Bisphosphine-Catalyzed Mixed Double-Michael Reactions: Asymmetric Synthesis of Oxazolidines, Thiazolidines, and Pyrrolidines

Abstract

Bisphosphine-catalyzed mixed double-Michael reactions have been developed to afford β-amino carbonyl derivatives of oxazolidines, thiozolidines, and pyrrolidines in excellent yields and with high diastereoselectivities. Efficient reactions between amino acid-derived pronucleophiles, e.g., β-amino alcohols,β-amino thiols, and γ-amino diesters, as Michael donors and electron-deficient acetylenes, e.g., propiolates, acetylacetylene, and tosylacetylene, as Michael acceptors provided access to azolidines containing both diversity of substituents and asymmetry. This methodology—the first examples of mixed double-Michael reactions of acetylenes—is operationally simple and involves mild conditions. Mechanistically, it constitutes a rare example of the anchimeric assistance of bisphosphines in organocatalysis.

Five-membered nitrogen atom-containing heterocycles are structural components of many natural products and pharmaceuticals;¹ in addition, many of them—for example, enantiopure azolidine derivatives—have been employed as synthetic intermediates, auxiliaries, ligands, and catalysts for asymmetric synthesis.² Consequently, there is a high demand for new methods for the efficient construction of optically active azolidine derivatives.³ As part of a program aimed at developing phosphine-mediated annulation reactions,⁴ we sought a novel route toward highly substituted and functionalized five-membered-ring nitrogen atom-containing heterocycles. In light of recent reports on the phosphine-catalyzed conjugate additions of electron-deficient olefins and acetylenes with alcohols,⁵ herein we report a bisphosphine-catalyzed mixed double-Michael process⁶ that generates azolidines (2; eq 1). Use of amino acid-derived pronucleophiles (1) as Michael donors and electron-deficient acetylenes as Michael acceptors provides efficient access to azolidines containing both diversity and asymmetry.

Our initial evaluation of the proposed double-Michael addition began with the reaction between amino alcohol 1a and methyl propiolate (Table 1). Employing PPh₃ as the catalyst gave the desired double-Michael adduct 2a in 35% yield in addition to a 40% yield of the mono-Michael adduct 3a (entry 1).⁷ Use of Ph₂PEt led to a moderate improvement in the yield of the oxazolidine product 2a (entry 2), but none was formed from the reaction catalyzed by Me₃P (entry 3).⁸ In contrast, diphenylphosphinopropane (DPPP) catalysis increased the yield of the desired double-Michael adduct 2a to 71% (entry 4).⁹ Further increases in the yield and reaction rate were achieved when performing the reaction in a more polar solvent, CH₃CN (entry 5). Based on the encouraging results we obtained with DPPP as the catalyst, we also tested the applicability of the homologous bisphosphines diphenylphosphinomethane (DPPM), diphenylphosphinoethane (DPPE), diphenylphosphinobutane (DPPB), and diphenylphosphinopentane (DPPPent). The appreciably poorer yield (37%) of the DPPM-mediated reaction, relative to those of the other bisphosphines (entries 6–9), provides a critical clue regarding the reaction mechanism (vide infra).

Table 1.

Evaluation of Catalysts for Double-Michael Additions^a

entry	catalyst	solvent	isolated yields (%)
			2a	3a
1b	Ph3P	toluene	35	40
2b	Ph2PEt	toluene	42	30
3b	Me3P	toluene	0	22
4b	DPPP	toluene	71	12
5	DPPPYc	CH3CN	92	0
6	DPPMc	CH3CN	37	42
7	DPPEc	CH3CN	84	0
8	DPPBc	CH3CN	82	0
9	DPPPentc	CH3CN	79	6

^aAll reactions were performed using 1 mmol of 1a, 1.1 mmol of methylpropiolate, and 10 mol% of the catalyst.

^bThese reactions were run for 48 h.

^cDPPM, DPPE, DPPP, DPPB, and DPPPent are acronyms for diphenylphosphinomethane, -ethane, -propane, -butane, and -pentane, respectively.

Scheme 1 presents a plausible mechanism for the dependence of the reaction on both the bidentate nature of the phosphine catalyst and the tether length between the two phosphine moieties. The reaction is triggered by the conjugate addition of the phosphine to the electron-deficient acetylene. The resulting vinyl anion 4 deprotonates the pronucleophile 1, which facilitates the first conjugate addition to form intermediate 6.^5b,10 Upon β-elimination of the phosphine, the mono-Michael product 3 is formed. The presence of an additional phosphine moiety at the optimal distance, as in DPPP, provides additional stabilization to the intermediate phosphonium ions 6 and 7. The latter undergoes S_N2 displacement to produce the cyclized product 2.¹¹ In the absence of anchimeric assistance, as in the case of the monodentate phosphines, the decreased stability of the phosphonium ion led to an unfavorable equilibrium for the formation of 6 from 3.¹² The relatively short tether of DPPM prohibits the orbital overlap required for anchimeric assistance because of geometrical constraints. The other phosphines for which intramolecular stabilization was possible, namely DPPE, DPPB, and DPPPent, gave results similar to those obtained using DPPP. Note that intramolecular stabilization of phosphonium ions by nitrogen atoms has precedent in the literature.¹³

Scheme 1.

Proposed mechanism for the formation of 2

With the optimal reaction conditions in hand, i.e., DPPP as catalyst and CH₃CN as solvent, we next explored the scope of the double-Michael reaction using a variety of amino acid-derived pronucleophiles and electron-deficient acetylenes (Table 2). The formation of oxazolidines from β-amino alcohols and methyl propiolate proceeded smoothly, with high yields and diastereoselectivities (entries 1 and 4). The Michael acceptors acetylacetylene and tosylacetylene also gave good results (entries 2 and 3). This methodology works well for the syntheses of thiazolidines from β-amino thiols (entries 5–7).¹⁴ All of the substrates provided similarly high yields and diastereoselectivities for the formation of thiazolidines.¹⁵

Table 2.

Syntheses of Various Azolidines ^a

entry	substrate	product	yield %b(cis:trans)c
1			92 (96:4)
2	1a		92 (94:6)
3	1a		87 (97:3)
4			91 (95:5)
5			93 (95:5)
6	1e		89 (96:4)
7			88 (96:4)
8			82 (94:6)
9	1h		91 (95:5)
10			80 (100:0)

^aAll reactions were performed using 1 mmol of the substrate, 1.1 equiv of the corresponding acetylene, and 10 mol% of DPPP in CH₃CN at 80 °C for 9 h.

^bIsolated yields after chromatographic purification.

^cDetermined through ¹H NMR spectroscopic analysis.

We further tested the generality of our reaction by using carbonucleophiles (entries 8–10) for the preparation of pyrrolidine derivatives, which are ubiquitous in natural products of pharmacological interest.¹⁶ Under the optimized conditions, we generated the pyrrolidines 2h and 2i from the valine-derived γ-amino malonate 1h (entries 8 and 9, respectively).¹⁷ Employing the cyclic γ-amino diester 1j furnished the octahydroindole derivative 2j as a single diastereoisomer in good yield (entry 10). Octahydroindoles, which are present in a large number of natural products, are often challenging synthetic targets.¹⁸

In summary, we have developed a remarkably simple protocol for the synthesis of oxazolidines, thiozolidines, pyrrolidines, and octahydroindoles. This mixed double-Michael process operates best under bisphosphine catalysis to provide β-amino carbonyl derivatives of azolidines¹⁹ in excellent yields and with high diastereoselectivities. Presumably, the use of bis(diphenylphosphine) derivatives allows intramolecular stabilization of the phosphonium ion intermediates. We are currently exploring the development of an enantioselective version of this ring-forming process from achiral starting materials and its application to the synthesis of selected drug candidates.

Supplementary Material

1si20070524_09. Supporting Information Available.

Representative experimental procedures and spectral data for all new compounds (PDF). Crystallographic data for 2a and 3a (CIF). This information is available free of charge via the Internet at http://pubs.acs.org.