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Synthesis 2012; 44(13): 1983-1992
DOI: 10.1055/s-0031-1290969
paper
© Georg Thieme Verlag Stuttgart · New York

Diastereocontrol in the Synthesis of 2,3,4-Trisubstituted Pyrrolidines and Tetrahydrofurans via a Palladium(II)-Catalyzed Three-Component Coupling Reaction

Sandeep Raikar
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, 2034 Becker Drive, Shankel Structural Biology Center, West Campus, Lawrence, KS 66047, USA, Fax: +1(785)8645396   Email: hmalina@ku.edu
,
Benoy Kumar Pal
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, 2034 Becker Drive, Shankel Structural Biology Center, West Campus, Lawrence, KS 66047, USA, Fax: +1(785)8645396   Email: hmalina@ku.edu
,
Helena C. Malinakova*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, 2034 Becker Drive, Shankel Structural Biology Center, West Campus, Lawrence, KS 66047, USA, Fax: +1(785)8645396   Email: hmalina@ku.edu
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Further Information

Publication History

Received: 31 January 2012

Accepted after revision: 23 March 2012

Publication Date:
05 June 2012 (online)

 
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Abstract

The synthesis of trisubstituted pyrrolidines and tetrahydrofurans from boronic acids, allenes, and imines or aldehydes via a five- and a three-step protocol, respectively, is described. The assignment­ of the relative stereochemistry in the pyrrolidines and tetrahydrofurans confirmed the mechanistically significant stereochemical divergence of the palladium-catalyzed three-component coupling reaction. The methodology is applicable to the preparation of combinatorial libraries of pyrrolidines related to pharmaceutical agents and bioactive natural products.


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Key words

stereoselective synthesis - heterocycles - palladium - multicomponent reactions - ring closure

Substituted pyrrolidines and tetrahydrofurans constitute structural cores of a variety of medicinally significant natural products and synthetic pharmaceutical agents.[ 1 ] Among these heterocycles, structures featuring an α-aryl functionality[ 2 ] as well as the neuroexcitatory amino acids[ 3 ] present particularly challenging targets for diastereocontrolled syntheses (Figure [1]).

Most frequently, various [3+2] cycloadditions are applied towards the synthesis of substituted pyrrolidines and tetrahydrofurans.[ 4 ] Alternatively, the functionalization of heterocyclic precursors, including the directed metalation of pyrrolidines[ 5 ] or additions to cyclic imines,[ 6 ] provides access to these structural motifs. In contrast, strategies relying on the construction of an acyclic precursor featuring all the requisite stereocenters followed by a ring-closure reaction remain less explored[ 7 ] owing to the challenges posed by acyclic stereocontrol.

Herein, we report a protocol for the synthesis of contiguously trisubstituted pyrrolidines and tetrahydrofurans that are structurally related to bioactive natural products and selected pharmaceutical agents (Figure [1]). Our work demonstrates the synthetic potential of a modular palladium-catalyzed coupling of boronic acids I, allenes II, and imines or aldehydes III affording homoallylic amines or alcohols IV, respectively, which we previously developed in our laboratories.[8] [9] We cyclized the homoallylic amines and alcohols IV to give pyrrolidines or tetrahydrofurans V, respectively, in four (for pyrrolidines) or two (for tetrahydrofurans) straightforward synthetic steps (Scheme [1]). The relative stereochemistry observed in pyrrolidines and tetrahydrofurans V confirmed the operation of stereochemically divergent mechanistic pathways in the palladium-catalyzed coupling step.

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Figure 1 Biologically active pyrrolidines and tetrahydrofurans

Although the preparation of tetrahydrofurans V proved less diastereoselective than the synthesis of pyrrolidines V, good yields of single diastereomers of tetrahydrofurans V were obtained using the synthetically practical route. The described methodology is well suited for the diastereocontrolled synthesis of libraries of substituted pyrrolidines[ 10 ] structurally related to the ETA antagonist atrasentan and allows for independent variations in all three C-substituents on the heterocyclic ring.[ 11 ]

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Scheme 1 Overview of the synthetic strategy

We previously reported a new method for the preparation of homoallylic amines using a palladium(II) acetate catalyzed three-component coupling.[ 8 ] anti-Stereochemistry in both the α-aryl- and α-ester-functionalized products was assigned based on X-ray crystallographic analysis of a single homoallylic amine.[ 8 ]

In contrast, the analogous allylation of aldehydes was most effectively catalyzed by a β-pinene-derived allylpalladium(II) dimer, yielding syn-diastereomers of homoallylic alcohols as major products (dr 2–32:1).[ 9 ] The assignment of the syn-stereochemistry in the homoallylic alcohols was based on the analysis of the corresponding 1H NMR spectroscopic coupling constants and their comparison to literature values.

Aiming to demonstrate the synthetic utility of homoallylic amines and alcohols IV, as well as to unequivocally confirm the mechanistically significant stereochemical divergence in their preparation,[8] [9] we sought a protocol for their conversion into pyrrolidines and tetrahydrofurans, respectively.

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Scheme 2 Preparation of pyrrolidines

Amines 4a–d bearing the N-4-methoxyphenyl (N-PMP) protecting group were prepared in good yields (60–71%) as single diastereomers (Scheme [2]).[ 8a ] Attempts at hydro­boration of the N-PMP-protected amines 4 were not productive, most likely owing to interference caused by the basic amine functionality.[ 12 ] After much experimentation, two reaction conditions for the removal of the PMP protecting group exploiting either periodic acid (H5IO6)[ 13 ] or oxidation with cerium(IV) ammonium nitrate (CAN)[ 14 ] were established and afforded amines 5a–d (Scheme [2]) in moderate to good yields (48–76%) following chromatographic purification, which caused some loss. Thus, crude amines 5 were reacted with tosyl chloride (TsCl) and triethylamine to afford sulfonamides 6a–d in good yields (62–72%) (Scheme [2]). Hydroboration of sulfonamides 6a–d under standard conditions provided the N-tosylamino alcohols 7a–d in moderate to good yields (56–66%) as single diastereomers (Scheme [2]).[ 15 ] Other hydroborating reagents[ 16 ] surveyed (BH3·SMe2 and 9-BBN-H) led only to low conversions of substrates 6. Straightforward ring closure of N-tosylamino alcohols 7a–d was achieved on treatment with TsCl and pyridine,[ 17 ] providing the desired pyrrolidines 8a–d as single diastereomers in good to high yields (66–86%).

X-ray crystallographic analysis of a single crystal of pyrrolidine 8a unequivocally established its relative stereochemistry as 2,3-anti,3,4-anti, confirming the original assignment of homoallylic amines 4a–d as anti [ 8 ] as well as the stereochemical course of the hydroboration reaction. Selective nuclear Overhauser effect (NOE) analysis of pyrrolidine 8a revealed the indicative correlation between the syn-hydrogens at C-2 and C-4 (Scheme [2]). The relative stereochemistry of pyrrolidines 8b–d was assigned by analogy with product 8a.

Seeking to apply the ring-closing sequence to the preparation of pyrrolidines with α-amino ester structures, mimicking the neuroexcitatory amino acids (see Figure [1]), we synthesized N-PMP-protected amine 4e (dr 9:1) in 51% yield after column chromatography (Scheme [3]). The established PMP removal/tosylation sequence afforded N-tosylamine 6e as a single diastereomer in acceptable yields (60% deprotection, 55% tosylation), synthesized without purification of the intermediate amine 5e (Scheme [3]). Unexpectedly, hydroboration of N-tosylamine 6e under the standard conditions[ 15 ] led to decarboxylation and loss of the α-amino ester functionality.

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Scheme 3 Synthesis of a cyclic amino ester

Thus, the hydroboration reaction had to be performed under milder basic conditions (NaBO3)[ 18 ] and with a limited reaction time for the oxidation (1 h max). Using these conditions, N-tosylamino alcohol 7e was obtained as a single diastereomer in good yield (65%). Unexpectedly, lactone 9 was also isolated in 25% yield. Treatment of N-tosylamino alcohol 7e with TsCl and pyridine[ 17 ] provided a mixture of diastereomeric pyrrolidines. Reasoning that epimerization of the sensitive α-amino ester functionality was the likely culprit, milder Mitsunobu conditions[ 19 ] were chosen for the ring closure. Indeed, an excellent yield (84%) of a single diastereomer of pyrrolidine 8e was obtained (Scheme [3]).

Complete spectroscopic characterization of pyrrolidine 8e, including selective NOE experiments, indicated the anti,anti relative stereochemistry. This was demonstrated by the correlation of the syn-hydrogens at C-2 and C-4, as well as that of hydrogens H-3 and H-5 shown in Scheme [3] (see also Supporting Information).

We recognized that successful application of the ring-closing protocol to homoallylic alcohols IV would open up access to trisubstituted tetrahydrofurans structurally related to biologically active lignans[1b] [c] (see Figure [1] and Scheme [4]).

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Scheme 4 Synthesis of tetrahydrofurans

Thus, alcohols 10a–d were prepared by the reported method.[ 9 ] As expected, mixtures of diastereomeric alcohols (determined by 1H NMR spectroscopy) were produced,[ 9 ] and the single major diastereomers 10a–d were easily isolated from the crude reaction mixtures, using column chromatography, in 54–65% yield (Scheme [4]).

Although an initial survey of the reactivity patterns of homoallylic alcohols IV (see Scheme [1]) revealed that a facile retro-allylation occurs under mild basic conditions,[ 12 ] hydroboration[ 15b ] afforded the corresponding diols 11a–d. Disappointingly, the diastereoselectivity of the hydroboration suffered, and diols 11a–d were isolated as 3:1 mixtures of chromatographically inseparable diastereomers (determined by 1H NMR spectroscopy). However, we were pleased to note that the treatment of the mixtures of the diastereomers of diols 11a–d with TsCl and pyridine[ 17 ] afforded tetrahydrofurans 12a–d as single diastereomers (60–73% yield) (Scheme [4]).

An alcohol monotosylated at the primary hydroxy group was isolated (22% yield) from the reaction mixture that provided furan 12a and was characterized. Although the yields of tetrahydrofurans 12a–d were only moderate to good, the isolation of single diastereomers 12a–d proved to be a synthetically practical process. The relative stereochemistry in tetrahydrofuran 12a, which must arise from the major diastereomer of diol 11a, was assigned based on selective NOE analysis. The indicative signals in the NOE spectra showed the correlation of hydrogens H-2 and H-3 with the same hydrogen, H-6, on the C-5 methylene group, and there was an absence of an H-2 and H-4 correlation. The data reveal that tetrahydrofuran 12a possesses syn,anti relative stereochemistry (Scheme [4]). The structures of furans 12b–d were assigned based on the above. The above results are in agreement with the previously assigned syn-stereochemistry for the major diastereomers of homoallylic alcohols 10.[ 9 ]

Treatment of the 3:1 mixture of the diastereomers of diol 11a under the Mitsunobu conditions[ 20 ] afforded tetrahydrofuran 12a in high yield (85%) as a mixture of chromatographically inseparable diastereomers (dr 9:1 by GC analysis).

The facial selectivity of the hydroboration appears to arise from a substrate-directed approach of borane (BH3) to the homoallylic compounds (Scheme [5]).[ 21 ] The notion that non-eclipsed transition states operate in such hydroboration reactions is strongly supported.[ 22 ] The diastereomers of the non-eclipsed transition states in which the steric interactions between the n-hexyl and C-3 aryl groups in the substrates are minimized are shown in Scheme [5].[ 23 ] The approach of BH3 from the face opposite to the ‘large’ substituent at the allylic carbon delivers the observed alcohols. The more efficient diastereocontrol observed in the hydroborations of N-tosylamines 6 correlates with the greater steric bulk of the N-tosyl group in comparison with the hydroxy group in alcohols 10.

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Scheme 5 Stereoselectivity of the hydroboration

In conclusion, a simple protocol for the conversion of boronic acids, allenes, and imines or aldehydes into single diastereomers of contiguously trisubstituted anti,anti-pyrrolidines or syn,anti–tetrahydrofurans, respectively, has been described. Unequivocal assignment of the relative stereochemistry in the heterocycles was achieved and serves to confirm the stereochemical divergence observed in the previously reported palladium-catalyzed three-component preparation of homoallylic alcohols (syn) and homoallylic amines (anti). The modular synthetic sequence can be applied towards the construction of combinatorial libraries of pyrrolidines with structures related to biologically active natural products and synthetic pharmaceutical agents.

NMR spectroscopic data were collected on a Bruker DRX-500 spectrometer at r.t. in CDCl3 with CHCl3 as the internal standard (δ 7.26 ppm for 1H and 77.00 ppm for 13C). Infrared spectra were measured using a Shimadzu FTIR-8400S spectrophotometer with samples prepared as thin films on salt (NaCl) plates. Mass spectra were measured under electrospray (ES) or FAB conditions on Micromass Ltd Quattro Ultima and VG Analytical ZAB instruments, respectively. Silica gel 60 plates (250 μm) and silica gel (40–63 μm) were used for TLC and column chromatography, respectively. Tetrahydrofuran was freshly distilled from sodium/benzophenone. Pyridine and Et3N were distilled from CaH2 and kept over 3-Å (8–12 mesh) molecular sieves under dry argon. Unless aqueous reagents were used, reactions were carried out under an argon atmosphere in oven-dried (at least 6 h at 140 °C) glassware. Allenes 2a and 2b,[8] [9] imines 3a–c,[8] [9] 1-aminobut-3-enes 4a and 4b,[ 8 ] and alcohols 10 [ 9 ] were prepared according to literature protocols. Other solvents and materials were used as received.


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(±)-(1R,2R)-2-n-Hexyl-1-[4-(methoxycarbonyl)phenyl]-1-[(4-methoxyphenyl)amino]-3-(2-naphthyl)but-3-ene (4c)

Following the published method,[ 8 ] amine 4c was obtained.

Yield: 0.540 g (60%); colorless oil.

Rf = 0.25 (EtOAc–hexane, 1:9).

IR (neat): 3300, 1720, 1512 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 8.0 Hz, 2 H), 7.81 (t, J = 6.0 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.72 (t, J = 5.0 Hz, 1 H), 7.65 (s, 1 H), 7.40–7.38 (m, 2 H), 7.36–7.31 (m, 3 H), 6.62 (d, J = 9.0 Hz, 2 H), 6.35 (d, J = 9.0 Hz, 2 H), 5.50 (s, 1 H), 5.30 (s, 1 H), 4.26 (br s, 1 H), 4.18 (d, J = 8.5 Hz, 1 H), 3.87 (s, 3 H), 3.66 (s, 3 H), 2.90 (td, J = 10.0, 4.0 Hz, 1 H), 1.45–1.35 (m, 2 H), 1.33–1.25 (m, 2 H), 1.22–1.12 (m, 6 H), 0.81 (t, J = 7.0 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.1, 22.5, 27.4, 29.2, 30.6, 31.6, 51.9, 53.1, 55.7, 62.3, 114.6 (2 C), 114.7 (2 C), 117.1, 125.7, 125.9 (2 C), 126.2, 127.5, 127.8 (2 C), 127.9, 128.1, 128.9, 129.6, 130.2, 132.6, 133.1, 139.3, 141.3, 148.8, 149.6, 152.1, 166.9.

HRMS–ES: m/z [M + H]+ calcd for C35H40NO3: 522.3008; found: 522.2993.


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(±)-(1R,2R)-2-(2-Ethylhexyl)-1,3-bis[4-(methoxycarbonyl)phenyl]-1-[(4-methoxyphenyl)amino]but-3-ene (4d)

Following the published method,[ 8 ] amine 4d was obtained.

Yield: 0.715 g (71%); colorless oil.

Rf = 0.20 (EtOAc–hexane, 1:9).

IR (neat): 3300, 1722, 1512 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.95–7.93 (m, 4 H), 7.40 (dd, J = 8.5, 1.5 Hz, 2 H), 7.29 (dd, J = 8.5, 1.5 Hz, 2 H), 6.63 (dd, J = 8.5, 1.5 Hz, 2 H), 6.36 (dd, J = 9.0, 3.5 Hz, 2 H), 5.45 (s, 0.5 H), 5.44 (s, 0.5 H), 5.34 (s, 1 H), 4.14–4.10 (m, 1 H), 3.92 (s, 1.5 H), 3.91 (s, 1.5 H), 3.89 (s, 3 H), 3.67 (s, 3 H), 2.94–2.89 (m, 1 H), 1.41–1.32 (m, 1 H), 1.29–1.10 (m, 11 H), 0.83 (t, J = 7.0 Hz, 1.5 H), 0.77 (t, J = 9.0 Hz, 1.5 H), 0.71 (t, J = 7.5 Hz, 1.5 H), 0.52 (t, J = 7.5 Hz, 1.5 H).

13C NMR (125 MHz, CDCl3): δ = 11.1 (9.3), 14.2 (14.1), 23.1 (22.9), 27.5 (26.6), 28.9, 31.4, 33.3, 34.2, 35.9, 35.4, 55.2 (52.1), 55.6, 62.0 (61.8), 114.6 (2 C), 114.7 (2 C), 127.4 (127.3) (2 C), 127.7 (2 C), 129.0, 129.07 (129.08), 129.5 (2 C), 129.6 (2 C), 129.7, 140.9, 146.43 (146.39), 148.59 (148.56), 149.4, 152.1, 166.8, 166.98 (166.96); signals for the minor diastereomer arising from the stereocenter in the side chain are given in parentheses.

HRMS–ES: m/z [M + Na]+ calcd for C35H43NO5Na: 580.3039; found: 580.3063.


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(±)-Ethyl (2R,3R)-3-Hexyl-2-[(4-methoxyphenyl)amino]-4-phenylpent-4-enoate (4e)

Following the published method,[ 8 ] amine 4e was obtained as a mixture of inseparable diastereomers (9:1).

Yield: 0.170 g (51%); yellow oil.

Rf = 0.58 (EtOAc–hexane, 1:7).

IR (neat): 3373, 1731, 1512 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 5 H), 6.75 (d, J = 8.8 Hz, 2 H), 6.55 (d, J = 8.8 Hz, 2 H), 5.43 (s, 0.1 H), 5.39 (s, 0.9 H), 5.22 (s, 0.9 H), 5.21 (s, 0.1 H), 3.87–3.79 (m, 1 H), 3.74 (s, 3 H), 3.77–3.67 (m, 1 H), 3.15 (quin, J = 6.4 Hz, 0.9 H), 3.08 (quin, J = 4.4 Hz, 0.1 H), 1.75–1.60 (m, 2 H), 1.55–1.45 (m, 1 H), 1.45–1.20 (m, 10 H), 1.06 (t, J = 7.2 Hz, 3 H), 0.90 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 14.0, (14.1), 22.6, (27.1), 27.3, 29.4, (29.39), (30.4), 31.0, (31.6), 31.7, (47.0), 47.3, 55.7, 60.6, 60.7, (60.8), (62.3), (114.6), 114.7 (2 C), 115.3 (2 C), (115.5), 116.0, (126.8), 127.2 (2 C), 127.4, 128.1 (2 C), (128.3), 141.2, (141.3), 142.4, 148.1, (148.4), 152.6, (152.7), 173.3; signals for the minor diastereomer are given in parentheses.

HRMS–ES: m/z [M + H]+ calcd for C26H36NO3: 410.2695; found: 410.2685.


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N-Tosylamines 6a–e via Amines 5a–e; General Procedure

Method A: To a solution of the corresponding amine 4 (1.0 equiv) in MeCN (3–8 mL) was successively added H5IO6 (1.2 equiv), H2O (0.2–1.0 mL) dropwise, and 1 M aq H2SO4 (0.5–2.0 mL). The mixtures was stirred at r.t. for 24 h. Then H2O (20 mL) was added, and the mixture was extracted with Et2O (4 × 20 mL). For small-scale preparations, the crude mixture was directly loaded on the silica column for separation.

Method B: To a solution of the corresponding amine 4 (1.0 equiv) in MeCN (2.0 mL) was added a solution of CAN (1.3 equiv) in H2O (3.0 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C and 3 h at r.t. Then, EtOAc (30 mL) was added, and the mixture was extracted with 5% aq NaHCO3 (30 mL).

For methods A and B, the organic extracts were dried (MgSO4), and the solvents were removed under reduced pressure to afford crude products that were partially purified by flash column chromatography [silica gel, MeOH–CH2Cl2, (1:19) for 5a–d or EtOAc–hexane (1:2) for 5e]. Amines 5a–e were formed as brown to yellow oils that yielded acceptable 1H and 13C NMR spectra (see Supporting Information). However, amines 5a–e were not fully characterized.

The selected amine 5 (1.0 equiv) was dissolved in THF (5–12 mL), TsCl (1.6 equiv) and Et3N (1.1 equiv) were added to the solution at 0 °C, and the mixture was stirred at r.t. under argon for 18 h. Then, H2O (6–10 mL) was added, and the mixture was extracted with Et2O (4 × 20 mL). The organic extracts were dried (MgSO4), and the solvents were removed under reduced pressure to afford the crude product, which was separated by flash column chromatography [silica gel, EtOAc–hexane (1:4, 1:5 or 1:7)]. N-Tosylamines 6a–e were formed as yellow oils.


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(±)-(1R,2R)-2-Hexyl-1,3-bis[4-(methoxycarbonyl)phenyl]-1-(tosylamino)but-3-ene (6a)

Following Method A, the amine intermediate 5a and the N-tosylamine product 6a were isolated.


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5a

Yield: 0.216 g (73%); brown oil.

Rf = 0.35 (MeOH–CH2Cl2, 1:19).

1H NMR (500 MHz, CDCl3): δ = 7.99 (d, J = 7.0 Hz, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 8.5 Hz, 2 H), 7.42 (d, J = 8.5 Hz, 2 H), 5.52 (s, 1 H), 5.29 (s, 1 H), 4.00 (d, J = 9.0 Hz, 1 H), 3.92 (s, 3 H), 3.90 (s, 3 H), 2.83–2.72 (m, 1 H), 2.29 (br s, 2 H), 1.34–1.01 (m, 10 H), 0.77 (t, J = 7.0 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 22.5, 27.1, 29.2, 29.7, 31.6, 32.4, 52.1, 52.7, 60.3, 116.2, 126.8 (2 C), 127.5 (2 C), 128.9, 129.2, 129.6 (2 C), 129.7 (2 C), 148.0, 149.6, 150.2, 166.92, 166.98.


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6a

Yield: 0.379 g (64%); yellow oil.

Rf = 0.32 (EtOAc–hexane, 1:4).

IR (neat): 3276, 1722 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.79 (d, J = 8.5 Hz, 2 H), 7.62 (d, J = 8.5 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.5 Hz, 2 H), 6.98 (d, J = 8.0 Hz, 2 H), 6.91 (d, J = 8.0 Hz, 2 H), 5.61 (d, J = 6.5 Hz, 1 H), 5.35 (s, 1 H), 5.07 (s, 1 H), 4.28 (t, J = 6.5 Hz, 1 H), 3.83 (s, 3 H), 3.80 (s, 3 H), 2.77–2.18 (m, 1 H), 2.21 (s, 3 H), 1.20–1.15 (m, 4 H), 1.14–1.09 (m, 2 H), 1.05–0.87 (m, 4 H), 0.70 (t, J = 6.5 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 21.3, 22.4, 26.8, 29.1, 30.7, 31.5, 50.7, 52.0, 52.1, 60.6, 118.2, 126.7 (2 C), 127.0 (2 C), 127.5 (2 C), 128.9, 129.0, 129.1 (2 C), 129.2 (2 C), 129.6 (2 C), 137.1, 143.1, 144.3, 146.4, 147.2, 166.7, 166.8.

HRMS–ES: m/z [M + Na]+ calcd for C33H39NO6SNa: 600.2396; found: 600.2380.


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(±)-(1R,2R)-2-Hexyl-3-[4-(methoxycarbonyl)phenyl]-1-(4-nitrophenyl)-1-(tosylamino)but-3-ene (6b)

Following Method A, the amine intermediate 5b and the N-tosylamine product 6b were isolated.


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5b

Yield: 0.212 g (72%); brown oil.

Rf = 0.40 (MeOH–CH2Cl2, 1:19).

1H NMR (500 MHz, CDCl3): δ = 8.15 (d, J = 8.5 Hz, 2 H), 7.99 (d, J = 8.5 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.47 (d, J = 8.5 Hz, 2 H), 5.54 (s, 1 H), 5.29 (s, 1 H), 4.08 (d, J = 8.5 Hz, 1 H), 3.92 (s, 3 H), 2.79 (td, J = 9.0, 3.0 Hz, 1 H), 1.90–1.69 (m, 2 H), 1.34–1.05 (m, 10 H), 0.78 (t, J = 7.0 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 22.5, 27.1, 29.2, 31.6, 32.2, 52.2, 52.6, 59.9, 116.5, 123.5 (2 C), 126.8 (2 C), 128.4 (2 C), 129.1, 129.7 (2 C), 147.2, 147.7, 149.6, 151.8, 166.8.


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6b

Yield: 0.280 g (62%); yellow oil.

Rf = 0.30 (EtOAc–hexane, 1:4).

IR (neat): 3276, 1720 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.91 (d, J = 8.5 Hz, 2 H), 7.88 (d, J = 8.5 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.19 (d, J = 4.5 Hz, 2 H), 7.17 (d, J = 4.5 Hz, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 5.51 (s, 1 H), 5.19 (s, 1 H), 5.09 (d, J = 5.5 Hz, 1 H), 4.37 (dd, J = 8.0, 5.0 Hz, 1 H), 3.92 (s, 3 H), 2.85–2.81 (m, 1 H), 2.34 (s, 3 H), 1.32–1.04 (m, 10 H), 0.80 (t, J = 7.0 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 21.4, 22.5, 27.0, 29.0, 30.8, 31.5, 51.2, 52.2, 60.0, 118.9, 123.2 (2 C), 126.6 (2 C), 127.1 (2 C), 128.4 (2 C), 129.4 (2 C), 129.5, 129.8 (2 C), 136.8, 143.8, 145.6, 146.9, 147.0, 147.1, 166.6.

HRMS–ES: m/z [M + Na]+ calcd for C31H36N2O6SNa: 587.2192; found: 587.2180.


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(±)-(1R,2R)-2-Hexyl-1-[4-(methoxycarbonyl)phenyl]-3-(2-naphthyl)-1-(tosylamino)but-3-ene (6c)

Following Method B, the intermediate amine 5c was obtained and was not characterized, and N-tosylamine 6c was isolated.


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5c

Yield: 0.043 g (48%); yellow oil.


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6c

Yield: 0.213 g (65%); yellow oil.

Rf = 0.33 (EtOAc–hexane, 1:4).

IR (neat): 3200, 1722 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.86–7.74 (m, 2 H), 7.72 (d, J = 8.5 Hz, 2 H), 7.66 (d, J = 5 Hz, 1 H), 7.60 (d, J = 1.0 Hz, 1 H), 7.48 (t, J = 1.5 Hz, 1 H), 7.39 (t, J = 2.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.37–7.30 (m, 1 H), 7.11 (d, J = 8.5 Hz, 2 H), 6.98 (d, J = 7.5 Hz, 2 H), 5.54 (s, 1 H), 5.18 (s, 1 H), 5.09 (d, J = 5.0 Hz, 1 H), 4.37 (dd, J = 8.5, 5.0 Hz, 1 H), 3.86 (s, 3 H), 2.93 (td, J = 8.5, 4.0 Hz, 1 H), 2.27 (s, 3 H), 1.36–1.06 (m, 10 H), 0.78 (t, J = 7.0 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 21.1, 21.8, 27.1, 29.1, 30.8, 31.5, 51.5, 52.0, 60.8, 117.5, 123.6, 125.0, 125.5, 126.1, 126.3, 127.1, 127.5, 127.7, 128.1, 128.2, 128.5, 129.1 (2 C), 129.2 (2 C), 129.8, 132.7, 133.1, 136.9, 138.6, 143.1, 144.6, 148.0, 166.7.

HRMS–ES: m/z [M + Na]+ calcd for C35H39NO4SNa: 592.2498; found: 592.2480.


#

(±)-(1R,2R)-2-(2-Ethylhexyl)-1,3-bis[4-(methoxycarbonyl)phenyl]-1-(tosylamino)but-3-ene (6d)

Following Method A, the amine intermediate 5d and the N-tosyl amine product 6d were isolated.


#

5d

Yield: 0.224 g (76%); brown oil.

Rf = 0.30 (MeOH–CH2Cl2, 1:19).

1H NMR (500 MHz, CDCl3): δ = 7.99 (t, J = 8.0 Hz, 4 H), 7.52 (dd, J = 8.5, 2.0 Hz, 2 H), 7.45 (dd, J = 8.0, 1.5 Hz, 2 H), 5.54 (s, 1 H), 5.33 (s, 1 H), 4.00 (d, J = 9.0 Hz, 1 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 2.93–2.87 (m, 1 H), 2.06–1.77 (m, 2 H), 1.36–0.94 (m, 9 H), 0.91–0.88 (m, 2 H), 0.80 (t, J = 7.5 Hz, 1.5 H), 0.72 (t, J = 7.5 Hz, 1.5 H), 0.65 (t, J = 7.5 Hz, 1.5 H), 0.46 (t, J = 7. Hz, 1.5 H); two diastereomers arise from the stereocenter in the branched alkyl substituent.


#

6d

Yield: 0.270 g (72%); pale-yellow oil.

Rf = 0.45 (EtOAc–hexane, 1:5).

IR (neat): 3278, 1722 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.91 (dd, J = 8.5, 1.5 Hz, 2 H), 7.74 (d, J = 8.5 Hz, 2 H), 7.37(d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.07 (d, J = 8.0 Hz, 2 H), 7.02 (d, J = 8.0 Hz, 2 H), 5.43 (s, 1 H), 5.16 (s, 1 H), 5.03 (t, J = 4.5 Hz, 1 H), 4.29 (quin, J = 3.5 Hz, 1 H), 3.86 (s, 3 H), 3.82 (s, 3 H), 2.85 (td, J = 11.3, 3.0 Hz, 1 H), 2.32 (s, 3 H), 1.35–1.23 (m, 2 H), 1.21–0.82 (m, 9 H), 0.79 (t, J = 7.5 Hz, 1.5 H), 0.75 (t, J = 7.5 Hz, 1.5 H), 0.63 (t, J = 6.0 Hz, 1.5 H), 0.51 (t, J = 7.5 Hz, 1.5 H).

13C NMR (125 MHz, CDCl3): δ = 9.4 (10.8), 14.0, 21.3, 22.8 (22.9), 24.4, 26.3, 27.6 (28.7), 31.5 (33.0), 34.7, 35.3 (35.7), 49.0 (49.1), 52.1 (52.2), 60.8 (60.9), 119.10 (119.11), 126.8 (2 C) (126.9), 127.1 (2 C), 127.6 (2 C) (127.7), 129.1 (2 C) (129.2), 129.31 (2 C) (129.32), 129.37, 129.61 (129.65), 129.68 (2 C) (129.69), 136.94 (136.96), 143.2, 144.4 (144.5), 145.8 (145.9), 147.9, (166.63) 166.65, 166.7. Signals for the minor diastereomer arising from the stereocenter in the side chain are given in parentheses.

HRMS–ES: m/z [M + Na]+ calcd for C35H43NO6SNa: 628.2709; found: 628.2701.


#

(±)-Ethyl (2R,3R)-3-Hexyl-4-phenyl-2-(tosylamine)pent-4-enoate (6e)

Following Method A, the amine intermediate 5e was obtained as a mixture of inseparable diastereomers (9:1), and N-tosylamine 6e was isolated as a single diastereomer.


#

5e

Yield: 0.150 g (60%); brown oil.

Rf = 0.25 (EtOAc–hexane, 1:2).

1H NMR (400 MHz, CDCl3): δ = 7.44–7.23 (m, 5 H), 5.45 (s, 0.1 H), 5.40 (s, 0.9 H), 5.17 (s, 0.9 H), 5.14 (s, 0.1 H), 3.83–3.75 (m, 1 H), 3.53 (d, J = 5.2 Hz, 1 H), 3.52–3.45 (m, 1 H), 3.15 (quin, J = 5.6 Hz, 1 H), 2.36 (br s, 2 H), 1.75–1.60 (m, 2 H), 1.55–1.10 (m, 8 H), 1.04 (t, J = 7.2 Hz, 3 H), 0.90 (t, J = 6.8 Hz, 3 H).


#

6e

Yield: 0.118 g (55%); yellow oil.

Rf = 0.7 (EtOAc–hexane, 1:7).

IR (neat): 3276, 1737, 1598 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 2 H), 7.26–7.21 (m, 7 H), 5.40 (s, 1 H), 5.20 (s, 1 H), 5.09 (d, J = 10.0 Hz, 1 H), 3.97 (dd, J = 10.4, 4.0 Hz, 1 H), 3.37–3.27 (m, 1 H), 3.21–3.15 (m, 1 H), 3.14–3.06 (m, 1 H), 2.39 (s, 3 H), 1.78–1.66 (m, 2 H), 1.48–1.23 (m, 8 H), 0.92 (t, J = 6.8 Hz, 3 H), 0.77 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.4, 14.1, 21.4, 22.6, 27.1, 29.3, 31.6, 31.7, 45.8, 57.5, 61.1, 116.4, 126.8 (2 C), 127.2 (2 C), 127.5, 128.1 (2 C), 129.4 (2 C), 136.8, 142.4, 143.4, 146.6, 170.2.

HRMS–ES: m/z [M + Na]+ calcd for C26H35NO4SNa: 480.2185; found: 480.2169.


#

Amino Alcohols 7a–d and Diols 11a–d; General Procedure

To a solution of the corresponding N-tosylamine 6 or alcohol 10 (1.0 equiv) in THF (5–10 mL) at 0 °C was added 1 M BH3·THF complex in THF (5.0 equiv). The solution was stirred at r.t. under argon for 24 h for amines 6 and for 4 h for alcohols 10. Then, 3 M aq NaOH (9.0 equiv) was added at 0 °C, followed by 30% aq H2O2 (9.0 equiv), and the mixture was stirred for 30 min at 0 °C and for 2 h at r.t. Finally, H2O (20 mL) was added, and the mixture was extracted with EtOAc (4 × 20 mL). The organic extracts were dried (MgSO4), and the solvents were removed under reduced pressure to afford the crude product that was separated by flash column chromatography [silica gel, EtOAc–hexane (1:1 or 3:7) for 7a–d or EtOAc­–hexane (1:7) for 11a–d]. Amino alcohols 7a–d and diols 11a–d were formed as colorless oils.


#

(±)-(1R,2R,3S)-2-Hexyl-4-hydroxy-1,3-bis[4-(methoxycarbonyl)phenyl]-1-(tosylamino)butane (7a)

Yield: 0.048 g (65%); colorless oil.

Rf = 0.45 (EtOAc–hexane, 1:1).

IR (neat): 3500, 3271, 1722 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.0 Hz, 2 H), 7.70 (d, J = 8.5 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 6.98 (d, J = 8.0 Hz, 2 H), 6.20 (d, J = 8.5 Hz, 1 H), 4.44 (t, J = 8.0 Hz, 1 H), 3.93–3.85 (m, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 3.79 (dd, J = 10.5, 8.0 Hz, 1 H), 3.32 (q, J = 6.0 Hz, 1 H), 2.52 (br s, 1 H), 2.27 (s, 3 H), 2.25–2.20 (m, 1 H), 1.06–0.94 (m, 3 H), 0.92–0.75 (m, 7 H), 0.72 (t, J = 7.5 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.0, 21.3, 22.4, 27.7, 28.3, 29.2, 31.3, 45.6, 48.0, 52.1, 52.2, 59.7, 64.2, 126.8 (2 C), 127.3 (2 C), 128.7, 128.8, 128.9 (2 C), 129.2 (2 C), 129.4 (2 C), 129.8 (2 C), 137.5, 143.1, 145.4, 145.9, 166.7, 167.0.

HRMS–ES: m/z [M + Na]+ calcd for C33H41NO7SNa: 618.2501; found: 618.2510.


#

(±)-(1R,2R,3S)-2-Hexyl-4-hydroxy-3-[4-(methoxycarbonyl)phenyl]-1-(4-nitrophenyl)-1-(tosylamino)butane (7b)

Yield: 0.140 g (61%); colorless oil.

Rf = 0.30 (EtOAc–hexane, 1:1).

IR (neat): 3492, 3375, 3269, 1720 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.5 Hz, 2 H), 7.87 (d, J = 9.0 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 2 H), 7.30 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H), 7.01 (d, J = 8.0 Hz, 2 H), 6.51 (d, J = 8.5 Hz, 1 H), 4.47 (t, J = 8.5 Hz, 1 H), 3.95–3.89 (m, 1 H), 3.91 (s, 3 H), 3.82 (dd, J = 10.5, 3.0 Hz, 1 H), 3.33 (q, J = 5.5 Hz, 1 H), 2.78 (br s, 1 H), 2.32–2.25 (m, 1 H), 2.28 (s, 3 H), 1.12–0.99 (m, 3 H), 0.90–0.65 (m, 7 H), 0.72 (t, J = 7.5 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 21.3, 22.3, 27.7, 28.4, 29.2, 31.3, 45.5, 48.0, 52.2, 59.6, 64.1, 125.9, 126.3, 126.6, 126.8 (2 C), 127.1, 127.6, 127.7, 128.5, 128.8, 129.2, 129.4, 132.5, 133.4, 137.7, 137.8, 143.0, 146.0, 166.7.

HRMS–ES: m/z [M + Na]+ calcd for C31H38N2O7SNa: 605.2297; found: 605.2310.


#

(±)-(1R,2R,3S)-2-Hexyl-4-hydroxy-1-[4-(methoxycarbonyl)phenyl]-3-(2-naphthyl)-1-(tosylamino)butane (7c)

Yield: 0.066 g (56%); colorless oil.

Rf = 0.25 (EtOAc–hexane, 3:7).

IR (neat): 3488, 3365, 3272, 1722 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.87–7.79 (m, 5 H), 7.62 (br s, 1 H), 7.52–7.47 (m, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.32 (dd, J = 8.0, 2.0 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.01 (d, J = 8.0 Hz, 2 H), 5.54 (d, J = 8.0 Hz, 1 H), 4.65 (t, J = 6.5 Hz, 1 H), 3.91–3.87 (m, 1 H), 3.90 (s, 3 H), 3.82–3.74 (m, 1 H), 3.18 (q, J = 5.5 Hz, 1 H), 2.35–2.28 (m, 1 H), 2.30 (s, 3 H), 1.63 (br s, 1 H), 1.14–1.06 (m, 2 H), 1.03–0.90 (m, 8 H), 0.75 (t, J = 7.5 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.0, 21.4, 22.5, 27.8, 28.5, 29.2, 31.5, 46.3, 48.2, 52.1, 59.3, 64.8, 125.9, 126.4, 126.7, 126.8 (2 C), 127.1 (2 C), 127.6, 127.8 (2 C), 128.6, 128.8, 129.2 (2 C), 129.4 (2 C), 132.6, 133.4, 137.7, 137.8, 143.0, 146.0, 166.7.

HRMS–ES: m/z [M + Na]+ calcd for C35H41NO5SNa: 610.2603; found: 610.2570.


#

(±)-(1R,2R,3S)-2-(2-Ethylhexyl)-4-hydroxy-1,3-bis[4-(methoxycarbonyl)phenyl]-1-(tosylamino)butane (7d)

Yield: 0.166 g (66%); colorless oil.

Rf = 0.41 (EtOAc–hexane, 3:7).

IR (neat): 3494, 3272, 1722 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.00 (dd, J = 8.5, 7.0 Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.41 (dd, J = 8.0, 5.5 Hz, 2 H), 7.25 (dd, J = 8.5, 5.0 Hz, 2 H), 7.09 (d, J = 8.5 Hz, 2 H), 7.02 (d, J = 7.5 Hz, 2 H), 5.62 (t, J = 9.5 Hz, 1 H), 4.52 (t, J = 6.0 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 3.82–3.77 (m, 1 H), 3.75–3.67 (m, 1 H), 3.20 (quin, J = 5 Hz, 1 H), 2.35–2.29 (m, 1 H), 2.29 (s, 3 H), 1.76 (br s, 1 H), 1.22–0.97 (m, 4 H), 0.94–0.82 (m, 7 H), 0.81 (t, J = 6.0 Hz, 1.5 H), 0.77 (t, J = 7.5 Hz, 1.5 H), 0.57 (t, J = 7.0 Hz, 1.5 H), 0.50 (t, J = 7.0 Hz, 1.5 H).

13C NMR (125 MHz, CDCl3): δ = 14.1 (14.2), 21.1 (21.3), 23.06 (23.09), 24.0 (25.5), 27.7 (28.2), 31.2, 32.5, 32.9 (33.0), 35.9 (36.0), 43.7, 43.8, (48.3) 48.4, 52.1, 59.8 (60.4), 64.0, 126.81 (126.83) (2 C), 127.1 (2 C), 128.81 (128.84), 128.92 (128.95), 129.0, 129.2 (2 C), 129.4 (2 C), 129.8 (2 C), 137.6 (137.7), 143.10 (143.13), 145.7, 145.84, 145.88, 166.65 (166.66), 166.83 (166.86); signals for the minor diastereomer arising from the stereocenter in the side chain are given in parentheses.

HRMS–ES: m/z [M + H]+ calcd for C35H46NO7S: 624.2995; found: 624.3000.


#

(±)-(1R,2S,3R)-2-Hexyl-1,4-dihydroxy-3-(4-methoxyphenyl)-1-phenylbutane (11a)

Diol 11a was obtained as a mixture of inseparable diastereomers (3:1).

Yield: 0.143 g (85%); colorless heavy oil.

Rf = 0.58 (EtOAc–hexane, 1:7).

IR (neat): 3373, 1724, 1606 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.36–7.20 (m, 7 H), 6.95 (d, J = 8.4 Hz, 0.5 H), 6.90 (d, J = 8.4 Hz, 1.5 H), 5.05 (s, 0.75 H), 4.67 (s, 0.25 H), 4.09 (d, J = 4.8 Hz, 1.5 H), 4.03–3.96 (br m, 0.25 H), 3.88 (t, J = 9.2 Hz, 0.25 H), 3.83 (s, 3 H), 3.13–3.07 (m, 0.25 H), 3.04 (q, J = 6.0 Hz, 0.75 H), 2.70–2.57 (m, 1 H), 2.47–2.33 (m, 1 H), 2.05–2.00 (m, 0.75 H), 1.96–1.87 (m, 0.25 H), 1.41–1.23 (m, 2 H), 1.20–0.86 (m, 8 H), 0.79 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.0, 22.4, (22.5), (25.4), 25.7, 28.1, (28.9), 29.3, (29.5), 31.4, 47.9, (48.1), 49.4, (50.1), 55.2, (55.3), 64.1, (65.0), 72.8, (73.8), 113.9 (2 C), (114.4), (125.3), 125.6 (2 C), (126.6), 126.8, (128.0), 128.1 (2 C), (129.41), 129.45 (2 C), (133.6), 134.5, 143.9, (144.0), 158.2, (158.5); signals for the minor diastereomer are given in parentheses.

HRMS–FAB: m/z [M]+ calcd for C23H32O3: 356.2351; found: 356.2347.


#

(±)-(1R,2S,3R)-2-Hexyl-1,4-dihydroxy-1,3-bis(4-methoxyphenyl)butane (11b)

Diol 11b was obtained as a mixture of inseparable diastereomers (3:1).

Yield: 0.09 g (92%); colorless heavy oil.

Rf = 0.45 (EtOAc–hexane, 1:7).

IR (neat): 3650, 1512, 1247 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 8.8 Hz, 2 H), 7.19–7.16 (m, 2 H), 6.94 (d, J = 8.4 Hz, 0.5 H), 6.90–6.84 (m, 3.5 H), 4.98 (d, J = 2.0 Hz, 0.75 H), 4.63 (d, J = 2.4 Hz, 0.25 H), 4.06 (d, J = 5.2 Hz, 1.5 H), 3.98 (dd, J = 10.8, 5.2 Hz, 0.25 H), 3.86 (dd, J = 10.8, 8.4 Hz, 0.25 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.10–3.05 (m, 0.25 H), 3.02 (q, J = 6.8 Hz, 0.75 H), 2.42–2.23 (br, 2 H), 2.02–1.96 (m, 0.75 H), 1.90–1.83 (m, 0.25 H), 1.40–1.24 (m, 2 H), 1.21–0.98 (m, 7 H), 0.96–0.87 (m, 1 H), 0.81 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = (14.02), 14.05, 22.51, (22.57), (25.4), 25.9, (28.0), 28.1, (29.0), 29.4, 31.51, (31.58), 47.8, (48.3), 49.3, (50.0), 55.2, (55.6), 64.1, (65.0), 72.6, (73.6), (74.6), 75.4, (113.7), 113.8 (2 C), 114.0 (2 C), (114.3), (126.4), 126.7 (2 C), (127.6), 128.0 (2 C), (132.9), (133.7), 134.0, 134.3, 158.2, (158.3), 158.4, (158.5); signals for the minor diastereomer are given in parentheses.

HRMS–ES: m/z [M + Na]+ calcd for C24H34O4Na: 409.2355; found: 409.2384.


#

(±)-(1R,2S,3R)-2-Hexyl-1,4-dihydroxy-3-(4-methoxyphenyl)-1-(4-nitrophenyl)butane (11c)

Diol 11c was obtained as a mixture of inseparable diastereomers (3:1).

Yield: 0.065 g (62%); colorless heavy oil.

Rf = 0.38 (EtOAc–hexane, 1:7).

IR (neat): 3440, 1637, 1550, 1250 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 8.8 Hz, 2 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 1.5 H), 6.87 (d, J = 8.4 Hz, 0.5 H), 5.14 (s, 0.75 H), 4.77 (s, 0.25 H), 4.19–4.08 (m, 1.5 H), 4.03 (dd, J = 10.8, 5.6 Hz, 0.25 H), 3.91 (dd, J = 10.4, 7.6 Hz, 0.25 H), 3.83 (s, 3 H), 3.14–3.06 (m, 1 H), 2.51 (br s, 2 H), 2.09–2.01 (m, 0.75 H), 1.99–1.94 (m, 0.25 H), 1.31–1.24 (m, 2 H), 1.17–0.92 (m, 7 H), 0.85–0.74 (m, 1 H), 0.78 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 22.4, (22.5), (25.3), 25.7, 27.9, (28.8), 29.2, (29.4), 31.7, 47.6, (48.1), (50.0), 50.2, 55.2, (55.3), 64.0, (64.8), 71.7, (73.4), 114.1 (2 C), (114.6), 123.2 (2 C), (123.3), (126.3), 126.5 (2 C), 129.3 (2 C), (133.1), 134.2, 146.7, 152.0, 158.4, (158.8); signals for the minor diastereomer are given in parentheses.

HRMS–FAB: m/z [M]+ calcd for C23H31NO5: 401.2202; found: 401.2197.


#

(±)-(1R,2S,3R)-1-(2-Furyl)-2-hexyl-1,4-dihydroxy-3-(4-meth­oxyphenyl)butane (11d)

Diol 11d was obtained as a mixture of inseparable diastereomers (3:1).

Yield: 0.082 g (68%); colorless heavy oil.

Rf = 0.5 (EtOAc–hexane, 1:7).

IR (neat): 3700, 1610, 1514, 1249 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.38 (dd, J = 1.6, 0.8 Hz, 0.75 H), 7.33 (dd, J = 2.0, 0.8 Hz, 0.25 H), 7.26 (d, J = 1.6 Hz, 0.5 H), 7.22 (d, J = 8.8 Hz, 1.5 H), 6.92 (d, J = 8.8 Hz, 0.5 H), 6.88 (d, J = 8.4 Hz, 1.5 H), 6.37 (dd, J = 3.2, 2.0 Hz, 0.75 H), 6.33 (dd, J = 3.2, 2.0 Hz, 0.25 H), 6.28 (dt, J = 3.2, 0.8 Hz, 0.75 H), 6.20 (dt, J = 3.2, 0.8 Hz, 0.25 H), 5.03(d, J = 2.4 Hz, 0.75 H), 4.63 (d, J = 1.6 Hz, 0.25 H), 4.07–3.94 (m, 1.75 H), 3.88–3.83 (m, 0.25 H), 3.82 (s, 3 H), 3.07–3.02 (m, 0.25 H), 2.94–2.89 (m, 0.75 H), 2.45–2.30 (br m, 2 H), 2.27–2.21 (m, 0.75 H), 2.13–2.08 (m, 0.25 H), 1.40–1.03 (m, 10 H), 0.83 (t, J = 6.8 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.02, (14.06), 22.52, (22.53), 27.8, (27.94), (27.97), 28.0, (29.31), 29.33, 31.48, (31.59), (47.7), (48.2), 49.7, 51.2, (55.24), 55.28, (68.9), (74.2), 74.9, 75.2, (107.7), 108.1, 109.9, (110.1), (113.7), 114.0 (2 C), 128.8 (2 C), (129.3), 132.3, (132.7), 142.0, (142.5), 154.5, (154.6), (158.2), 158.4; signals for the minor diastereomer are given in parentheses.

HRMS–FAB: m/z [M]+ calcd for C21H30O4: 346.2144; found: 346.2170.


#

(±)-Ethyl (2R,3R,4S)-3-Hexyl-5-hydroxy-4-phenyl-2-(tosylamino)pentanoate (7e)

To a solution of N-tosylamine 6e (0.105 g, 0.23 mmol, 1 equiv) in THF (5 mL) at 0 °C was added 1 M BH3·THF complex in THF (0.75 mL, 1.38 mmol, 6 equiv) dropwise. The mixture was stirred for 1 h at 0 °C and then for 10 h at r.t. Then, H2O (2 mL) was added, followed by NaBO3·4H2O (0.531 g, 3.45 mmol, 15 equiv), and the mixture was stirred for 1 h at r.t. The purification procedure described above for alcohols 7a–d was followed to afford alcohol 7e and lactone 9.


#

7e

Yield: 0.070 g (65%); colorless oil.

Rf = 0.25 (EtOAc–hexane, 1:7).

IR (neat): 3575, 3200, 1745 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.4 Hz, 2 H), 7.37–7.25 (m, 5 H), 7.18 (d, J = 8.4 Hz, 2 H), 5.48 (d, J = 9.6 Hz, 1 H), 4.18 (dd, J = 10.0, 3.2 Hz, 1 H), 4.01 (dq, J = 7.2, 2.0 Hz, 2 H), 3.76 (t, J = 5.6 Hz, 2 H), 2.87 (q, J = 6.4 Hz, 1 H), 2.43 (s, 3 H), 2.38–2.30 (m, 1 H), 1.75 (t, J = 5.2 Hz, 1 H), 1.35–0.97 (m, 10 H), 1.16 (t, J = 7.2 Hz, 3 H), 0.84 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 14.0, 21.5, 22.5, 27.3, 28.9, 29.1, 31.5, 43.7, 49.4, 56.7, 61.7, 65.3, 127.2 (2 C), 127.3, 128.5 (2 C), 128.8 (2 C), 129.5 (2 C), 137.2, 140.7, 143.4, 172.2.

HRMS–ES: m/z [M + Na]+ calcd for C26H37NO5SNa: 498.2290; found: 498.2286.


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9

Yield: 0.027 g (25%); colorless oil.

Rf = 0.55 (EtOAc–hexane, 1:7).

IR (neat): 3285, 1755 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.4 Hz, 2 H), 7.42–7.26 (m, 7 H), 5.57 (d, J = 4.8 Hz, 1 H), 4.44 (dd, J = 6.8, 5.2 Hz, 1 H), 4.43 (dd, J = 12.0, 6.8 Hz, 1 H), 4.20 (t, J = 11.6 Hz, 1 H), 3.13–3.08 (m, 1 H), 2.69–2.62 (m, 1 H), 2.43 (s, 3 H), 1.78–1.68 (m, 1 H), 1.34–1.07 (m, 7 H), 1.05–0.95 (m, 2 H), 0.84 (t, J = 6.8 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.0, 21.5, 22.5, 26.0, 29.0, 30.5, 31.5, 42.6, 44.5, 53.9, 70.8, 127.0 (2 C), 127.4 (2 C), 127.7, 129.2 (2 C), 129.9 (2 C), 136.3, 139.7, 144.0, 170.9.

HRMS–ES: m/z [M + Na]+ calcd for C24H31NO4SNa: 452.1872; found: 452.1869.


#

Pyrrolidines 8a–d and Tetrahydrofurans 12a–d; General Procedure

To a solution of the corresponding amino alcohol 7 or diol 11 (1.0 equiv) in CH2Cl2 (2–5 mL) at 0 °C was added py (12 equiv) and TsCl (3.0 equiv). The solution was stirred for 30 min at 0 °C and for 24 h at r.t. Cold H2O (5 mL) was added, and the mixture was extracted with CH2Cl2 (4 × 20 mL). The combined organic layers were dried (MgSO4), and solvent was removed under reduced pressure to afford the crude product that was separated by flash column chromatography (silica gel). Pyrrolidines 8a–d and tetrahydrofurans 12a–d were formed as white solids or colorless oils.


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(±)-(2R,3R,4S)-3-Hexyl-2,4-bis[4-(methoxycarbonyl)phenyl]-1-tosylpyrrolidine (8a)[ 24 ]

Yield: 0.037 g (66%); white solid; mp 169–171 °C.

Rf = 0.8 (EtOAc–hexane, 3:7).

IR (neat): 1722 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.96 (dd, J = 6.5, 1.5 Hz, 4 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.24 (dd, J = 8.0, 2.0 Hz, 4 H), 4.40 (d, J = 9.0 Hz, 1 H), 4.10 (dd, J = 11.0, 8.0 Hz, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 3.56 (t, J = 11.5 Hz, 1 H), 2.79 (sext, J = 7.5 Hz, 1 H), 2.41 (s, 3 H), 2.35–2.28 (m, 1 H), 1.30–1.21 (m, 2 H), 1.08–1.02 (m, 2 H), 0.95–0.88 (m, 4 H), 0.84–0.77 (m, 2 H), 0.73 (t, J = 6.5 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 21.5, 22.3, 26.2, 29.1, 30.2, 31.3, 49.9, 52.1, 52.2, 55.9, 56.3, 69.1, 127.3 (2 C), 127.4 (2 C), 127.7 (2 C), 129.3, 129.4, 129.6 (2 C), 129.8 (2 C), 130.1 (2 C), 135.5, 143.6, 144.2, 147.1, 166.7, 166.8.

HRMS–ES: m/z [M + Na]+ calcd for C33H39NO6SNa: 600.2396; found: 600.2372.


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(±)-(2R,3R,4S)-3-Hexyl-4-[4-(methoxycarbonyl)phenyl]-2-(4-nitrophenyl)-1-tosylpyrrolidine (8b)

Yield: 0.060 g (83%); white solid; mp 140–143 °C.

Rf = 0.42 (EtOAc–hexane, 1:4).

IR (neat): 1719 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.17 (d, J = 9.0 Hz, 2 H), 7.96 (d, J = 8.5 Hz, 2 H), 7.58 (d, J = 8.5 Hz, 2 H), 7.52 (d, J = 9.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.5 Hz, 2 H), 4.40 (d, J = 9.0 Hz, 1 H), 4.07 (dd, J = 11.5, 8.0 Hz, 1 H), 3.89 (s, 3 H), 3.60 (t, J = 11.0 Hz, 1 H), 2.75 (sext, J = 7.5 Hz, 1 H), 2.43 (s, 3 H), 2.33–2.27 (m, 1 H), 1.29–1.21 (m, 2 H), 1.06–1.02 (m, 2 H), 0.92 (quin, J = 3.5 Hz, 4 H), 0.82–0.77 (m, 2 H), 0.73 (t, J = 7.5 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 21.6, 22.4, 26.2, 29.1, 29.9, 31.3, 49.7, 52.2, 55.9, 56.3, 68.7, 123.8 (2 C), 127.4 (2 C), 127.6 (2 C), 128.1 (2 C), 129.4, 129.8 (2 C), 130.1 (2 C), 134.9, 143.8, 144.1, 147.3, 149.6, 166.7.

HRMS–ES: m/z [M + Na]+ calcd for C31H36N2O6SNa: 587.2192; found: 587.2206.


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(±)-(2R,3R,4S)-3-Hexyl-2-[4-(methoxycarbonyl)phenyl]-4-(2-naphthyl)-1-tosylpyrrolidine (8c)

Yield: 0.042 g (86%); colorless oil.

Rf = 0.3 (EtOAc–hexane, 1:4).

IR (neat): 1721 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.00 (d, J = 8.0 Hz, 2 H), 7.81–7.76 (m, 3 H), 7.59 (s, 1 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.49–7.46 (m, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.30 (dd, J = 8.5, 1.5 Hz, 1 H), 7.26 (d, J = 8.0 Hz, 2 H), 4.47 (d, J = 9.0 Hz, 1 H), 4.16 (dd, J = 11.0, 7.5 Hz, 1 H), 3.93 (s, 3 H), 3.67 (t, J = 11.0 Hz, 1 H), 2.91 (sext, J = 8.0 Hz, 1 H), 2.48–2.40 (m, 1 H), 2.44 (s, 3 H), 1.34–1.29 (m, 2 H), 1.07–1.00 (m, 2 H), 0.93–0.90 (m, 4 H), 0.89–0.84 (m, 2 H), 0.71 (t, J = 5 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 21.6, 22.4, 26.1, 29.3, 30.1, 31.3, 50.0, 52.1, 55.7, 56.5, 69.2, 125.2, 125.9, 126.3, 126.7, 127.3 (2 C), 127.4 (2 C), 127.5, 127.7, 128.6, 129.3, 129.6 (2 C), 129.8 (2 C), 132.7, 133.4, 135.7, 136.1, 143.5, 147.5, 166.9.

HRMS–ES: m/z [M + Na]+ calcd for C35H39NO4SNa: 592.2498; found: 592.2489.


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(±)-(2R,3R,4S)-3-(2-Ethylhexyl)-2,4-bis[4-(methoxycarbonyl)phenyl]-1-tosylpyrrolidine (8d)

Yield: 0.060 g (78%); colorless oil.

Rf = 0.45 (EtOAc–hexane, 1:5).

IR (neat): 1722 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.96 (dd, J = 8.5, 6.5 Hz, 4 H), 7.49 (dd, J = 8.5, 6.0 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.21 (d, J = 7.0 Hz, 2 H), 4.34 (dd, J = 9.0, 5.0 Hz, 1 H), 4.13–4.08 (m, 1 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 3.57 (td, J = 11.0, 2.5 Hz, 1 H), 2.76 (qd, J = 10.5, 2.0 Hz, 1 H), 2.45–2.36 (m, 1 H), 2.40 (s, 3 H), 1.29–1.22 (m, 1 H), 1.20–1.13 (m, 1 H), 0.97–0.86 (m, 2 H), 0.78–0.67 (m, 7 H), 0.67 (t, J = 7.0 Hz, 3 H), 0.37 (dt, J = 10.0, 3.0 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 10.1, 13.94 (13.95), 14.2, 21.5, 22.7 (22.8), 25.31 (25.39), 28.2, 32.3 (32.4), 35.71 (35.79), 36.15 (36.25), 51.5, 52.15 (52.12), 53.65 (53.60), 56.39 (56.30), 70.50 (70.44), 127.29 (127.31) (2 C), 127.53 (127.56) (2 C), 127.75 (127.78) (2 C), 129.31, 129.38, 129.54 (2 C), 129.75 (2 C), 130.04 (2 C), 135.58 (135.63), 143.54, 144.36 (144.44), 146.95 (147.00), 166.69, 166.82; signals for the minor diastereomer arising from the stereocenter in the side chain are given in parentheses.

HRMS–ES: m/z [M + Na]+ calcd for C35H43NO6SNa: 628.2709; found: 628.2702.


#

(±)-(2R,3S,4R)-3-Hexyl-4-(4-methoxyphenyl)-2-phenyltetrahydrofuran (12a)

Yield: 0.075 g (65%); colorless oil.

Rf = 0.7 (EtOAc–hexane, 1:7).

IR (neat): 1610, 1514, 1249 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.37–7.27 (m, 5 H), 7.23 (d, J = 8.4 Hz, 2 H), 6.90 (d, J = 8.4 Hz, 2 H), 5.30 (d, J = 8.0 Hz, 1 H), 4.48 (t, J = 8.4 Hz, 1 H), 3.92 (t, J = 8.8 Hz, 1 H), 3.83 (s, 3 H), 3.18 (q, J = 8.8 Hz, 1 H), 2.48 (quin, J = 7.2 Hz, 1 H), 1.19–0.96 (m, 8 H), 0.93–0.85 (m, 2 H), 0.80 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.0, 22.4, 27.9, 29.2, 29.4, 31.5, 49.8, 51.5, 55.2, 75.0, 84.1, 114.0 (2 C), 126.8 (2 C), 127.1, 127.9 (2 C), 128.7, 133.2, 140.8 (2 C), 158.3.

HRMS–FAB: m/z [M]+ calcd for C23H30O2: 338.2246; found: 338.2254.


#

(±)-(2R,3S,4R)-3-Hexyl-2,4-(4-methoxyphenyl)tetrahydrofuran (12b)

Yield: 0.048 g (73%); colorless oil.

Rf = 0.7 (EtOAc–hexane, 1:7).

IR (neat): 1612, 1512, 1247 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.4 Hz, 4 H), 6.90 (dd, J = 8.8, 2.4 Hz, 4 H), 5.25 (d, J = 8.0 Hz, 1 H), 4.45 (t, J = 8.4 Hz, 1 H), 3.89 (t, J = 8.8 Hz, 1 H), 3.84 (s, 3 H), 3.83 (s, 3 H), 3.16 (q, J = 8.8 Hz, 1 H), 2.44 (quin, J = 7.6 Hz, 1 H), 1.21–0.98 (m, 8 H), 0.93–0.86 (m, 2 H), 0.80 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.0, 22.4, 27.9, 29.2, 29.5, 31.5, 49.9, 51.5, 55.24, 55.27, 74.9, 83.8, 113.3 (2 C), 114.0 (2 C), 128.0 (2 C), 128.7 (2 C), 132.9, 133.1, 158.3, 158.7.

HRMS–ES: m/z [M + H]+ calcd for C24H33O3: 369.2430; found: 369.2404.


#

(±)-(2R,3S,4R)-3-Hexyl-4-(4-methoxyphenyl)-2-(4-nitrophenyl)tetrahydrofuran (12c)

Yield: 0.033 g (65%); colorless oil.

R f = 0.5 (EtOAc–hexane, 1:7).

IR (neat): 1606, 1514, 1346, 1249 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 8.8 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 5.35 (d, J = 7.6 Hz, 1 H), 4.49 (t, J = 8.4 Hz, 1 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.83 (s, 3 H), 3.19 (q, J = 8.0 Hz, 1 H), 2.53 (quin, J = 7.2 Hz, 1 H), 1.21–0.94 (m, 10 H), 0.80 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 13.9, 22.4, 27.8, 29.1, 29.7, 31.5, 49.8, 51.6, 55.3, 74.9, 83.0, 114.1 (2 C), 123.3 (2 C), 127.5 (2 C), 128.5 (2 C), 132.8, 147.1, 148.5, 158.5.

HRMS–FAB: m/z [M]+ calcd for C23H29O4: 383.2097; found: 383.2095.


#

(±)-(2R,3S,4R)-2-(2-Furyl)-3-(1-hexyl)-4-(4-methoxyphenyl)tetrahydrofuran (12d)

Yield: 0.038 g (60%); colorless oil.

Rf = 0.65 (EtOAc–hexane, 1:7).

IR (neat): 1610, 1514, 1249 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.43 (t, J = 0.8 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 2 H), 6.90 (d, J = 8.4 Hz, 2 H), 6.39–6.33 (m, 1 H), 6.29 (d, J = 3.2 Hz, 1 H), 5.27 (d, J = 7.6 Hz, 1 H), 4.43 (t, J = 8.4 Hz, 1 H), 3.88–3.80 (m, 1 H), 3.82 (s, 3 H), 3.35 (q, J = 8.8 Hz, 1 H), 2.56–2.44 (m, 1 H), 1.25–0.91 (m, 10 H), 0.82 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 14.0, 22.4, 28.0, 28.4, 29.3, 31.4, 49.7, 51.3, 55.2, 75.2, 77.8, 108.1, 109.9, 114.0 (2 C), 128.8 (2 C), 132.3, 142.0, 154.5, 158.4.

HRMS–FAB: m/z [M]+ calcd for C21H28O3: 328.2038; found: 328.2061.


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(±)-(2R,3R,4S)-2-(Ethoxycarbonyl)-3-hexyl-4-phenyl-1-tosylpyrrolidine (8e)

To a solution of amino alcohol 7e (0.011 g, 0.023 mmol, 1 equiv) in dry THF (1.5 mL) at 0 °C was added Ph3P (0.006 g, 0.023 mmol, 1 equiv) and DEAD (4 μL, 0.025 mmol, 1.1 equiv). The solution was stirred at 0 °C for 1 h and then allowed to warm to r.t. over 6 h for a total reaction time of 7 h and then was directly purified using flash column chromatography (silica gel, EtOAc–hexane, 1:10) to afford pyrrolidine 8e.

Yield: 0.009 g (84%); colorless oil.

Rf = 0.65 (EtOAc–hexane, 1:7).

IR (neat): 1741 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.34–7.23 (m, 3 H), 7.18 (d, J = 8.4 Hz, 2 H), 4.26–4.21 (m, 2 H), 4.05 (d, J = 8.0 Hz, 1 H), 3.87 (dd, J = 10.8, 8.0 Hz, 1 H), 3.47 (t, J = 10.8 Hz, 1 H), 2.73–2.66 (m, 1 H), 2.47 (s, 3 H), 2.47–2.40 (m, 1 H), 1.42–1.35 (br m, 2 H), 1.37 (t, J = 7.2 Hz, 3 H), 1.24–1.01 (m, 8 H), 0.84 (t, J = 7.2 Hz, 3 H).

13C NMR (125 MHz, CDCl3): δ = 12.9, 13.0, 20.5, 21.4, 25.5, 28.1, 30.4, 30.6, 49.6, 50.6, 54.3, 60.4, 65.0, 126.3, 126.5 (2 C), 126.6 (2 C), 127.7 (2 C), 128.6 (2 C), 134.5, 137.5, 142.6, 171.2.

HRMS–ES: m/z [M + Na]+ calcd for C26H35NO4SNa: 480.2185; found: 480.2165.


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Acknowledgment

This work was supported by the National Institutes of Health, Kansas University Chemical Methodologies and Library Development Center of Excellence (NIH0063950 P50). We thank Dr. Todd D. Williams and Mr. Robert Drake for acquiring GC–MS spectra and Dr. Victor Day for X-ray crystallographic analysis. The GC instrument was purchased with support from NIH SIG S10 RR019398, and a National Science Foundation Major Research Instrumentation Program grant (CHE-0923449) was used to purchase the diffractometer and computers used in the X-ray studies.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
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Zoom Image
Figure 1 Biologically active pyrrolidines and tetrahydrofurans
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Scheme 1 Overview of the synthetic strategy
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Scheme 2 Preparation of pyrrolidines
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Scheme 3 Synthesis of a cyclic amino ester
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Scheme 4 Synthesis of tetrahydrofurans
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Scheme 5 Stereoselectivity of the hydroboration