Diversity-Oriented Synthesis Based on the DPPP-Catalyzed Mixed Double-Michael Reactions of Electron-Deficient Acetylenes and β-Amino Alcohols

In this study, we prepared oxizolidines through 1,3-bis(diphenylphosphino)-propane (DPPP)–catalyzed mixed double-Michael reactions of β-amino alcohols with electron-deficient acetylenes. These reactions are very suitable for the diversity-oriented parallel syntheses of oxizolidines because: (i) they are performed under mild metal-free conditions and (ii) the products are isolated without complicated work-up. To demonstrate the applicability of mixed double-Michael reactions for the preparation of five-membered-ring heterocycles, we prepared 60 distinct oxazolidines from five β-amino alcohols and 12 electron-deficient acetylenes. We synthesized 36 of these 60 oxazolidines in enantiomerically pure form from proteinogenic amino acid–derived β-amino alcohols.

A little over three decades ago, White and Baizer reported the first phosphine-catalyzed Michael additions of benzyl alcohol to activated olefins [32]. Only in the last two decades, however, did other synthetic research groups start studying Michael additions using nucleophilic phosphine catalysts and activated acetylenes. Inanaga demonstrated the first Michael additions of benzyl alcohol to activated acetylenes in the presence of nucleophilic phosphine catalysts [33]. When acetylenes are used as Michael acceptors, the Michael products possess one remaining degree of unsaturation, thereby enabling further incorporation of nucleophiles.
Capitalizing on the possibility of performing two consecutive Michael additions to activated acetylenes, Grossman elegantly demonstrated the double-Michael additions of carbon pro-nucleophiles to generate functionalized cyclohexanes under the influence of phosphine catalysts and bases [34,35]. Subsequently, Yavari employed catechol-an oxygen di-nucleophile-as the Michael donor [36]; although the yield of the resulting 1,3-benzodioxole was low (20%, isolated), he confirmed that heteroatom double-Michael addition under phosphine catalysis was possible [37]. Nevertheless, to this day, few heterocyclic compounds have been generated using double-Michael additions.
To overcome poor efficiency and the inability to incorporate other heteroatoms such as nitrogen and sulfur, in the phosphine-catalyzed double-Michael reactions, we set out to develop a route to generate various heterocyclic compounds under general and robust phosphine catalysis conditions. By employing DPPP as the catalyst, we have synthesized functionalized oxazolidines, thiazolidines, and pyrrolidines in high efficiency (Scheme 1) [30]. By employing dinucleophiles tethered through aromatic rings, we have obtained indolines, dihydropyrrolopyridines, benzimidazolines, tetrahydroquinolines, tetrahydroisoquinolines, dihydrobenzo-1,4-oxazines, and dihydrobenzo-3,1oxazines using our developed mixed double-Michael strategy [31].

Scheme 1. DPPP-Catalyzed Mixed Double-Michael Reactions.
Focusing on oxazolidines, here we report the synthesis of a library of 60 distinct oxazolidines through our mixed double-Michael strategy. Based on previously reported mixed double-Michael reactions [30,31], we knew that oxazolidines could be prepared from amino acid-derived pro-nucleophiles and electron-deficient acetylenes using DPPP as the catalyst. With such precedents in mind, here we expanded the reaction scope of the mixed double-Michael reaction to incorporate various oxygen-and-nitrogen-containing pro-nucleophiles and electron-deficient acetylenes. Under the reported conditions, we obtained the various oxazolidine derivatives rapidly and with high efficiency, enabling their future application in biological assays.

Preparation of Pro-Nucleophiles
The β-amino alcohol pro-nucleophiles that we used in the mixed double-Michael reactions were derived from natural L-amino acids and racemic cyclohexene oxide. We prepared the pro-nucleophiles derived from L-leucine, L-alanine, L-phenylalanine, and L-serine efficiently according to protocols described by Moberg and Craig [46]; first, we protected the amino groups of L-leucine, L-alanine, L-phenylalanine, and L-serine with p-toluenesulfonyl (tosyl) chloride and then we reduced their carboxylic acid units using lithium aluminum hydride [47,48]. We prepared the 2-aminocyclohexanolderived pro-nucleophile 1e from racemic cyclohexene oxide in three steps: opening of the epoxide with sodium azide, reduction of the azido group with palladium on charcoal [49,50], and then protection of the amino group with tosyl chloride [51].

Scheme 2.
Amino-Alcohol Pro-Nucleophiles. Table 1 lists the electron-deficient acetylenes that we prepared from corresponding aldehydes. Although the syntheses of the acetylenes 2a, 2c, and 2e have been reported previously, the acetylenes 2b, 2d, and 2f were unknown. Employing the protocol established by Oyelere and Calieno [52,53], we obtained each of these propargyl ketones in good yield after: (i) treating the pertinent aldehyde with ethynylmagnesium bromide at 0 °C, slowly warming to ambient temperature, and then working-up the mixture after 4 h and (ii) oxidizing the resulting propargyl alcohol, without further purification, using Jones reagent.

Synthesis of an Oxazolidine Library
With all the pro-nucleophiles and acetylenes at hand, we rapidly synthesized the desired chemical library of 60 distinct oxazolidines using DPPP as the catalyst (Tables 2-4). The oxazolidine library contained a diverse array of functional groups and provided several potential probes for examining various biological mechanisms.

General
All reactions were performed in flamed-dried or oven-dried round-bottom flasks, Schlenk flasks, or two-neck flasks. A glass water condenser, fitted with a rubber septum, was attached to each flask. All reactions were performed under a positive pressure of argon. A syringe pump and stainless-steel needles were used to inject the acetylene derivatives into the refluxing reaction mixtures. Reactions were monitored through thin-layer chromatography (TLC) on 0.25-mm SiliCycle silica gel plates. Plates were visualized under UV light or through p-anisaldehyde or potassium permanganate staining followed by heating (<1 min) with a heat gun. Flash column chromatography (FCC) was performed using SiliCycle Silica-P Flash silica gel (60 Å pore size, 40-63 µm). Organic solutions were concentrated using rotary evaporators.

Materials and Reagents
Reagents were used as received from commercial sources. Methyl propiolate and ethyl propiolate were purchased from TCI America. Tosyl acetylene and 3-butyn-2-one were purchased from Aldrich. Acetonitrile and dichloromethane were distilled from calcium hydride under a positive pressure of argon. Tetrahydrofuran was distilled from sodium and benzophenone under a positive pressure of argon.

Instrumentation
IR spectra were recorded using a Thermo Nicolet Avatar 370 FT-IR spectrometer. NMR spectra were recorded using Bruker ARX-400 instrument, calibrated to signals from the solvent as an internal reference [7.26 (residual CHCl 3 ) and 77.00 (CDCl 3 ) ppm for ¹H-and ¹³C-NMR spectra, respectively]. Data for 1 H NMR spectra are reported as follows: chemical shift (δ, ppm), multiplicity, coupling constant (Hz), and integration. Data for 13 C-NMR spectra are reported in terms of chemical shift. The following abbreviations are used to denote the multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet. Mass spectra of the samples were recorded using a Waters LCT Premier XE time-of-flight instrument controlled by MassLynx 4.1 software. Samples were infused through direct loop injection from a Waters Acquity UPLC into the multi-mode ionization source. The lock mass standard for accurate mass determination was leucine enkephalin (Sigma L9133). An Agilent Technologies 5975 inert XL mass-selective detector GCMS was also used.
Benzyl propiolate was prepared in 90% yield according to the protocol described by Ramachandran; spectral data matched those reported in the literature [57].