stereocenter. Major amounts of the alkene were observed, similarly to the synthesis of the analogous tetrahydrofuran (see above). Subsequent hydrogenation with H2 and Pd/C gave the desired product (±)‐6c in yields of 48–53 %. Methyl substitution at the β position in (±)‐4d and (±)‐5d gave moderate yields of the cyclization product with excellent diastereomeric induction (Entry 4). Exchanging the phenyl group at the 1‐position with a methyl group caused only a slightly higher yield and low diastereoselectivity (Entry 5), whereas exchanging the ester moiety for an additional phenyl group had a moderate influence on diastereoselectivity and allowed (±)‐6f to be obtained in 50 % yield (Entry 6). Employing substrates (+)‐4g or (+)‐5g, synthesized from a commercially available, enantiopure amino diol, led to low yields of 28–30 % and slightly higher diastereoselectivity. Furthermore, 5‐exo‐dig cyclization with (±)‐4h or (±)‐5h was possible, giving a slightly lower yield compared with the corresponding 5‐exo‐trig reaction (Entry 1), but excellent diastereoselectivity (Entry 8).

Table 4

Substrate scope of the photoredox‐catalyzed synthesis of pyrrolidines 6 a

Reagents and conditions B: 3,5‐bis(trifluoromethyl)benzoate ester 4 or oxalate ester 5 (0.4–1.0 mmol), fac‐[Ir(ppy)3] (1.0 mol‐%), and DMF (0.1 m) at 80 °C under 455 nm LED irradiation under N2 in a flow setup (flow rate 0.30–1.0 mL/h, 10–33 h).

Given as the sum of the isolated yield of both diastereomers; dr is based on the isolated yields of the diastereomers.

After hydrogenation, initial alkane/alkene ratio = 23:77 for (±)‐6c, 15:85 for (±)‐6c′.

Flow rate 0.15 mL/h.

dr determined by 1H NMR integration, inseparable diastereomers.

Although the method presented here produces epimers with respect to the stereocenter formed when cyclization at a prochiral allyl group takes place, enantiomeric and diastereomeric pyrrolidines with biologically relevant cores, that is, α‐ and β‐prolines, can be readily prepared as pure stereoisomers that would otherwise be difficult to obtain. For example, the asymmetric epoxidation of ethyl cinnamate 7 16 followed by ring‐opening with allylamine,17 N‐Boc protection, and oxalyl activation readily gave rise to 5a in good yield and in 93 % ee (Scheme 4). Photocyclization as described above gave rise to the readily separable diastereomers 6a and 6a′.

Scheme 4

Strategy for the enantioselective synthesis of substituted β‐proline esters. Reagents and conditions: (a)16 Shi catalyst (0.3 equiv.), Na2(EDTA) (4 × 10–5 m), Bu4NHSO4 (0.06 equiv.), Oxone (5.0 equiv.), NaHCO3 (15.5 equiv.), CH3CN/H2O, 0 °C to room temp., 24 h, 59 %; (b)17 allylamine (1.0 equiv.), EtOH, reflux, 24 h, 58 %; (c) Boc2O (1.2 equiv.), Et3N (1.2 equiv.), CH2Cl2, room temp., 24 h, 54 %; (d) ethyl oxalyl chloride (1.5 equiv.), pyridine (1.5 equiv.), CH2Cl2, 0 °C to room temp., 20 h, 93 %; (e) fac‐[Ir(ppy)3] (1.0 mol‐%), LED (455 nm), DMF, 80 °C, 1.0 mL/h, 60 %.

The mechanism for both deoxygenation protocols likely involves electron uptake by the activating group from excited Ir3+* species18 followed by carbon–oxygen bond mesolysis giving rise to a carbon‐centered radical. This can then be trapped either by hydrogen atom abstraction leading to undesired simple deoxygenation (not depicted) or in a 5‐exo‐trig fashion to give the tetrahydrofuran or pyrroldiine core structure. The primary radical thus formed undergoes hydrogen abstraction from the solvent or from a sacrificial amine radical cation (only when present, conditions A). Regeneration of the photocatalyst is accomplished by reduction with either ethyl oxalate,19 solvent (conditions B), or sacrificial triethylamine (conditions A). Hydrogen abstraction from the solvent could be verified through a deuteriation experiment (Scheme 5): The cyclization of 3a using [D7]DMF gave compound 11 with single deuteriation at the terminal methyl group.

Scheme 5

Proposed mechanism for visible‐light‐mediated deoxygenation of 1 and 3 following a 5‐exo‐trig cyclization. Trapping of the radical species by deuterium abstraction from [D7]DMF is shown.

The stereochemistry observed can be rationalized by competing chair‐ or boat‐type transition states (Scheme 6), as has been discussed for analogous radical cyclizations to cyclopentanes.20 A high preference for anti orientation of the substituents R1 and R2 at the diol or amino alcohol core appears to be the dominating control element, whereas the two possible conformations of the allyl side‐chain suffer from 1,3‐interactions with R2 in the chair orientation and with X in the boat orientation.

Scheme 6

Proposed stereochemical model for the radical cyclization process.

Conclusions

A protocol for the visible‐light‐mediated deoxygenation of monoallylated diols and β‐amino alcohols followed by an intramolecular 5‐exo‐trig/5‐exo‐dig cyclization has been developed for the synthesis of chiral tetrahydrofuran and pyrrolidine derivatives. The method features inexpensive, readily available starting materials, and a sustainable, halogen‐free activation of the hydroxy group towards radical reactions was realized by its transformation into either recyclable 3,5‐bis(trifluoromethyl)benzoate or inexpensive ethyl oxalate esters. Ethyl oxalate activated tartrates and ethyl oxalate or 3,5‐bis(trifluoromethyl)benzoate activated amino alcohols only require heat, a photoredox catalyst, and visible light to form chiral tetrahydrofuran or pyrrolidine derivatives in reasonable to good yields.

Experimental Section

General: All chemicals were used as received or purified according to standard procedures21 if necessary. Glassware was dried in an oven at 110 °C or flame‐dried and cooled under a dry atmosphere prior to use. All reactions were performed using Schlenk techniques. Blue‐light irradiation in batch processes was performed by using a CREE XLamp XP‐E D5‐15 LED (λ = 450–465 nm). In microreactor processes, eight OSRAM OSLON Black Series LD H9GP LEDs (λ = 455 ± 10 nm) were employed. Analytical TLC was performed on Merck TLC aluminium sheets coated with silica gel 60 F254. Reactions were monitored by TLC and visualized by a short‐wave UV lamp and stained with a solution of potassium permanganate, p‐anisaldehyde, ninhydrin, or Seebach's stain. Column flash chromatography was performed by using Merck flash silica gel 60 (0.040–0.063 mm). Melting points were measured with an automated melting‐point system (MPA 100) with digital image processing technology by Stanford Research Systems. ATR‐IR spectroscopy was carried out with a Cary 630 FTIR spectrometer or a Biorad Excalibur FTS 3000 spectrometer, equipped with a Specac Golden Gate Diamond Single Reflection ATR System. NMR spectra were recorded with Bruker Avance 300 and 400 spectrometers. Chemical shifts (δ) for 1H NMR are reported in parts per million (ppm) relative to the signal of CHCl3 at δ = 7.26 ppm, the DMSO quintet at δ = 2.50 ppm, or the water signal at δ = 4.79 ppm. Chemical shifts (δ) for 13C NMR are reported in parts per million (ppm) relative to the center‐line signal of the CDCl3 triplet at δ = 77.2 ppm and the [D6]DMSO septet at δ = 39.5 ppm. Coupling constants J are given in Hz. The following notations indicate the multiplicity of the signals: s = singlet, br. s = broad singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sept = septet, and m = multiplet, and combinations thereof. DEPT‐135 analysis for the Avance 400 spectrometer shows CH3 and CH peaks down and CH2 peaks up. DEPT‐135 analysis for the Avance 300 spectrometer shows CH3 and CH peaks up and CH2 peaks down. Mass spectra were recorded at the Central Analytical Laboratory at the Department of Chemistry of the University of Regensburg with a Varian MAT 311A, Finnigan MAT 95, Thermoquest Finnigan TSQ 7000, or Agilent Technologies 6540 UHD Accurate‐Mass Q‐TOF LC/MS spectrometer. Gas chromatographic analyses were performed with a Fisons Instruments gas chromatograph equipped with a capillary column (30 m × 250 µm × 0.25 µm) and a flame ionization detector. Enantiomeric excesses were determined by chiral HPLC (Phenomenex Lux Cellulose‐2, 4.6 × 250 mm, particle size 5 µm). The yields reported refer to the isolated compounds unless otherwise stated.

General Procedure for Reactions with Oxalates without a Sacrificial Electron Donor: A Schlenk tube equipped with a magnetic stirring bar was charged with ethyl oxalate ester (1.0 mmol, 1.0 equiv.) and fac‐[Ir(ppy)3] (6.55 mg, 10.0 µmol, 1.0 mol‐%), dissolved in DMF (10 mL, 0.1 m), sealed with a screw cap, and subsequently evacuated for 15 min and backfilled with N2. The screw cap was replaced with a Teflon‐sealed inlet for a glass rod, through which irradiation with a 455 nm high‐power LED took place from above while the reaction mixture was magnetically stirred and heated in an aluminium block at 80 °C from below. The reaction was monitored by TLC. Afterwards, the reaction mixture was diluted with EtOAc (300 mL) and extracted with water (5 × 100 mL). The combined organic layers were dried with Na2SO4, the solvent was evaporated under reduced pressure, and the residue purified by flash column chromatography.

General Procedure for Reactions with 3,5‐Bis(trifluoromethyl)benzoates with a Sacrificial Electron Donor: A Schlenk tube equipped with a magnetic stirring bar was charged with 3,5‐bis(trifluoromethyl)benzoate ester (0.50 mmol, 1.00 equiv.) and fac‐[Ir(ppy)3] (6.6 mg, 10 µmol, 2.0 mol‐%), sealed with a screw cap, and subsequently evacuated and backfilled with N2 (3 ×). MeCN (12.5 mL), Et3N (0.35 mL, 0.25 g, 2.5 mmol, 5.0 equiv.), and degassed water (0.90 mL, 0.90 g, 50 mmol, 100 equiv.) were added, and the reaction mixture was magnetically stirred until a homogeneous solution was obtained. The reaction mixture was degassed by using the freeze‐pump‐thaw method (5 ×), and the screw cap was replaced with a Teflon‐sealed inlet for a glass rod, through which irradiation with a 455 nm high‐power LED took place from above while the reaction mixture was magnetically stirred and heated at 80 °C in an aluminium block from below. After completion of the reaction, as judged by TLC (typically 1 h), the mixture was concentrated under reduced pressure and the residue purified by flash silica gel column chromatography.

General Procedure for the Reaction of Ethyl Oxalyl Esters and 3,5‐Bis(trifluoromethyl)benzoate Esters in a Microreactor Setup: A Schlenk tube equipped with a magnetic stirring bar was charged with ethyl oxalate ester (Reaction B, 1.0 equiv.) or 3,5‐bis(trifluoromethyl)benzoate ester (Reaction A; 1.0 equiv.), fac‐[Ir(ppy)3] (1.0 mol‐%), and DMF (0.1 m). The reaction mixture was degassed by sparging with N2 through a needle and a septum for 30 min or by the freeze‐pump‐thaw method (3 ×) and pumped through a microreactor (which was also sparged with N2) equipped with eight LEDs at a flow rate of 0.15–1.00 mL/h through a syringe pump while heated at 80 °C. Afterwards, the reaction mixture was diluted with diethyl ether (150 mL) or EtOAc (300 mL) and washed with brine (3 × 100 mL) or water (5 × 100 mL). The combined organic layers were dried with anhydrous Na2SO4, the solvent was evaporated under reduced pressure, and the residue purified by flash column chromatography.

Compound 2a: Elution with hexanes/EtOAc (6:1); colorless oil; yield: 45 mg (39 % with 1a, dr = 61:30:9) and 167 mg (73 % with 3a, dr = 62:28:8:2); R f (hexanes/EtOAc, 1:1) = 0.81. 1H NMR (major diastereomer, 400 MHz, CDCl3): δ = 4.80 (d, J = 6.1 Hz, 1 H), 4.26–4.16 (m, 4 H), 4.16–4.08 (m, 1 H), 3.63 (dd, J = 8.3, 6.2 Hz, 1 H), 3.24 (dd, J = 8.3, 6.1 Hz, 1 H), 2.67 (dquint, J = 13.4, 6.8 Hz, 1 H), 1.32–1.23 (m, 6 H), 1.01 (d, J = 7.0 Hz, 3 H) ppm. 1H NMR (minor diastereomer 1, 400 MHz, CDCl3): δ = 4.72 (d, J = 7.4 Hz, 1 H), 4.26–4.16 (m, 4 H), 4.16–4.08 (m, 1 H), 3.58 (t, J = 8.7 Hz, 1 H), 2.77 (dt, J = 11.1, 5.6 Hz, 1 H), 2.62–2.51 (m, 1 H), 1.32–1.23 (m, 6 H), 1.16–1.10 (m, 3 H) ppm. 1H NMR (minor diastereomer 2, 400 MHz, CDCl3): δ = 4.65 (d, J = 8.3 Hz, 1 H), 4.26–4.16 (m, 4 H), 4.16–4.08 (m, 1 H), 3.48 (t, J = 8.0 Hz, 1 H), 2.95 (t, J = 8.4 Hz, 1 H), 2.67 (dquint, J = 13.4, 6.8 Hz, 1 H), 1.32–1.23 (m, 6 H), 1.01 (d, J = 7.0 Hz, 3 H) ppm. 1H NMR (minor diastereomer 3, 400 MHz, CDCl3): δ = 4.59 (d, J = 2.3 Hz, 1 H), 4.26–4.16 (m, 4 H), 4.16–4.08 (m, 1 H), 3.41 (d, J = 7.3 Hz, 1 H), 2.77 (dt, J = 11.1, 5.6 Hz, 1 H), 2.62–2.51 (m, 1 H), 1.32–1.23 (m, 6 H), 1.01 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (major diastereomer, 101 MHz, CDCl3): δ = 172.0, 171.2, 78.7, 75.7, 61.5, 61.1, 52.3, 36.9, 14.4, 14.3, 13.4 ppm. 13C NMR (minor diastereomer 1, 101 MHz, CDCl3): δ = 172.2, 171.9, 79.9, 76.0, 61.4, 61.4, 55.8, 39.8, 15.9, 14.3, 14.3 ppm. IR(neat): ν̃ = 2979, 2939, 2877, 2190, 1731, 1464, 1372, 1275, 1180, 1095, 1027, 939, 858, 462 cm–1. HRMS (ESI): calcd. for C11H19O5 [M + H]+ 231.1227; found 231.1230.

Compound Elution with hexanes/EtOAc (6:1); colorless oil; yield: 163 mg (71 % with ent‐3b, dr = 57:37:6); R f (hexanes/EtOAc, 1:1) = 0.81. 1H NMR (major diastereomer, 300 MHz, CDCl3): δ = 4.75 (d, J = 6.1 Hz, 1 H), 4.23–4.02 (m, 5 H), 3.63–3.48 (m, 1 H), 3.20 (dd, J = 8.3, 6.1 Hz, 1 H), 2.68–2.44 (m, 1 H), 1.30–1.17 (m, 6 H), 0.96 (d, J = 7.0 Hz, 3 H) ppm. 1H NMR (minor diastereomer 1, 300 MHz, CDCl3): δ = 4.68 (d, J = 7.4 Hz, 1 H), 4.23–4.02 (m, 5 H), 3.63–3.48 (m, 1 H), 2.73 (dd, J = 8.8, 7.4 Hz, 1 H), 2.68–2.44 (m, 1 H), 1.30–1.17 (m, 6 H), 1.08 (dd, J = 6.6 Hz, 3 H) ppm. 1H NMR (minor diastereomer 2, 300 MHz, CDCl3): δ = 4.61 (d, J = 8.3 Hz, 1 H), 4.23–4.02 (m, 5 H), 3.44 (t, J = 8.0 Hz, 1 H), 2.91 (t, J = 8.4 Hz, 1 H), 2.68–2.44 (m, 1 H), 1.30–1.17 (m, 6 H), 1.07 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (major diastereomer, 75 MHz, CDCl3): δ = 172.0, 171.2, 78.7, 75.7, 61.5, 61.2, 52.3, 36.9, 14.4, 14.3, 13.4 ppm. 13C NMR (minor diastereomer 1, 75 MHz, CDCl3): δ = 172.2, 171.9, 79.8, 76.0, 61.5, 61.4, 55.8, 39.8, 15.8, 14.4, 13.4 ppm. HRMS (ESI): calcd. for C11H19O5 [M + H]+ 231.1227; found 231.1230.

Compound 2b: Elution with hexanes/EtOAc (3:1); colorless oil; yield: 168 mg (65 % with 3b, dr = 60:32:5:3); R f (hexanes/EtOAc, 1:1) = 0.83. 1H NMR (major diastereomer, 300 MHz, CDCl3): δ = 5.10–4.91 (m, 2 H), 4.69 (d, J = 6.3 Hz, 1 H), 4.07 (ddd, J = 8.3, 6.7, 4.3 Hz, 1 H), 3.64–3.47 (m, 1 H), 3.11 (dd, J = 8.4, 6.3 Hz, 1 H), 2.71–2.55 (m, 1 H), 1.25–1.13 (m, 12 H), 0.96 (d, J = 7.0 Hz, 3 H) ppm. 1H NMR (minor diastereomer 1, 300 MHz, CDCl3): δ = 5.10–4.91 (m, 2 H), 4.61 (d, J = 7.6 Hz, 1 H), 4.07 (ddd, J = 8.3, 6.7, 4.3 Hz, 1 H), 3.64–3.47 (m, 1 H), 2.71–2.55 (m, 1 H), 2.55–2.40 (m, 1 H), 1.25–1.13 (m, 12 H), 0.96 (d, J = 7.0 Hz, 3 H) ppm. 1H NMR (minor diastereomer 2, 300 MHz, CDCl3): δ = 5.10–4.91 (m, 2 H), 4.54 (d, J = 8.2 Hz, 1 H), 4.07 (ddd, J = 8.3, 6.7, 4.3 Hz, 1 H), 3.42 (t, J = 8.0 Hz, 1 H), 2.85 (t, J = 8.3 Hz, 1 H), 2.71–2.55 (m, 1 H), 2.85 (t, J = 8.3 Hz, 1 H), 1.25–1.13 (m, 12 H), 0.96 (d, J = 7.0 Hz, 3 H) ppm. 1H NMR (minor diastereomer 3, 300 MHz, CDCl3): δ = 5.10–4.91 (m, 2 H), 4.49 (d, J = 3.3 Hz, 1 H), 4.07 (ddd, J = 8.3, 6.7, 4.3 Hz, 1 H), 3.64–3.47 (m, 1 H), 2.71–2.55 (m, 2 H), 1.25–1.13 (m, 12 H), 0.96 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (major diastereomer 1, 75 MHz, CDCl3): δ = 171.4, 170.5, 78.7 75.6, 68.8, 68.6, 52.3, 36.7, 21.9, 21.9, 21.8, 21.7, 13.3 ppm. 13C NMR (major diastereomer 2, 75 MHz, CDCl3): δ = 171.5, 171.4, 79.8, 75.9, 68.8, 68.6, 56.1, 39.8, 21.9, 21.8, 21.8, 21.7, 15.5 ppm. IR (neat): ν̃ = 2980, 2940, 2879, 1727, 1469, 1375, 1273, 1180, 1145, 1103, 989, 944, 902, 829 cm–1. HRMS (ESI): calcd. for C13H23O5 [M + H]+ 259.1540; found 259.1545.

Compound 2c: Elution with hexanes/EtOAc (6:1 to 2:1); colorless oil; yield: 28 mg (38 % with 1c, dr = 65:21:14) and 183 mg (75 % with 3c, dr = 60:34:5:1); R f (hexanes/EtOAc, 1:1) = 0.92. 1H NMR (major diastereomer, 300 MHz, CDCl3): δ = 4.71 (d, J = 5.0 Hz, 1 H), 4.18–4.08 (m, 5 H), 3.64 (dt, J = 13.8, 8.2 Hz, 1 H), 3.21 (dd, J = 8.4, 5.0 Hz, 1 H), 2.48–2.32 (m, 1 H), 1.66–1.28 (m, 2 H), 1.27–1.20 (m, 6 H), 0.88 (ddd, J = 7.5, 6.1, 3.9 Hz, 3 H) ppm. 13C NMR (major diastereomer 1, 75 MHz, CDCl3): δ = 171.9, 171.4, 79.1, 73.3, 61.4, 61.0, 51.6, 44.1, 21.0, 14.3, 14.2, 12.8 ppm. 13C NMR (major diastereomer 2, 75 MHz, CDCl3): δ = 172.5, 171.6, 79.9, 74.3, 61.3, 61.3, 54.2, 46.5, 25.1, 14.3, 14.2, 12.4 ppm. IR (neat): ν̃ = 2970, 2938, 2878, 1729, 1464, 1372, 1266, 1179, 1135, 1095, 1028, 943, 857, 433 cm–1. HRMS (ESI): calcd. for C12H21O5 [M + H]+ 245.1384; found 245.1388.

Compound 2e: Elution with hexanes/EtOAc (5:1); colorless oil; yield: 41 mg (31 % with 1e, dr ≥ 95:5) and 137 mg (53 % with 3e, dr ≥ 95:5); R f (hexanes/EtOAc, 3:1) = 0.48. 1H NMR (400 MHz, CDCl3): δ = 4.62 (d, J = 7.2 Hz, 1 H), 4.28–4.16 (m, 4 H), 4.13 (t, J = 8.2 Hz, 1 H), 3.76 (t, J = 8.7 Hz, 1 H), 2.90 (t, J = 7.8 Hz, 1 H), 2.40 (q, J = 8.2 Hz, 1 H), 1.73–1.61 (m, 1 H), 1.28 (t, J = 7.1 Hz, 6 H), 0.94 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 173.1, 171.4, 80.7, 73.0, 61.3, 61.2, 52.6, 51.6, 30.7, 20.9, 20.7, 14.2, 14.1 ppm. IR (neat): ν̃ = 2963, 2876, 1732, 1468, 1447, 1372, 1263, 1221, 1192, 1106, 1026, 969, 861, 715, 575 cm–1;HRMS (ESI): calcd. for C13H23O5 [M + H]+ 259.1540; found 259.1548.

Compound 2f: Elution with hexanes/EtOAc (6:1); colorless oil; yield: 56 mg (46 % with 1f, dr > 95:5) and 68 mg (70 % with 3f, dr ≥ 95:5); R f (hexanes/EtOAc, 1:1) = 0.80. 1H NMR (300 MHz, CDCl3): δ = 4.89 (d, J = 8.0 Hz, 1 H), 4.27–4.12 (m, 4 H), 3.69 (s, 2 H), 2.89 (d, J = 8.0 Hz, 1 H), 1.31–1.23 (m, 6 H), 1.20 (s, J = 3.9 Hz, 3 H), 1.02 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.3, 170.6, 81.6, 78.8, 61.4, 61.1, 58.1, 43.7, 24.9, 22.0, 14.4, 14.3 ppm. IR (neat): ν̃ = 2978, 2874, 1729, 1466, 1371, 1337, 1264, 109, 1179, 1093, 1028, 968, 940, 860, 716, 441 cm–1. HRMS (ESI): calcd. for C12H21O5 [M + H]+ 245.1384; found 245.1388.

Compound 2h: Elution with hexanes/EtOAc (6:1); colorless oil; yield: 35 mg (32 % with 1h, dr = 53:47) and 170 mg (63 % with 3h, dr = 57:43); R f (hexanes/EtOAc, 3:1) = 0.60. 1H NMR (major diastereomer, 300 MHz, CDCl3): δ = 4.91 (d, J = 8.4 Hz, 1 H), 4.23–4.14 (m, 4 H), 3.36 (dd, J = 8.3, 6.5 Hz, 1 H), 2.37–2.27 (m, 1 H), 2.15–2.05 (m, 1 H), 1.75–1.29 (m, 7 H), 1.28–1.22 (m, 6 H) ppm. 1H NMR (minor diastereomer, 300 MHz, CDCl3): δ = 4.72 (d, J = 5.9 Hz, 1 H), 4.23–4.14 (m, 4 H), 3.01 (dd, J = 5.7, 4.9 Hz, 1 H), 2.37–2.27 (m, 1 H), 1.91–1.79 (m, 1 H), 1.75–1.29 (m, 7 H), 1.28–1.22 (m, 6 H) ppm. 13C NMR (major diastereomer, 75 MHz, CDCl3): δ = 173.0, 170.3, 79.2, 76.4, 61.3, 61.1, 53.3, 41.3, 27.7, 24.2, 23.2, 19.8, 14.4, 14.3 ppm. 13C NMR (minor diastereomer, 75 MHz, CDCl3): δ = 172.9, 172.0, 78.7, 78.3, 61.4, 61.3, 53.2, 42.7, 28.1, 27.0, 23.3, 21.0, 14.3, 14.3 ppm. IR (neat): ν̃ = 2970, 2938, 2878, 1729, 1464, 1372, 1266, 1179, 1135, 1095, 1028, 943, 857, 433 cm–1. HRMS (ESI): calcd. for C14H23O5 [M + H]+ 271.1540; found 271.1543.

Compound 2i: Elution with hexanes/EtOAc (10:0 to 8:2); colorless oil; yield: 70 mg (48 % with 1i, dr = 78:22); R f (hexanes/EtOAc, 4:1) = 0.27. 1H NMR (major diastereomer, 400 MHz, CDCl3): δ = 7.34–7.10 (m, 5 H), 4.84 (d, J = 5.9 Hz, 1 H), 4.28–4.15 (m, 4 H), 3.95 (dd, J = 8.5, 6.1 Hz, 1 H), 3.78 (dd, J = 8.5, 6.2 Hz, 1 H), 3.35 (dd, J = 8.0, 5.8 Hz, 1 H), 2.84–2.76 (m, 2 H), 2.53 (dd, J = 13.5, 10.3 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm. 1H NMR (minor diastereomer, 400 MHz, CDCl3): δ = 7.34–7.10 (m, 5 H), 4.69 (d, J = 6.9 Hz, 1 H), 4.28–4.15 (m, 2 H), 4.15–4.00 (m, 3 H), 3.78–3.71 (m, 1 H), 2.84–2.76 (m, 4 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.21 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (major diastereomer, 101 MHz, CDCl3): δ = 171.7, 171.0, 139.3, 128.7, 128.6, 126.5, 78.9, 73.1, 61.4, 61.2, 51.5, 43.7, 34.1, 14.3, 14.2 ppm. 13C NMR (minor diastereomer, 101 MHz, CDCl3): δ = 172.0, 171.5, 138.9, 128.8, 128.6, 126.5, 79.9, 74.1, 61.4, 61.3, 53.8, 46.0, 37.9, 14.2, 14.1 ppm. IR (neat): ν̃ = 2983, 2942, 1729, 1455, 1372, 1262, 1178, 1097, 1027, 951, 860, 746, 700, 493 cm–1. HRMS (ESI): calcd. for C17H23O5 [M + H]+ 307.1540; found 307.1543.

Compound 2j: Elution with hexanes/EtOAc (25:1); colorless oil; yield: 20 mg (42 % with 1j, dr = 49:42:9); R f (hexanes/EtOAc, 6:1) = 0.55. 1H NMR (major diastereomer, 400 MHz, CDCl3): δ = 7.38–7.20 (m, 10 H), 5.34 (d, J = 5.4 Hz, 1 H), 4.36 (dd, J = 8.3, 7.1 Hz, 1 H), 3.75 (t, J = 8.0 Hz, 1 H), 3.34 (dd, J = 7.6, 5.3 Hz, 1 H), 2.68 (sept, J = 7.3 Hz, 1 H), 0.72 (d, J = 7 Hz, 3 H) ppm. 13C NMR (major diastereomer, 101 MHz, CDCl3): δ = 143.6, 139.7, 128.9, 128.4, 128.3, 127.1, 126.6, 125.4, 85.1, 74.8, 57.4, 37.4, 13.5 ppm. IR (neat): ν̃ = 2968, 2930, 2874, 1742, 1603, 1495, 1453, 1382, 1279, 1245, 1182, 1140, 1069, 1047, 1027, 925, 803, 748, 698, 611, 580, 528 cm–1. HRMS (ESI): calcd. for C17H18O [M + H]+ 238.1352; found 238.1352.

Compound 2k: Elution with hexanes/EtOAc (10:1); colorless oil; yield: 26 mg (57 % with 1k, dr = 67:19:14); R f (hexanes/EtOAc, 6:1) = 0.25. 1H NMR (major diastereomer, 300 MHz, CDCl3): δ = 7.41–7.14 (m, 5 H), 4.46 (d, J = 8.5 Hz, 1 H), 4.32–4.25 (m, 1 H), 4.23–4.09 (m, 2 H), 3.72 (dd, J = 10.1, 8.4 Hz, 1 H), 2.93 (dd, J = 10.1, 8.5 Hz, 1 H), 2.57–2.39 (m, 1 H), 1.18 (t, J = 7.2 Hz, 3 H), 0.99 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (major diastereomer, 75 MHz, CDCl3): δ = 172.7, 139.6, 128.8, 127.8, 127.2, 84.1, 76.3, 60.9, 58.3, 43.5, 14.2, 14.2 ppm. 13C NMR (minor diastereomer 1, 75 MHz, CDCl3): δ = 172.5, 142.4, 128.4, 127.2, 125.0, 83.6, 75.5, 61.2, 55.8, 36.5, 15.5, 14.3 ppm. 13C NMR (minor diastereomer 2, 75 MHz, CDCl3): δ = 171.4, 137.4, 128.3, 127.7, 124.7, 82.0, 76.0, 60.4, 56.4, 42.4, 38.2, 13.6 ppm. IR (neat): ν̃ = 2962, 2873, 1745, 1603, 1456, 1377, 1270, 1187, 1108, 1083, 1029, 965, 939, 864, 754, 700, 520 cm–1. HRMS (ESI): calcd. for C14H19O3 [M + H]+ 235.1329; found 235.1331.

Compounds (±)‐6a and (±)‐6a′: Elution with n‐pentane/diethyl ether (20:1 to 3:1); colorless oils; yield: 131 mg (39 %) of 6a and 79 mg (23 %) of 6a′ using 5a; 126 mg (38 %) of 6a and 76 mg (23 %) of 6a′ using 4a; R f (6a, n‐pentane/EtOAc, 3:1) = 0.20; R f (6a′, n‐pentane/EtOAc, 3:1) = 0.25. 1H NMR (6a, 400 MHz, CDCl3): δ = 7.33–7.14 (m, 5 H), 5.06 (m, 1 H), 4.25–3.98 (m, 2 H), 3.84–3.66 (m, 1 H), 3.58–3.33 (m, 1 H), 3.06–2.82 (m, 1 H), 2.71–2.54 (m, 1 H), 1.45 (br. s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.12 (m, 6 H), 1.01 (d, J = 7.0 Hz, 3 H) ppm. 1H NMR (6a′, 400 MHz, CDCl3): δ = 7.35–7.11 (m, 5 H), 5.16–4.85 (m, 1 H), 4.24–3.98 (m, 3 H), 3.18 (t, J = 10.7 Hz, 1 H), 2.63–2.40 (m, 2 H), 1.46–1.01 (m, 15 H) ppm. 13C NMR (6a, 101 MHz, CDCl3): δ = 171.6, 154.6, 143.8, 128.4, 127.1, 127.1, 126.0, 79.6, 62.3, 60.8, 57.9, 53.5, 33.9, 28.6, 28.2, 14.6, 14.4 ppm. 13C NMR (6a′, 101 MHz, CDCl3): δ = 172.3, 154.1, 143.9, 128.4, 127.1, 125.9, 79.7, 65.2, 61.9, 61.0, 54.6, 37.4, 28.1, 16.0, 14.4. IR (6a, neat): ν̃ = 2974, 2930, 1730, 1685, 1480, 1398, 1282, 1256, 1230, 1185, 1141, 1036, 1006, 887, 760, 701 cm–1. IR (6a′, neat): ν̃ = 2978, 2933, 1733, 1692, 1480, 1394, 1279, 1163, 1126, 1025, 951, 895, 861, 760, 701 cm–1. HRMS (6a, ESI): calcd. for C19H28NO4 [M + H]+ 334.2013; found 334.2020. HRMS (6a′, ESI): calcd. for C19H27NNaO4 [M + Na]+ 356.1832; found 356.1838.

Compounds (±)‐6b and (±)‐6b′: Elution with n‐pentane/diethyl ether (20:1 to 3:1); colorless oils; yield: 128 mg (38 %) of 6b and 32 mg (9 %) of 6b′ using 5b; 106 mg (41 %) of 6b and 27 mg (11 %) of 6b′ using 4b; R f (6b, n‐pentane/EtOAc, 3:1) = 0.33; R f (6b′, n‐pentane/EtOAc, 3:1) = 0.40. 1H NMR (6b, 400 MHz, CDCl3): δ = 7.34–7.16 (m, 5 H), 5.29–4.93 (m, 1 H), 4.18 (m, 2 H), 3.84–3.61 (m, 1 H), 3.58–3.29 (m, 1 H), 3.09–2.81 (m, 1 H), 2.38 (q, J = 7.2 Hz, 1 H), 1.53–1.08 (m, 14 H), 0.98–0.84 (m, 3 H) ppm. 1H NMR (6b′, 400 MHz, CDCl3): δ = 7.36–7.12 (m, 5 H), 5.08–4.81 (m, 1 H), 4.22–4.02 (m, 3 H), 3.20 (t, J = 10.7 Hz, 1 H), 2.63 (t, J = 10.0 Hz, 1 H), 2.47–2.31 (m, 1 H), 1.74–1.53 (m, 2 H), 1.51–1.30 (m, 3 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.10 (s, 6 H), 0.92 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (6b, 101 MHz, CDCl3): δ = 172.2, 154.6, 143.6, 142.5, 128.6, 128.4, 127.1, 125.8, 125.6, 79.6, 63.7, 63.3, 60.7, 56.7, 55.2, 51.4, 50.8, 41.2, 40.8, 28.6, 28.2, 22.2, 14.4, 14.3, 12.7, 12.2 ppm. 13C NMR (6b′, 101 MHz, CDCl3): δ = 172.7, 154.2, 143.9, 128.5, 127.1, 125.8, 79.8, 65.5, 61.0, 60.4, 52.9, 44.0, 28.2, 25.0, 14.4, 12.2 ppm. IR (6b, neat): ν̃ = 2989, 2930, 2863, 1733, 1681, 1480, 1405, 1279, 1163, 1074, 1014, 928, 898, 865, 768, 705 cm–1. IR (6b′, neat): ν̃ = 3034, 2989, 2930, 2866, 1733, 1685, 1480, 1405, 1279, 1163, 1107, 1070, 1010, 961, 928, 895, 764, 705 cm–1. HRMS (6b, ESI): calcd. for C20H29NNaO4 [M + Na]+ 370.1989; found 370.1992. HRMS (6b′, ESI): calcd. for C20H29NNaO4 [M + Na]+ 370.1989; found 370.1991.

Compounds (±)‐6c and (±)‐6c′: Elution with n‐pentane/diethyl ether (20:1 to 1:1); colorless oils; yield: 49 mg (25 %) of 6c and 45 mg (23 %) of 6c′ using 5c; 57 mg (28 %) of 6c and 51 mg (25 %) of 6c′ using 4c; R f (6c, n‐pentane/EtOAc, 3:1) = 0.35; R f (6b′, n‐pentane/EtOAc, 3:1) = 0.40. 1H NMR (6c, 400 MHz, CDCl3): δ = 7.36–7.14 (m, 5 H), 5.11 (d, J = 65.5 Hz, 1 H), 4.30–4.07 (m, 2 H), 3.76 (dt, J = 45.3, 9.5 Hz, 1 H), 3.44 (td, J = 10.7, 4.0 Hz, 1 H), 2.91 (dd, J = 14.8, 6.6 Hz, 1 H), 2.17–2.00 (m, 1 H), 1.64–1.51 (m, 1 H), 1.47 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.22 (s, 6 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 7.2 Hz, 3 H) ppm. 1H NMR (6c′, 400 MHz, CDCl3): δ = 7.81–6.80 (m, 5 H), 4.98–4.77 (m, 1 H), 4.13 (ddq, J = 10.8, 7.2, 3.7 Hz, 2 H), 4.07–3.91 (m, 1 H), 3.29 (t, J = 10.9 Hz, 1 H), 2.71 (t, J = 9.9 Hz, 1 H), 2.40 (tt, J = 10.9, 7.6 Hz, 1 H), 1.68 (dd, J = 13.7, 6.6 Hz, 1 H), 1.50–1.35 (m, 2 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.09 (s, 7 H), 0.93 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (6c, 101 MHz, CDCl3): δ = 172.9, 172.8, 154.7, 154.5, 143.2, 142.3, 128.6, 128.4, 128.4, 127.2, 127.1, 125.6, 125.5, 64.7, 64.5, 60.7, 60.7, 55.0, 54.0, 50.7, 50.1, 47.0, 46.1, 28.9, 28.9, 28.7, 28.3, 22.0, 21.8, 21.6, 21.6, 14.4 ppm. 13C NMR (6c′, 101 MHz, CDCl3): δ = 173.4, 154.2, 143.8, 128.5, 127.2, 125.7, 79.7, 66.5, 61.0, 58.8, 50.8, 48.4, 30.3, 28.1, 21.0, 19.9, 14.3 ppm. IR (6c, neat): ν̃ = 3034, 2967, 1733, 1696, 1476, 1390, 1275, 1163, 1126, 1018, 951, 898, 865, 768, 701 cm–1. IR (6c′, neat): ν̃ = 2967, 2937, 1730, 1696, 1476, 1390, 1256, 1215, 1163, 1115, 1040, 943, 902, 772, 701 cm–1. HRMS (6c, ESI): calcd. for C21H31NNaO4 [M + Na]+ 384.2145; found 384.2153. HRMS (6c′, ESI): calcd. for C21H31NNaO4 [M + Na]+ 384.2145; found 384.2151.

Compound (±)‐6d: Elution with n‐pentane/diethyl ether (7:1 to 1:1); colorless oil; yield: 61 mg (38 % with 5d) and 59 mg (45 % with 4d); R f (n‐pentane/EtOAc, 3:1) = 0.29. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.09 (m, 5 H), 5.11 (d, J = 9.5 Hz, 1 H), 4.30–3.98 (m, 2 H), 3.69 (d, J = 10.8 Hz, 1 H), 3.38 (d, J = 10.7 Hz, 1 H), 2.74 (d, J = 9.5 Hz, 1 H), 1.41 (s, 2 H), 1.26–1.19 (m, 6 H), 1.09 (s, 7 H), 1.03 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.5, 154.4, 144.1, 128.3, 127.0, 126.1, 79.6, 64.0, 62.8, 61.0, 60.7, 40.6, 28.5, 28.1, 25.3, 22.4, 14.4 ppm. IR (neat): ν̃ = 3034, 2974, 2933, 2874, 1730, 1692, 1457, 1394, 1364, 1297, 1264, 1226, 1185, 1156, 1007, 1028, 898, 861, 757, 701 cm–1. HRMS (ESI): calcd. for C20H29NNaO4 [M + Na]+ 370.1989; found 370.1995.

Compounds (±)‐6e and (±)‐6e′: Elution with n‐pentane/diethyl ether (20:1 to 3:1); colorless oils; yield: 80 mg (35 %) of 6e and 71 mg (31 %) of 6e′ using 5e; 48 mg (35 %) of 6e and 43 mg (31 %) of 6e′ using 4e; R f (6e, n‐pentane/EtOAc, 3:1) = 0.29; R f (6e′, n‐pentane/EtOAc, 3:1) = 0.40. 1H NMR (6e, 400 MHz, CDCl3): δ = 4.11 (m, 3 H), 3.44 (dd, J = 10.6, 6.7 Hz, 1 H), 3.21 (s, 1 H), 2.55 (m, 2 H), 1.43 (s, 9 H), 1.29–1.19 (m, 6 H), 0.94 (d, J = 6.7 Hz, 3 H) ppm. 1H NMR (6e′, 400 MHz, CDCl3): δ = 4.15 (q, J = 7.1 Hz, 2 H), 3.89 (s, 1 H), 3.80 (s, 1 H), 2.82 (t, J = 10.7 Hz, 1 H), 2.31 (tt, J = 10.6, 6.6 Hz, 1 H), 2.20 (dd, J = 10.8, 8.4 Hz, 1 H), 1.42 (s, 9 H), 1.30 (d, J = 6.0 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.03 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (6e, 101 MHz, CDCl3): δ = 172.4, 154.6, 79.2, 60.5, 55.0, 52.6, 33.8, 28.6, 20.7, 14.4, 14.1 ppm. 13C NMR (6e′, 101 MHz, CDCl3): δ = 172.8, 154.2, 79.4, 60.9, 59.8, 57.0, 53.2, 36.5, 28.6, 21.03, 16.2, 14.4 ppm. IR (6e, neat): ν̃ = 2974, 2937, 2876, 1733, 1692, 1457, 1390, 1282, 1252, 1174, 1107, 1062, 1029, 954, 869, 775 cm–1. IR (6e′, neat): ν̃ = 2974, 2933, 2876, 1733, 1692, 1457, 1394, 1290, 1256, 1163, 1096, 1033, 910, 869, 772 cm–1. HRMS (6e, ESI): calcd. for C14H25NNaO4 [M + Na]+ 294.1676; found 294.1678. HRMS (6e′, ESI): calcd. for C14H25NNaO4 [M + Na]+ 294.1676; found 294.1683.

Compound (±)‐6f: Elution with n‐pentane/diethyl ether (1:1); colorless oil; yield: 82 mg (50 % with 4f, dr = 74:26); R f (n‐pentane/diethyl ether, 1:1) = 0.13. 1H NMR (major diastereomer, 400 MHz, CDCl3): δ = 7.40–7.08 (m, 10 H), 5.12 (s, 1 H), 3.99 (dd, J = 12.1, 7.9 Hz, 1 H), 3.41 (dd, J = 12.1, 10.2 Hz, 1 H), 3.25–3.18 (m, 1 H), 2.82–2.62 (m, 1 H), 1.91 (s, 3 H), 0.68 (d, J = 6.8 Hz, 3 H) ppm. 1H NMR (minor diastereomer, 400 MHz, CDCl3): δ = 7.40–7.08 (m, 10 H), 5.50 (s, 1 H), 3.89 (dd, J = 9.9, 7.6 Hz, 1 H), 3.32 (t, J = 10.0 Hz, 1 H), 3.25–3.18 (m, 1 H), 2.82–2.62 (m, 1 H), 2.24 (s, 3 H), 0.70 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (major diastereomer, 101 MHz, CDCl3): δ = 170.6, 142.8, 140.4, 129.1, 128.9, 128.1, 127.7, 127.2, 125.6, 69.1, 58.7, 52.4, 33.2, 22.5, 13.9 ppm. 13C NMR (minor diastereomer, 101 MHz, CDCl3): δ = 169.5, 142.6, 139.9, 128.7, 128.6, 128.2, 127.1, 127.0, 125.5, 66.5, 56.5, 53.9, 35.0, 23.0, 13.9 ppm. IR (neat): ν̃ = 3063, 3030, 2963, 2930, 2874, 1722, 1648, 1495, 1454, 1409, 1357, 1279, 1245, 1178, 1137, 1081, 1029, 973, 913, 865, 801, 749, 701 cm–1. HRMS (APCI): calcd. for C19H22NO [M + H]+ 280.1696; found 280.1702.

Compound (+)‐6gA: Elution with n‐pentane/diethyl ether (2:1); colorless oil; yield: 132 mg (30 % with 5g, dr = 73:27); isolation of major diastereomer by additional column chromatography, yield: 96 mg (22 %); R f (n‐pentane/diethyl ether, 1:1) = 0.33; [α]D 25 = +1.7 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.6 Hz, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 4.76–4.51 (m, 1 H), 4.37 (d, J = 10.9 Hz, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 4.23–3.87 (m, 2 H), 3.06–2.81 (m, 2 H), 2.27 (s, 1 H), 1.49 (s, 9 H), 1.33 (t, J = 7.1 Hz, 3 H), 0.93 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 157.7, 154.3, 151.6, 147.6, 147.4, 129.3, 129.1, 125.6, 124.2, 80.9, 80.4, 66.0, 65.4, 63.3, 56.9, 55.7, 54.5, 53.9, 41.5, 41.0, 40.4, 34.4, 32.0, 31.6, 30.5, 29.8, 28.6, 14.9, 14.0 ppm. IR (neat): ν̃ = 2967, 2930, 2874, 1771, 1745, 1692, 1603, 1521, 1394, 1346, 1305, 1252, 1159, 1129, 1014, 853, 753, 701 cm–1. HRMS (ESI): calcd. for C13H16N2O5 [M + H – C4H8]+ 381.1292; found 381.1293.

Compound (+)‐6gB: Elution with n‐pentane/diethyl ether (2:1); colorless oil; yield: 88 mg (28 % with 4g, dr = 68:32); isolation of major diastereomer by additional column chromatography, yield: 56 mg (18 %); R f (n‐pentane/diethyl ether, 1:1) = 0.61; [α]D 25 = +2.5 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.23–8.08 (m, 4 H), 8.01 (s, 1 H), 7.40 (d, J = 8.7 Hz, 2 H), 4.71 (dd, J = 10.9, 3.6 Hz, 1 H), 4.65–4.43 (m, 1 H), 4.42–4.19 (m, 1 H), 4.19–3.97 (m, 1 H), 3.07–2.72 (m, 2 H), 2.34–2.19 (m, 1 H), 1.50 (s, 9 H), 0.92 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 163.5, 154.5, 153.9, 147.7, 147.3, 132.8, 132.5, 132.1, 131.8, 129.6, 128.9, 126.6, 124.2, 121.5, 81.1, 80.6, 66.7, 66.1, 63.1, 58.5, 57.6, 54.6, 54.0, 42.0, 41.6, 28.6, 14.9 ppm. 19F NMR (282 MHz, CDCl3): δ = –63.59 ppm. IR (neat): ν̃ = 2971, 2930, 2874, 1733, 1692, 1603, 1525, 1457, 1394, 1349, 1279, 1249, 1170, 1133, 984, 913, 846, 753 cm–1. HRMS (ESI): calcd. for C26H26F6N2NaO6 [M + Na]+ 599.1587; found 599.1587.

Compound (±)‐6h: Elution with n‐pentane/diethyl ether (7:1 to 1:1); colorless oil; yield: 140 mg (47 % with 5h) and 97 mg (45 % with 4h); R f (n‐pentane/EtOAc, 3:1) = 0.34. 1H NMR (400 MHz, CDCl3): δ = 7.40–7.04 (m, 5 H), 5.39–5.13 (m, 3 H), 4.36 (dq, J = 15.0, 2.2 Hz, 1 H), 4.28–4.12 (m, 3 H), 3.46 (s, 1 H), 1.56–1.13 (m, 12 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.2, 154.1, 143.1, 142.0, 128.5, 127.3, 125.7, 111.2, 79.9, 65.9, 63.9, 61.4, 58.4, 51.2, 28.3, 14.2 ppm. IR (neat): ν̃ = 3064, 2978, 2933, 2870, 1733, 1696, 1454, 1390, 1320, 1252, 1159, 1111, 1033, 898, 753, 701 cm–1. HRMS (APCI): calcd. for C19H26NO4 [M + H]+ 332.1856; found 332.1861.

Compound 11: Elution with hexanes/EtOAc (6:1); colorless oil; yield: 167 mg (73 % with 3a, dr = 59:32:9); R f (hexanes/EtOAc, 1:1) = 0.81. 1H NMR (major diastereomer, 400 MHz, CDCl3): δ = 4.80 (d, J = 6.1 Hz, 1 H), 4.26–4.16 (m, 4 H), 4.16–4.08 (m, 1 H), 3.63 (dd, J = 8.3, 6.2 Hz, 1 H), 3.24 (dd, J = 8.3, 6.1 Hz, 1 H), 2.67 (dquint, J = 13.4, 6.8 Hz, 1 H), 1.32–1.23 (m, 6 H), 1.04–0.98 (m, 2 H) ppm. 1H NMR (minor diastereomer 1, 400 MHz, CDCl3): δ = 4.72 (d, J = 7.4 Hz, 1 H), 4.26–4.16 (m, 4 H), 4.16–4.08 (m, 1 H), 3.58 (t, J = 8.7 Hz, 1 H), 2.77 (dt, J = 11.1, 5.6 Hz, 1 H), 2.62–2.51 (m, 1 H), 1.32–1.23 (m, 6 H), 1.15–1.10 (m, 2 H) ppm. 1H NMR (minor diastereomer 2, 400 MHz, CDCl3): δ = 4.65 (d, J = 8.3 Hz, 1 H), 4.26–4.16 (m, 4 H), 4.16–4.08 (m, 1 H), 3.48 (t, J = 8.0 Hz, 1 H), 2.95 (t, J = 8.4 Hz, 1 H), 2.67 (dquint, J = 13.4, 6.8 Hz, 1 H), 1.32–1.23 (m, 6 H), 1.15–1.10 (m, 2 H) ppm. 13C NMR (major diastereomer, 75 MHz, CDCl3): δ = 172.0, 171.2, 78.7, 75.7, 61.5, 61.2, 52.3, 36.8, 14.5, 14.3, 13.4 ppm. HRMS (ESI): calcd. for C11H18DO5 [M + H]+ 232.1290; found 232.1288.

Supporting Information

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